Changes in patterns of age-related network connectivity are associated with risk for schizophrenia.

Alterations in fMRI-based brain functional network connectivity (FNC) are associated with schizophrenia (SCZ) and the genetic risk or subthreshold clinical symptoms preceding the onset of SCZ, which often occurs in early adulthood. Thus, age-sensitive FNC changes may be relevant to SCZ risk-related FNC. We used independent component analysis to estimate FNC from childhood to adulthood in 9,236 individuals. To capture individual brain features more accurately than single-session fMRI, we studied an average of three fMRI scans per individual. To identify potential familial risk-related FNC changes, we compared age-related FNC in first-degree relatives of SCZ patients mostly including unaffected siblings (SIB) with neurotypical controls (NC) at the same age stage. Then, we examined how polygenic risk scores for SCZ influenced risk-related FNC patterns. Finally, we investigated the same risk-related FNC patterns in adult SCZ patients (oSCZ) and young individuals with subclinical psychotic symptoms (PSY). Age-sensitive risk-related FNC patterns emerge during adolescence and early adulthood, but not before. Young SIB always followed older NC patterns, with decreased FNC in a cerebellar-occipitoparietal circuit and increased FNC in two prefrontal-sensorimotor circuits when compared to young NC. Two of these FNC alterations were also found in oSCZ, with one exhibiting reversed pattern. All were linked to polygenic risk for SCZ in unrelated individuals (R2 varied from 0.02 to 0.05). Young PSY showed FNC alterations in the same direction as SIB when compared to NC. These results suggest that age-related neurotypical FNC correlates with genetic risk for SCZ and is detectable with MRI in young participants.

Childhood urbanicity is associated with emotional episodic memory-related striatal function and common variation in NTRK2.

BACKGROUND: Childhoods in urban or rural environments may differentially affect the risk of neuropsychiatric disorders, possibly through memory processing and neural response to emotional stimuli. Genetic factors may not only influence individuals' choices of residence but also modulate how the living environment affects responses to episodic memory. METHODS: We investigated the effects of childhood urbanicity on episodic memory in 410 adults (discovery sample) and 72 adults (replication sample) with comparable socioeconomic statuses in Beijing, China, distinguishing between those with rural backgrounds (resided in rural areas before age 12 and relocated to urban areas at or after age 12) and urban backgrounds (resided in cities before age 12). We examined the effect of childhood urbanicity on brain function across encoding and retrieval sessions using an fMRI episodic memory paradigm involving the processing of neutral or aversive pictures. Moreover, genetic association analyses were conducted to understand the potential genetic underpinnings that might contribute to memory processing and neural mechanisms influenced by early-life urban or rural environments. RESULTS: Episodic memory retrieval accuracy for more difficult neutral stimuli was similar between those with urban and rural childhoods, whereas aversive stimuli elicited higher retrieval accuracy in the urban group (P = 0.023). For aversive stimuli, subjects with urban childhood had relatively decreased engagement of the striatum at encoding and decreased engagement of the hippocampus at retrieval. This more efficient striatal encoding of aversive stimuli in those with urban childhoods was associated with common variation in neurotrophic tyrosine kinase receptor type 2 (NTRK2) (right striatum: P = 1.58×10-6). These findings were confirmed in the replication sample. CONCLUSIONS: We suggest that this differential striatal processing of aversive stimuli observed in individuals with urban or rural childhoods may represent mechanisms by which childhood urbanicity may affect brain circuits, heightening behavioral responses to negative stressors associated with urban environments. NTRK2-associated neural processes in the striatum may play a role in these processes.

A generative-discriminative framework that integrates imaging, genetic, and diagnosis into coupled low dimensional space.

