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  • Dual effect of 5-HT1B/1D receptors on dopamine neurons in ventral tegmental area: implication for the functional switch after chronic cocaine exposure
    Biol. Psychiatry (IF 11.501) Pub Date : 2020-01-22
    Ming Gao; Taleen S. Der-Ghazarian; Shuangtao Li; Shenfeng Qiu; Janet L. Neisewander; Jie Wu

    Background 5-HT1B/1D receptor (5-HT1B/1DR) agonists undergo an abstinence-induced “switch” in their effects on cocaine-related behaviors, which may involve changes in modulation of dopamine (DA) neurons in the ventral tegmental area (VTA). However, it is unclear how 5-HT1B/1DRs affect VTA DA neuronal function, and whether modulation of these neurons mediates the abstinence-induced switch after chronic cocaine exposure. Methods We examined the ability of 5-HT1B/1DRs to modulate D2 autoreceptors (D2ARs) and synaptic transmission in the VTA by slice recording and single unit recording in vivo in naive mice and in mice with chronic cocaine treatment. Results We report a bi-directional modulation of VTA DA neuronal firing through the interaction of VTA 5-HT1B/1DRs and D2ARs. In both VTA slices and the VTA of anesthetized mice, the 5-HT1B/1DR agonist CP94253 decreased DA neuronal firing rate and evoked excitatory postsynaptic currents (eEPSCs) to DA neurons in slice. Paradoxically, CP94253 decreased quinpirole-induced inhibition of DA neurons by reducing D2AR-mediated G protein-gated inwardly rectifying potassium (GIRK) current. This manifested decreased GABAAR-mediated evoked inhibitory postsynaptic currents (eIPSCs) in slice, resulting in disinhibition of DA neurons, in opposition to the 5-HT1B/1DR-induced inhibition. This dual effect was verified in chronic cocaine-treated and mild stress-treated, male mice on day 1 and 20 post-treatment. Conclusion This study revealed dual effects of CP94253 on VTA DA neurons that are dependent on D2AR sensitivity, with anti-inhibition under normal D2AR sensitivity and inhibition under low D2AR sensitivity. These dual effects may underlie the ability of CP94253 to both enhance and inhibit cocaine-induced behaviors.

  • Early Adversity and the Neotenous Human Brain
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-06-29
    Nim Tottenham

    Human brain development is optimized to learn from environmental cues. The protracted development of the cortex and its connections with subcortical targets has been argued to permit more opportunity for acquiring complex behaviors. This review uses the example of amygdala-medial prefrontal cortex circuitry development to illustrate a principle of human development—namely, that the extension of the brain’s developmental timeline allows for the (species-expected) collaboration between child and parent in co-construction of the human brain. The neurobiology underlying affective learning capitalizes on this protracted timeline to develop a rich affective repertoire in adulthood. Humans are afforded this luxuriously slow development in part by the extended period of caregiving provided by parents, and parents aid in scaffolding the process of maturation during childhood. Just as adequate caregiving is a potent effector of brain development, so is adverse caregiving, which is the largest environmental risk factor for adult mental illness. There are large individual differences in neurobiological outcomes following caregiving adversity, indicating that these pathways are probabilistic, rather than deterministic, and prolonged plasticity in human brain development may also allow for subsequent amelioration by positive experiences. The extant research indicates that the development of mental health cannot be considered without consideration of children in the context of their families.

  • Maternal effects as causes of risk for obsessive-compulsive disorder
    Biol. Psychiatry (IF 11.501) Pub Date : 2020-01-22
    Behrang Mahjani; Lambertus Klei; Christina M. Hultman; Henrik Larsson; Bernie Devlin; Joseph D. Buxbaum; Sven Sandin; Dorothy E. Grice

    Background While genetic variation has a known impact on the risk for obsessive‐compulsive disorder (OCD), there is also evidence that there are maternal components to this risk. Here, we partition sources of variation, namely direct genetic and maternal genetic effects, on risk for OCD. Methods The study population consists of 822,843 individuals from the Swedish Medical Birth Register, born in Sweden between January 1, 1982, to December 31, 1990, and followed for a diagnosis of OCD through December 31, 2013. Diagnostic information about OCD was obtained using the Swedish National Patient Register. Results 7,184 (0.87%) individuals in the birth cohort were diagnosed with OCD. After exploring various generalized linear mixed models to fit the diagnostic data, genetic maternal effects accounted for 7.6% (95% CI, 6.9%-8.3%) of the total variance in risk for OCD for the best model and direct additive genetics for 35% (95% CI, 32.3%-36.9%). These findings were robust under alternative models. Conclusions Our results establish genetic maternal effects as influencing risk for OCD in offspring. We also show that additive genetic effects in OCD are overestimated when maternal effects are not modeled.

  • Shared Transcriptional Signatures in Major Depressive Disorder and Mouse Chronic Stress Models
    Biol. Psychiatry (IF 11.501) Pub Date : 2020-01-22
    Joseph R. Scarpa; Mena Fatma; Yong-Hwee E. Loh; Said Romaric Traore; Theo Stefan; Ting Huei Chen; Eric J. Nestler; Benoit Labonté

    Background Most of our knowledge of the biological basis of major depressive disorder (MDD) is derived from studies of chronic stress models in rodents. While these models capture certain aspects of the behavioral and neuroendocrine features of MDD, the extent to which they reproduce the molecular pathology of the human syndrome remains unknown. Methods We systematically compared transcriptional signatures in two brain regions implicated in depression—medial prefrontal cortex (mPFC) and nucleus accumbens (NAc)—of humans with MDD and of three chronic stress models in mice: chronic variable stress (CVS), social isolation in adulthood (SI) and chronic social defeat stress (CSDS). We used differential expression analysis combined with weighted gene co-expression network analysis (WGCNA) to create interspecies gene networks and assess the capacity of each stress paradigm to recapitulate the transcriptional organization of gene networks in human MDD. Results Our results show significant overlap between transcriptional alterations in mPFC and NAc in human MDD and the three mouse chronic stress models, with each of the chronic stress paradigms capturing distinct aspects of MDD abnormalities. CVS and SI better reproduce differentially expressed genes, while CSDS and SI better reproduce gene networks characteristic of human MDD. We also identified several gene networks and their constituent genes that are most significantly associated with human MDD and mouse stress models. Conclusions This study demonstrates the ability of three chronic stress models in mice to recapitulate distinct aspects of the broad molecular pathology of human MDD, with no one mouse model apparently better than another.

  • Gene expression in patient-derived neural progenitors implicates WNT5A signaling in the etiology of schizophrenia
    Biol. Psychiatry (IF 11.501) Pub Date : 2020-01-22
    Oleg V. Evgrafov; Chris Armoskus; Bozena B. Wrobel; Valeria N. Spitsyna; Tade Souaiaia; Jennifer S. Herstein; Christopher P. Walker; Joseph D. Nguyen; Adrian Camarena; Jonathan R. Weitz; Jae Mun ‘Hugo’ Kim; Edder Lopez Duarte; Kai Wang; George M. Simpson; Janet L. Sobell; Helena Medeiros; Michele T. Pato; Carlos N. Pato; James A. Knowles

    Background GWAS of schizophrenia demonstrated that variations in the non-coding regions are responsible for most of common variation heritability of the disease. It is hypothesized that these risk variants alter gene expression. Thus, studying alterations in gene expression in schizophrenia may provide a direct approach to understanding the etiology of the disease. In this study we use Cultured Neural progenitor cells derived from Olfactory Neuroepithelium (CNON) as a genetically unaltered cellular model to elucidate the neurodevelopmental aspects of schizophrenia. methods We performed a gene expression study using RNA-Seq of CNON from 111 controls and 144 individuals with schizophrenia. Differentially expressed (DEX) genes were identified with DESeq2, using covariates to correct for sex, age, library batches and one surrogate variable component. Results 80 genes were DEX (FDR<10%), showing enrichment in cell migration, cell adhesion, developmental process, synapse assembly, cell proliferation and related gene ontology categories. Cadherin and Wnt signaling pathways were positive in overrepresentation test, and, in addition, many genes are specifically involved in Wnt5A signaling. The DEX genes were modestly, but significantly, enriched in the genes overlapping SNPs with genome-wide significant association from the PGC GWAS of schizophrenia (PGC SCZ2). We also found substantial overlap with genes associated with other psychiatric disorders or brain development, enrichment in the same GO categories as genes with mutations de novo in schizophrenia, and studies of iPSC-derived neural progenitor cells. Conclusions CNON cells are a good model of the neurodevelopmental aspects of schizophrenia and can be used to elucidate the etiology of the disorder.