We propose a novel optimization framework that integrates imaging and genetics data for simultaneous biomarker identification and disease classification. The generative component of our model uses a dictionary learning framework to project the imaging and genetic data into a shared low dimensional space. We have coupled both the data modalities by tying the linear projection coefficients to the same latent space. The discriminative component of our model uses logistic regression on the projection vectors for disease diagnosis. This prediction task implicitly guides our framework to find interpretable biomarkers that are substantially different between a healthy and disease population. We exploit the interconnectedness of different brain regions by incorporating a graph regularization penalty into the joint objective function. We also use a group sparsity penalty to find a representative set of genetic basis vectors that span a low dimensional space where subjects are easily separable between patients and controls. We have evaluated our model on a population study of schizophrenia that includes two task fMRI paradigms and single nucleotide polymorphism (SNP) data. Using ten-fold cross validation, we compare our generative-discriminative framework with canonical correlation analysis (CCA) of imaging and genetics data, parallel independent component analysis (pICA) of imaging and genetics data, random forest (RF) classification, and a linear support vector machine (SVM). We also quantify the reproducibility of the imaging and genetics biomarkers via subsampling. Our framework achieves higher class prediction accuracy and identifies robust biomarkers. Moreover, the implicated brain regions and genetic variants underlie the well documented deficits in schizophrenia.

KCNH2-3.1 mediates aberrant complement activation and impaired hippocampal-medial prefrontal circuitry associated with working memory deficits.

Increased expression of the 3.1 isoform of the KCNH2 potassium channel has been associated with cognitive dysfunction and with schizophrenia, yet little is known about the underlying pathophysiological mechanisms. Here, by using in vivo wireless local field potential recordings during working memory processing, in vitro brain slice whole-cell patching recordings and in vivo stereotaxic hippocampal injection of AAV-encoded expression, we identified specific and delayed disruption of hippocampal-mPFC synaptic transmission and functional connectivity associated with reductions of SERPING1, CFH, and CD74 in the KCNH2-3.1 overexpression transgenic mice. The differentially expressed genes in mice are enriched in neurons and microglia, and reduced expression of these genes dysregulates the complement cascade, which has been previously linked to synaptic plasticity. We find that knockdown of these genes in primary neuronal-microglial cocultures from KCNH2-3.1 mice impairs synapse formation, and replenishing reduced CFH gene expression rescues KCNH2-3.1-induced impaired synaptogenesis. Translating to humans, we find analogous dysfunctional interactions between hippocampus and prefrontal cortex in coupling of the fMRI blood oxygen level-dependent (BOLD) signal during working memory in healthy subjects carrying alleles associated with increased KCNH2-3.1 expression in brain. Our data uncover a previously unrecognized role of the truncated KCNH2-3.1 potassium channel in mediating complement activation, which may explain its association with altered hippocampal-prefrontal connectivity and synaptic function. These results provide a potential molecular link between increased KCNH2-3.1 expression, synapse alterations, and hippocampal-prefrontal circuit abnormalities implicated in schizophrenia.

Sequence Variation Associated with SLC12A5 Gene Expression Is Linked to Brain Structure and Function in Healthy Adults.

A single-nucleotide polymorphism in the promoter region of the Matrix Metalloproteinase-9 (MMP9) gene, rs3918242, has been shown to affect MMP9 expression in macrophages and was associated with schizophrenia by two independent groups. However, rs3918242's effects on MMP9 expression were not replicable in cell lines or brain tissue. Additionally, publically available data indicate that rs3918242 genotype is related not to MMP9 expression, but rather to expression of SLC12A5, a nearby gene coding for a K+/Cl- cotransporter, whose expression has also been related to schizophrenia. Here, we studied brain structure and function in healthy participants stratified by rs3918242 genotype using structural MRI (N = 298), functional MRI during an N-back working memory task (N = 554), and magnetoencephalography (MEG) during the same task (N = 190). We found rs3918242 was associated with gray matter volume (GMV) in the insula and dorsolateral prefrontal cortex bilaterally, closely replicated in discovery and replication samples; and with inferior parietal lobule (IPL) GMV when the samples were meta-analytically combined. Additionally, using both fMRI and MEG, rs3918242 was associated with right IPL working memory-related activation, replicated in two cohorts and across imaging modalities. These convergent results provide further impetus for examinations of the relationship of SLC12A5 with brain structure and function in neuropsychiatric disease.

Integrated DNA methylation and gene expression profiling across multiple brain regions implicate novel genes in Alzheimer's disease.