  • Aberrant cortical ensembles and schizophrenia-like sensory phenotypes in setd1a mice.
    Biol. Psychiatry (IF 11.501) Pub Date : 2020-01-16
    Jordan P. Hamm; Yuriy Shymkiv; Jun Mukai; Joseph A. Gogos; Rafael Yuste

    Background A breakdown of synchrony within neuronal ensembles leading to destabilization of network “attractors” could be a defining aspect of neuropsychiatric diseases like schizophrenia (SZ), representing a common downstream convergence point for the diverse etiological pathways associated with the disease. Using a mouse genetic model, here we demonstrate how altered ensembles are associated with pathological sensory cortical processing phenotypes resulting from loss of function mutations in the setd1a gene, a recently identified rare risk genotype with very high penetrance for SZ. Methods We employed fast two-photon calcium imaging of neuronal populations (GCaMP6s, 10Hz, 100-250 cells, layer 2/3 of primary visual cortex, i.e. V1) in awake head-fixed mice (setd1a+/- vs wildtype littermate controls) during rest and visual stimulation with moving full-field square-wave gratings (0.04 cpd; 2.0 cps; 100% contrast, 12 directions). Multielectrode recordings were analyzed in the time-frequency domain to assess stimulus induced oscillations and cross-layer phase synchrony. Results Neuronal activity and orientation/direction selectivity were unaffected in setd1a+/- mice, but correlations between cell pairs in V1 showed altered distributions compared to WT, in both ongoing and visually-evoked activity. Further, population-wide “ensemble activations” in setd1a+/- mice were markedly less reliable over time during rest and visual stimulation, resulting in unstable encoding of basic visual information. This alteration of ensembles coincided with reductions in alpha and high-gamma band phase synchrony within and between cortical layers. Conclusion These results provide new evidence for an ensemble hypothesis of SZ and highlight the utility of setd1a+/- mice for modeling sensory processing phenotypes.

  • Reciprocal copy number variations at 22q11.2 produce distinct and convergent neurobehavioral impairments relevant for Schizophrenia and Autism Spectrum Disorder
    Biol. Psychiatry (IF 11.501) Pub Date : 2020-01-13
    Amy Lin; Ariana Vajdi; Leila Kushan-Wells; Gerhard Helleman; Laura Pacheco Hansen; Rachel K. Jonas; Maria Jalbrzikowski; Lyle Kingsbury; Armin Raznahan; Carrie E. Bearden

    Background 22q11.2 deletions and duplications are copy number variations (CNVs) that predispose to developmental neuropsychiatric disorders. Both CNVs are associated with autism spectrum disorder (ASD), while the deletion confers disproportionate risk for schizophrenia. Neurobehavioral profiles associated with these reciprocal CNVs in conjunction with brain imaging measures have not been reported. Method We profiled the impact of 22q11.2 CNVs on neurobehavioral measures relevant to ASD and psychosis in 106 22q11.2 deletion carriers, 38 22q11.2 duplication carriers, and 82 demographically-matched controls. To determine whether brain-behavior relationships were altered in CNV carriers, we further tested for interactions between group and regional brain structure on neurobehavioral domains. Results Cognitive deficits were observed in both CNV groups, with the lowest IQs in deletion carriers. ASD and dimensionally-measured ASD traits were elevated in both CNV groups; however, duplication carriers exhibited increased stereotypies compared to deletion carriers. Moreover, discriminant analysis using ASD sub-domains distinguished between CNV cases with 76% accuracy. Both psychotic disorder diagnosis and dimensionally-measured positive and negative symptoms were elevated in deletion carriers. Finally, control participants showed an inverse relationship between processing speed and cortical thickness in heteromodal association areas, which was absent in both CNV groups. Conclusions 22q11.2 CNVs differentially modulate intellectual functioning and psychosis-related symptomatology but converge on broad ASD-related symptomatology. However, subtle differences in ASD profiles distinguish CNV groups. Processing speed impairments, coupled with the lack of normative relationship between processing speed and cortical thickness in CNV carriers, implicate aberrant development of the cortical mantle in the pathology underlying impaired processing speed ability.