Late-onset Alzheimer's disease (AD) is a complex age-related neurodegenerative disorder that likely involves epigenetic factors. To better understand the epigenetic state associated with AD, we surveyed 420,852 DNA methylation (DNAm) sites from neurotypical controls (N = 49) and late-onset AD patients (N = 24) across four brain regions (hippocampus, entorhinal cortex, dorsolateral prefrontal cortex and cerebellum). We identified 858 sites with robust differential methylation collectively annotated to 772 possible genes (FDR < 5%, within 10 kb). These sites were overrepresented in AD genetic risk loci (p = 0.00655) and were enriched for changes during normal aging (p < 2.2 × 10-16), and nearby genes were enriched for processes related to cell-adhesion, immunity, and calcium homeostasis (FDR < 5%). To functionally validate these associations, we generated and analyzed corresponding transcriptome data to prioritize 130 genes within 10 kb of the differentially methylated sites. These 130 genes were differentially expressed between AD cases and controls and their expression was associated with nearby DNAm (p < 0.05). This integrated analysis implicates novel genes in Alzheimer's disease, such as ANKRD30B. These results highlight DNAm differences in Alzheimer's disease that have gene expression correlates, further implicating DNAm as an epigenetic mechanism underlying pathological molecular changes associated with AD. Furthermore, our framework illustrates the value of integrating epigenetic and transcriptomic data for understanding complex disease.

Schizophrenia polygenic risk score predicts mnemonic hippocampal activity.

The use of polygenic risk scores has become a practical translational approach to investigating the complex genetic architecture of schizophrenia, but the link between polygenic risk scores and pathophysiological components of this disorder has been the subject of limited research. We investigated in healthy volunteers whether schizophrenia polygenic risk score predicts hippocampal activity during simple memory encoding, which has been proposed as a risk-associated intermediate phenotype of schizophrenia. We analysed the relationship between polygenic risk scores and hippocampal activity in a discovery sample of 191 unrelated healthy volunteers from the USA and in two independent replication samples of 76 and 137 healthy unrelated participants from Europe and the USA, respectively. Polygenic risk scores for each individual were calculated as the sum of the imputation probability of reference alleles weighted by the natural log of odds ratio from the recent schizophrenia genome-wide association study. We examined hippocampal activity during simple memory encoding of novel visual stimuli assessed using blood oxygen level-dependent functional MRI. Polygenic risk scores were significantly associated with hippocampal activity in the discovery sample [P = 0.016, family-wise error (FWE) corrected within Anatomical Automatic Labeling (AAL) bilateral hippocampal-parahippocampal mask] and in both replication samples (P = 0.033, FWE corrected within AAL right posterior hippocampal-parahippocampal mask in Bari sample, and P = 0.002 uncorrected in the Duke Neurogenetics Study sample). The relationship between polygenic risk scores and hippocampal activity was consistently negative, i.e. lower hippocampal activity in individuals with higher polygenic risk scores, consistent with previous studies reporting decreased hippocampal-parahippocampal activity during declarative memory tasks in patients with schizophrenia and in their healthy siblings. Polygenic risk scores accounted for more than 8% of variance in hippocampal activity during memory encoding in discovery sample. We conclude that polygenic risk scores derived from the most recent schizophrenia genome-wide association study predict significant variability in hippocampal activity during memory encoding in healthy participants. Our findings validate mnemonic hippocampal activity as a genetic risk associated intermediate phenotype of schizophrenia, indicating that the aggregate neurobiological effect of schizophrenia risk alleles converges on this pattern of neural activity.awy004media15749593779001.

Genetic risk mechanisms of posttraumatic stress disorder in the human brain.

Posttraumatic stress disorder (PTSD) follows exposure to a traumatic event in susceptible individuals. Recently, genome-wide association studies have identified a number of genetic sequence variants that are associated with the risk of developing PTSD. To follow up on identifying the molecular mechanisms of these risk variants, we performed genotype to RNA sequencing-derived quantitative expression (whole gene, exon, and exon junction levels) analysis in the dorsolateral prefrontal cortex (DLPFC) of normal postmortem human brains. We further investigated genotype-gene expression associations within the amygdala in a smaller independent RNA sequencing (Genotype-Tissue Expression [GTEx]) dataset. Our DLPFC analyses identified significant expression quantitative trait loci (eQTL) associations for a "candidate" PTSD risk SNP rs363276 and the expression of two genes: SLC18A2 and PDZD8, where the PTSD risk/minor allele T was associated with significantly lower levels of gene expression for both genes, in the DLPFC. These eQTL associations were independently confirmed in the amygdala from the GTEx database. Rs363276 "T" carriers also showed significantly increased activity in the amygdala during an emotional face-matching task in healthy volunteers. Taken together, our preliminary findings in normal human brains represent a tractable approach to identify mechanisms by which genetic variants potentially increase an individual's risk for developing PTSD. © 2016 Wiley Periodicals, Inc.

Effects of neuregulin 3 genotype on human prefrontal cortex physiology.

The neuregulin 3 gene (NRG3) plays pleiotropic roles in neurodevelopment and is a putative susceptibility locus for schizophrenia. Specifically, the T allele of NRG3 rs10748842 has been associated with illness risk, altered cognitive function, and the expression of a novel splice isoform in prefrontal cortex (PFC), but the neural system effects are unexplored. Here, we report an association between rs10748842 and PFC physiology as measured by functional magnetic resonance imaging of human working memory performance, where a convincing link between increased genetic risk for schizophrenia and increased activation in some PFC areas has been established. In 410 control individuals (195 males, 215 females), we detected a highly significant effect of NRG3 genotype manifesting as an unanticipated increase in ventrolateral PFC activation in nonrisk-associated C allele carriers. An additional analysis including 78 patients with schizophrenia spectrum disorders (64 males, 14 females) and 123 unaffected siblings (53 males, 70 females) revealed a whole-brain significant genotype by group interaction in right dorsolateral PFC (DLPFC), manifesting as a relative activation increase in healthy controls and siblings (C > T/T) and as a hypoactivation in patients (T/T > C). These observed genotype-dependent effects in PFC were not explained by task performance and did not conform to established locales of prefrontal inefficiency linked to genetic risk for schizophrenia. Our data indicate a complex modulation of brain physiology by rs10748842, which does not fit the simple inefficiency model of risk association in DLPFC and suggests that other neurobiological mechanisms are involved.

A variable number of tandem repeats in the 3'-untranslated region of the dopamine transporter modulates striatal function during working memory updating across the adult age span.

Dopamine modulation of striatal function is critical for executive functions such as working memory (WM) updating. The dopamine transporter (DAT) regulates striatal dopamine signaling via synaptic reuptake. A variable number of tandem repeats in the 3'-untranslated region of SLC6A3 (DAT1-3'-UTR-VNTR) is associated with DAT expression, such that 9-repeat allele carriers tend to express lower levels (associated with higher extracellular dopamine concentrations) than 10-repeat homozygotes. Aging is also associated with decline of the dopamine system. The goal of the present study was to investigate the effects of aging and DAT1-3'-UTR-VNTR on the neural activity and functional connectivity of the striatum during WM updating. Our results showed both an age-related decrease in striatal activity and an effect of DAT1-3'-UTR-VNTR. Ten-repeat homozygotes showed reduced striatal activity and increased striatal-hippocampal connectivity during WM updating relative to the 9-repeat carriers. There was no age by DAT1-3'-UTR-VNTR interaction. These results suggest that, whereas striatal function during WM updating is modulated by both age and genetically determined DAT levels, the rate of the age-related decline in striatal function is similar across both DAT1-3'-UTR-VNTR genotype groups. They further suggest that, because of the baseline difference in striatal function based on DAT1-3'-UTR-VNTR polymorphism, 10-repeat homozygotes, who have lower levels of striatal function throughout the adult life span, may reach a threshold of decreased striatal function and manifest impairments in cognitive processes mediated by the striatum earlier in life than the 9-repeat carriers. Our data suggest that age and DAT1-3'-UTR-VNTR polymorphism independently modulate striatal function.

Quantitative Brain Amyloid PET.