  • Psilocybin induces time-dependent changes in global functional connectivity
    Biol. Psychiatry (IF 11.501) Pub Date : 2020-01-13
    Katrin H. Preller; Patricia Duerler; Joshua B. Burt; Jie Lisa Ji; Brendan Adkinson; Philipp Stämpfli; Erich Seifritz; Grega Repovs; John H. Krystal; John D. Murray; Alan Anticevic; Franz X. Vollenweider

    Background The use of Psilocybin in scientific and experimental clinical contexts has triggered renewed interest in the mechanism of action of psychedelics. However, its time-dependent systems-level neurobiology remains sparsely investigated in humans. Methods We therefore conducted a double-blind, randomized, counterbalanced, cross-over study during which 23 healthy human participants received placebo and 0.2 mg/kg of psilocybin p.o. on two different test days. Participants underwent MRI scanning at three time points between administration and peak effects: 20 mins, 40 mins, and 70 mins after administration. Resting-state functional connectivity was quantified via a data-driven global brain connectivity method and compared to cortical gene expression maps. Results Psilocybin reduced associative, but concurrently increased sensory brain-wide connectivity. This pattern emerged over time from administration to peak-effects. Furthermore, we show that baseline connectivity is associated with the extent of Psilocybin-induced changes in functional connectivity. Lastly, Psilocybin induced changes correlated time-dependently with spatial gene expression patterns of the 5-HTR2A and 5-HTR1A. Conclusions These results suggest that the integration of functional connectivity in sensory and the disintegration in associative regions may underlie the psychedelic state and pinpoint the critical role of the serotonin 2A and 1A receptor systems. Furthermore, baseline connectivity may represent a predictive marker of the magnitude of changes induced by psilocybin and may therefore contribute to a personalized medicine approach within the potential framework of psychedelic treatment.

  • Low-dose Perampanel rescues cortical gamma dysregulation associated with parvalbumin interneuron GluA2 upregulation in epileptic Syngap1+/- mice
    Biol. Psychiatry (IF 11.501) Pub Date : 2020-01-10
    Brennan J. Sullivan; Simon Ammanuel; Pavel A. Kipnis; Yoichi Araki; Richard L. Huganir; Shilpa D. Kadam

    Background Loss-of-function SYNGAP1 mutations cause a neurodevelopmental disorder characterized by intellectual disability and epilepsy. SYNGAP1 is a Ras-GTPase-activating protein that underlies the formation and experience-dependent regulation of postsynaptic densities. The mechanisms that contribute to this proposed monogenic cause of intellectual disability and epilepsy remain unresolved. Methods Here, we establish the phenotype of the epileptogenesis in a Syngap1+/- mouse model using 24h video electroencephalogram/electromyogram (vEEG/EMG) recordings at advancing ages. We administered an acute low-dose of Perampanel, an FDA approved AMPAR antagonist, during a follow-on 24h vEEG to investigate the role of AMPARs in SYNGAP1 haploinsufficiency. To determine the region- and location-specific differences in the expression of the GluA2 AMPAR subunit, immunohistochemistry was performed. Results A progressive worsening of the epilepsy with emergence of multiple seizure phenotypes, interictal spike frequency, sleep dysfunction, and hyperactivity was identified in Syngap1+/- mice. Interictal spikes emerged predominantly during NREM in 24h vEEG of Syngap1+/- mice. Myoclonic seizures occurred at behavioral-state transitions both in Syngap1+/- mice and during an overnight EEG from a child with SYNGAP1 haploinsufficiency. In Syngap1+/- mice, EEG spectral power analyses identified a significant loss of gamma power modulation during behavioral-state transitions. A significant region-specific increase of GluA2 AMPAR subunit expression in the somas of parvalbumin-positive (PV+) interneurons was identified. Conclusions Acute dosing with Perampanel significantly rescued behavioral-state dependent cortical gamma homeostasis, identifying a novel mechanism implicating Ca2+ impermeable AMPARs on PV+ interneurons underlying circuit dysfunction in SYNGAP1 haploinsufficiency.

  • Cholinergic Modulation of Disorder-Relevant Neural Circuits in Generalised Anxiety Disorder
    Biol. Psychiatry (IF 11.501) Pub Date : 2020-01-08
    Toby Wise; Fiona Patrick; Nicholas Meyer; Ndaba Mazibuko; Alice E. Oates; Anne H.M. van der Bijl; Philippe Danjou; Susan M. O’Connor; Elizabeth Doolin; Caroline Wooldridge; Deborah Rathjan; Christine Macare; Steven CR. Williams; Adam Perkins; Allan H. Young

    Background Generalised anxiety disorder is associated with hyperactivity in amygdala-prefrontal networks, and normalisation of this aberrant function is thought to be critical for successful treatment. Preclinical evidence implicates cholinergic neurotransmission in the function of these systems and suggests that cholinergic modulation may have anxiolytic effects. However, the effects of cholinergic modulators on the function of anxiety-related networks in humans has not been investigated. Methods We administered a novel α7 nicotinic acetylcholine receptor negative allosteric modulator, BNC210, to 24 individuals (3 male) with generalised anxiety disorder and assessed its effects on neural responses to fearful face stimuli.materials-methods Results BNC210 reduced amygdala reactivity to fearful faces relative to placebo, similarly to lorazepam, and also reduced connectivity between the amygdala and the anterior cingulate cortex, a network involved in regulating anxious responses to aversive stimuli.results Conclusions These results demonstrate for the first time that the function of disorder relevant neural circuits in generalised anxiety disorder can be beneficially altered through modulation of cholinergic neurotransmission and suggests potential for this system as a novel target for anxiolytic pharmacotherapy.results

  • Aβ-Positivity Predicts Cognitive Decline but Cognition Predicts Progression to Aβ-Positivity
    Biol. Psychiatry (IF 11.501) Pub Date : 2020-01-07
    Jeremy A. Elman; Matthew S. Panizzon; Daniel E. Gustavson; Carol E. Franz; Mark E. Sanderson-Cimino; Michael J. Lyons; William S. Kremen

    Background Stage 1 of the NIA-AA’s proposed Alzheimer’s disease (AD) continuum is defined as β-amyloid (Aβ) positive but cognitively normal. Identifying at-risk individuals before Aβ reaches pathological levels could have great benefits for early intervention. Although Aβ levels become abnormal long before severe cognitive impairments appear, increasing evidence suggests subtle cognitive changes may begin early, potentially before Aβ surpasses the threshold for abnormality. We examined whether baseline cognitive performance would predict progression from normal to abnormal levels of Aβ. Methods We examined the association of baseline cognitive composites (Preclinical Alzheimer Cognitive Composite [PACC]; ADNI memory factor score [ADNI_MEM]) with progression to Aβ-positivity in 292 non-demented, Aβ-negative Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants. Additional analyses included continuous CSF biomarker levels to examine the effects of subthreshold pathology. Results Forty participants progressed to Aβ-positivity during follow-up. Poorer baseline performance on both cognitive measures was significantly associated with increased odds of progression. More abnormal levels of baseline CSF p-tau and subthreshold Aβ were associated with increased odds of progression to Aβ-positivity. Nevertheless, baseline ADNI_MEM performance predicted progression even after controlling for baseline biomarker levels and APOE genotype (PACC was trend level). Survival analyses were largely consistent: controlling for baseline biomarker levels, baseline PACC still significantly predicted progression time to Aβ-positivity (ADNI_MEM was trend level). Conclusions The possibility of intervening before Aβ reaches pathological levels is of obvious benefit. Low cost, non-invasive cognitive measures can be informative for determining who is likely to progress to Aβ-positivity, even after accounting for baseline subthreshold biomarker levels.