Since the development of amyloid tracers for PET imaging, there has been interest in quantifying amyloid burden in the brains of patients with Alzheimer disease. Quantitative amyloid PET imaging is poised to become a valuable approach in disease staging, theranostics, monitoring, and as an outcome measure for interventional studies. Yet, there are significant challenges and hurdles to overcome before it can be implemented into widespread clinical practice. On November 17, 2022, the U.S. Food and Drug Administration, Society of Nuclear Medicine and Molecular Imaging, and Medical Imaging and Technology Alliance cosponsored a public workshop comprising experts from academia, industry, and government agencies to discuss the role of quantitative brain amyloid PET imaging in staging, prognosis, and longitudinal assessment of Alzheimer disease. The workshop discussed a range of topics, including available radiopharmaceuticals for amyloid imaging; the methodology, metrics, and analytic validity of quantitative amyloid PET imaging; its use in disease staging, prognosis, and monitoring of progression; and challenges facing the field. This report provides a high-level summary of the presentations and the discussion.

Effective connectivity of AKT1-mediated dopaminergic working memory networks and pharmacogenetics of anti-dopaminergic treatment.

Working memory is a limited capacity system that integrates and manipulates information across brief periods of time, engaging a network of prefrontal, parietal and subcortical brain regions. Genetic control of these heritable brain processes have been suggested by functional genetic variations influencing dopamine signalling, which affect prefrontal activity during complex working memory tasks. However, less is known about genetic control over component working memory cortical-subcortical networks in humans, and the pharmacogenetic implications of dopamine-related genes on cognition in patients receiving anti-dopaminergic drugs. Here, we examined predictions from basic models of dopaminergic signalling in cortical and cortical-subcortical circuitries implicated in dissociable working memory maintenance and manipulation processes. We also examined pharmacogenetic effects on cognition in the context of anti-dopaminergic drug therapy. Using dynamic causal models of functional magnetic resonance imaging in normal subjects (n = 46), we identified differentiated effects of functional polymorphisms in COMT, DRD2 and AKT1 genes on prefrontal-parietal and prefrontal-striatal circuits engaged during maintenance and manipulation, respectively. Cortical synaptic dopamine monitored by the COMT Val158Met polymorphism influenced prefrontal control of both parietal processing in working memory maintenance and striatal processing in working memory manipulation. DRD2 and AKT1 polymorphisms implicated in DRD2 signalling influenced only the prefrontal-striatal network associated with manipulation. In the context of anti-psychotic drugs, the DRD2 and AKT1 polymorphisms altered dose-response effects of anti-psychotic drugs on cognition in schizophrenia (n = 111). Thus, we suggest that genetic modulation of DRD2-AKT1-related prefrontal-subcortical circuits could at least in part influence cognitive dysfunction in psychosis and its treatment.

A common allele in the oxytocin receptor gene (OXTR) impacts prosocial temperament and human hypothalamic-limbic structure and function.

The evolutionarily highly conserved neuropeptide oxytocin is a key mediator of social and emotional behavior in mammals, including humans. A common variant (rs53576) in the oxytocin receptor gene (OXTR) has been implicated in social-behavioral phenotypes, such as maternal sensitivity and empathy, and with neuropsychiatric disorders associated with social impairment, but the intermediate neural mechanisms are unknown. Here, we used multimodal neuroimaging in a large sample of healthy human subjects to identify structural and functional alterations in OXTR risk allele carriers and their link to temperament. Activation and interregional coupling of the amygdala during the processing of emotionally salient social cues was significantly affected by genotype. In addition, evidence for structural alterations in key oxytocinergic regions emerged, particularly in the hypothalamus. These neural characteristics predicted lower levels of reward dependence, specifically in male risk allele carriers. Our findings identify sex-dependent mechanisms impacting the structure and function of hypothalamic-limbic circuits that are of potential clinical and translational significance.

Neurophysiological correlates of age-related changes in working memory updating.

Normal aging is associated with a gradual decline in executive functions such as set-shifting, inhibition, and updating, along with a progressive decline of neurotransmitter systems including the dopamine system. Modulation from the dopamine system is thought to be critical for the gating of information during working memory. Given the known relationships between executive aging, cognition, and dopamine, this study aims to explore the neurobiology underlying age-related changes in working memory updating using fMRI with healthy subjects from across the adult age spectrum. Our results indicate that older age is associated with poorer performance, reduced meso-cortico-striatal activation, and reduced functional coupling between the caudate and the VLPFC during the updating task. Additionally, caudate activation is associated with improved accuracy and VLPFC activation with faster reaction times in the full sample. Thus, older subjects' under-recruitment of and reduced functional coupling between these regions may specifically underlie age-related changes in working memory updating. These results are consistent with computational models of executive cognition and dopamine-mediated age-related cognitive decline.

Normal aging modulates prefrontoparietal networks underlying multiple memory processes.

A functional decline of brain regions underlying memory processing represents a hallmark of cognitive aging. Although a rich literature documents age-related differences in several memory domains, the effect of aging on networks that underlie multiple memory processes has been relatively unexplored. Here we used functional magnetic resonance imaging during working memory and incidental episodic encoding memory to investigate patterns of age-related differences in activity and functional covariance patterns common across multiple memory domains. Relative to younger subjects, older subjects showed increased activation in left dorso-lateral prefrontal cortex along with decreased deactivation in the posterior cingulate. Older subjects showed greater functional covariance during both memory tasks in a set of regions that included a positive prefronto-parietal-occipital network as well as a negative network that spanned the default mode regions. These findings suggest that the memory process-invariant recruitment of brain regions within prefronto-parietal-occipital network increases with aging. Our results are in line with the dedifferentiation hypothesis of neurocognitive aging, thereby suggesting a decreased specialization of the brain networks supporting different memory networks.

Genetic variation in FGF20 modulates hippocampal biology.

We explored the effect of single-nucleotide polymorphisms (SNPs) in the fibroblast growth factor 20 gene (FGF20) associated with risk for Parkinson's disease on brain structure and function in a large sample of healthy young-adult human subjects and also in elderly subjects to look at the interaction between genetic variations and age (N = 237; 116 men; 18-87 years). We analyzed high-resolution anatomical magnetic resonance images using voxel-based morphometry, a quantitative neuroanatomical technique. We also measured FGF20 mRNA expression in postmortem human brain tissue to determine the molecular correlates of these SNPs (N = 108; 72 men; 18-74 years). We found that the T allele carriers of rs12720208 in the 3'-untranslated region had relatively larger hippocampal volume (p = 0.0059) and diminished verbal episodic memory (p = 0.048) and showed steeper decreases of hippocampal volume with normal aging (p = 0.026). In postmortem brain, T allele carriers had greater expression of hippocampal FGF20 mRNA (p = 0.037), consistent with a previously characterized microRNA mechanism. The C allele matches a predicted miR-433 microRNA binding domain, whereas the T allele disrupts it, resulting in higher FGF20 protein translation. The strong FGF20 genetic effects in hippocampus are presumably mediated by activation of the FGFR1 (FGF receptor 1), which is expressed in mammalian brain most abundantly in the hippocampus. These associations, from mRNA expression to brain morphology to cognition and an interaction with aging, confirm a role of FGF20 in human brain structure and function during development and aging.

Selective updating of working memory content modulates meso-cortico-striatal activity.

Accumulating evidence from non-human primates and computational modeling suggests that dopaminergic signals arising from the midbrain (substantia nigra/ventral tegmental area) mediate striatal gating of the prefrontal cortex during the selective updating of working memory. Using event-related functional magnetic resonance imaging, we explored the neural mechanisms underlying the selective updating of information stored in working memory. Participants were scanned during a novel working memory task that parses the neurophysiology underlying working memory maintenance, overwriting, and selective updating. Analyses revealed a functionally coupled network consisting of a midbrain region encompassing the substantia nigra/ventral tegmental area, caudate, and dorsolateral prefrontal cortex that was selectively engaged during working memory updating compared to the overwriting and maintenance of working memory content. Further analysis revealed differential midbrain-dorsolateral prefrontal interactions during selective updating between low-performing and high-performing individuals. These findings highlight the role of this meso-cortico-striatal circuitry during the selective updating of working memory in humans, which complements previous research in behavioral neuroscience and computational modeling.

Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans.

AKT1-dependent molecular pathways control diverse aspects of cellular development and adaptation, including interactions with neuronal dopaminergic signaling. If AKT1 has an impact on dopaminergic signaling, then genetic variation in AKT1 would be associated with brain phenotypes related to cortical dopaminergic function. Here, we provide evidence that a coding variation in AKT1 that affects protein expression in human B lymphoblasts influenced several brain measures related to dopaminergic function. Cognitive performance linked to frontostriatal circuitry, prefrontal physiology during executive function, and frontostriatal gray-matter volume on MRI were altered in subjects with the AKT1 variation. Moreover, on neuroimaging measures with a main effect of the AKT1 genotype, there was significant epistasis with a functional polymorphism (Val158Met) in catechol-O-methyltransferase [COMT], a gene that indexes cortical synaptic dopamine. This genetic interaction was consistent with the putative role of AKT1 in dopaminergic signaling. Supportive of an earlier tentative association of AKT1 with schizophrenia, we also found that this AKT1 variant was associated with risk for schizophrenia. These data implicate AKT1 in modulating human prefrontal-striatal structure and function and suggest that the mechanism of this effect may be coupled to dopaminergic signaling and relevant to the expression of psychosis.

Nonlinear response of the anterior cingulate and prefrontal cortex in schizophrenia as a function of variable attentional control.

Previous studies have reported abnormal prefrontal and cingulate activity during attentional control processing in schizophrenia. However, it is not clear how variation in attentional control load modulates activity within these brain regions in this brain disorder. The aim of this study in schizophrenia is to investigate the impact of increasing levels of attentional control processing on prefrontal and cingulate activity. Blood oxygen level-dependent (BOLD) responses of 16 outpatients with schizophrenia were compared with those of 21 healthy subjects while performing a task eliciting increasing levels of attentional control during event-related functional magnetic resonance imaging at 3 T. Results showed reduced behavioral performance in patients at greater attentional control levels. Imaging data indicated greater prefrontal activity at intermediate attentional control levels in patients but greater prefrontal and cingulate responses at high attentional control demands in controls. The BOLD activity profile of these regions in controls increased linearly with increasing cognitive loads, whereas in patients, it was nonlinear. Correlation analysis consistently showed differential region and load-specific relationships between brain activity and behavior in the 2 groups. These results indicate that varying attentional control load is associated in schizophrenia with load- and region-specific modification of the relationship between behavior and brain activity, possibly suggesting earlier saturation of cognitive capacity.

Neural correlates of probabilistic category learning in patients with schizophrenia.

Functional neuroimaging studies of probabilistic category learning in healthy adults report activation of cortical-striatal circuitry. Based on previous findings of normal learning rate concurrent with an overall performance deficit in patients with schizophrenia, we hypothesized that relative to healthy adults, patients with schizophrenia would display preserved caudate nucleus and abnormal prefrontal cortex activation during probabilistic category learning. Forty patients with schizophrenia receiving antipsychotic medication and 25 healthy participants were assessed on interleaved blocks of probabilistic category learning and control tasks while undergoing blood oxygenation level-dependent functional magnetic resonance imaging. In addition to the whole sample of patients with schizophrenia and healthy adults, a subset of patients and healthy adults matched for good learning was also compared. In the whole sample analysis, patients with schizophrenia displayed impaired performance in conjunction with normal learning rate relative to healthy adults. The matched comparison of patients and healthy adults classified as good learners revealed greater caudate and dorsolateral prefrontal cortex activity in the healthy adults and greater activation in a more rostral region of the dorsolateral prefrontal, cingulate, parahippocampal and parietal cortex in patients. These results demonstrate that successful probabilistic category learning can occur in the absence of normal frontal-striatal function. Based on analyses of the patients and healthy adults matched on learning and performance, a minority of patients with schizophrenia achieve successful probabilistic category learning and performance levels through differential activation of a circumscribed neural network which suggests a compensatory mechanism in patients showing successful learning.