  • Heterogeneity of Striatal Dopamine Function in Schizophrenia: Meta-analysis of Variance
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-07-25
    Stefan P. Brugger; Ilinca Angelescu; Anissa Abi-Dargham; Romina Mizrahi; Vahid Shahrezaei; Oliver D. Howes

    Background It has been hypothesized that dopamine function in schizophrenia exhibits heterogeneity in excess of that seen in the general population. However, no previous study has systematically tested this hypothesis. Methods We employed meta-analysis of variance to investigate interindividual variability of striatal dopaminergic function in patients with schizophrenia and in healthy control subjects. We included 65 studies that reported molecular imaging measures of dopamine synthesis or release capacities, dopamine D2/3 receptor (D2/3R) or dopamine transporter (DAT) availabilities, or synaptic dopamine levels in 983 patients and 968 control subjects. Variability differences were quantified using variability ratio (VR) and coefficient of variation ratio. Results Interindividual variability of striatal D2/3R (VR = 1.26, p < .0001) and DAT (VR = 1.31, p = .01) availabilities and synaptic dopamine levels (VR = 1.38, p = .045) but not dopamine synthesis (VR = 1.12, p = .13) or release (VR = 1.08, p = .70) capacities were significantly greater in patients than in control subjects. Findings were robust to variability measure. Mean dopamine synthesis (g = 0.65, p = .004) and release (g = 0.66, p = .03) capacities, as well as synaptic levels (g = 0.78, p = .0006), were greater in patients overall, but mean synthesis capacity did not differ from that of control subjects in treatment-resistant patients (p > .3). Mean D2/3R (g = 0.17, p = .14) and DAT (g = -0.20, p = .28) availabilities did not differ between groups. Conclusions Our findings demonstrate significant heterogeneity of striatal dopamine function in schizophrenia. They suggest that while elevated dopamine synthesis and release capacities may be core features of the disorder, altered D2/3R and DAT availabilities and synaptic dopamine levels may occur only in a subgroup of patients. This heterogeneity may contribute to variation in treatment response and side effects.

  • Association of Cortical Glutamate and Working Memory Activation in Patients With Schizophrenia: A Multimodal Proton Magnetic Resonance Spectroscopy and Functional Magnetic Resonance Imaging Study
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-07-26
    Jakob Kaminski; Tobias Gleich; Yu Fukuda; Teresa Katthagen; Jürgen Gallinat; Andreas Heinz; Florian Schlagenhauf

    Background Cognitive deficits such as working memory (WM) impairment are core features of schizophrenia. One candidate marker for the integrity of synaptic neurotransmission necessary for cognitive processes is glutamate. It is frequently postulated that antipsychotic medication possibly alters functional mechanisms in the living brain. We tested in vivo for group differences in activation of the dorsolateral prefrontal cortex (DLPFC) during WM performance and the association with glutamate concentration in DLPFC depending on medication status. Methods A total of 90 subjects (35 control subjects, 36 medicated patients, and 19 unmedicated patients) contributed magnetic resonance spectroscopy data. We estimated glutamate in left DLPFC. Subjects performed an n-back WM task (2-back vs. 0-back) during functional magnetic resonance imaging, and local activation in left DLPFC was measured. For analysis of association with medication status, we calculated linear regression models including an interaction effect with group. Results Medicated and unmedicated patients with schizophrenia showed impaired performance. We found significantly reduced WM activation in left DLPFC in medicated patients and a trendwise reduction in unmedicated patients as compared with control subjects. We found no group difference in local glutamate concentration. However, we found differential effects of medication status on the association between local glutamate concentration and WM activation in left DLPFC, with a positive association in unmedicated patients but not in medicated patients. Conclusions We provide evidence that WM-dependent activation is associated with glutamate concentration in unmedicated patients with schizophrenia. Our finding points to putative allostatic changes that affect the functioning of the brain and might be altered through medication.

  • Evaluating the Impact of Nonrandom Mating: Psychiatric Outcomes Among the Offspring of Pairs Diagnosed With Schizophrenia and Bipolar Disorder
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-07-09
    Ashley E. Nordsletten; Gustaf Brander; Henrik Larsson; Paul Lichtenstein; James J. Crowley; Patrick F. Sullivan; Naomi R. Wray; David Mataix-Cols

    Background Nonrandom mating has been shown for psychiatric diagnoses, with hypothesized—but not quantified—implications for offspring liability. This national cohort study enumerated the incidence of major psychiatric disorders among the offspring of parent pairs affected with schizophrenia (SCZ) and/or bipolar disorder (BIP) (i.e., dual-affected pairs). Methods Participants were all Swedish residents alive or born between 1968 and 2013 (n = 4,255,196 unique pairs and 8,343,951 offspring). Offspring with dual-affected, single-affected, and unaffected parents were followed (1973–2013) for incidence of broad psychiatric disorders. Primary outcomes included hazard ratio (HR) and cumulative incidence for SCZ and BIP in the offspring. Additional outcomes included any neuropsychiatric, anxiety, depressive, personality, or substance use disorders. Cumulative incidences of SCZ and BIP were used to inform heritability models for these disorders. Results Hazards were highest within disorder (e.g., offspring of dual-SCZ pairs had sharply raised hazards for SCZ [HR = 55.3]); however, they were significantly raised for all diagnoses (HR range = 2.89–11.84). Incidences were significantly higher for the majority of outcomes, with 43.4% to 48.5% diagnosed with “any” disorder over follow-up. Risks were retained, with modest attenuations, for the offspring of heterotypic pairs. The estimated heritability of liability for SCZ (h2 = 0.62, 95% confidence interval = 0.55–0.70) and BIP (h2 = 0.52, 95% confidence interval = 0.46–0.58) did not differ significantly from estimates derived from single-affected parents. Conclusions Risks for a broad spectrum of psychiatric diagnoses are significantly raised in the offspring of dual-affected parents, in line with expectations from a polygenic model of liability to disease risk. How these risks may contribute to population maintenance of these disorders is considered.

  • The Electroretinogram May Differentiate Schizophrenia From Bipolar Disorder
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-06-27
    Marc Hébert; Chantal Mérette; Anne-Marie Gagné; Thomas Paccalet; Isabel Moreau; Joëlle Lavoie; Michel Maziade

    Background The retina is recognized as an approachable part of the brain owing to their common embryonic origin. The electroretinogram (ERG) has proved to be a valuable tool to investigate psychiatric disorders. We therefore investigated its accuracy as a tool to differentiate schizophrenia (SZ) from bipolar disorder (BP) even after balancing patients for their main antipsychotic medication. Methods ERG cone and rod luminance response functions were recorded in 150 patients with SZ and 151 patients with BP and compared with 200 control subjects. We created a subgroup of subjects—45 with SZ and 45 with BP—balanced for their main antipsychotic medication. Results A reduced cone a-wave amplitude and a prolonged b-wave latency were observed in both disorders, whereas a reduced cone b-wave amplitude was present in SZ only. Reduced mixed rod-cone a- and b-wave amplitudes were observed in both disorders. Patients with SZ were distinguishable from control subjects with 0.91 accuracy, 77% sensitivity, and 91% specificity with similar numbers for patients with BP (0.89, 76%, and 88%, respectively). Patients with SZ and patients with BP could be differentiated with an accuracy of 0.86 (whole sample) and 0.83 (subsamples of 45 patients with 80% sensitivity and 82% specificity). Antipsychotic dosages were not correlated with ERG parameters. Conclusions The ERG waveform parameters used in this study provided a very accurate distinction between the two disorders when using a logistic regression model. This supports the ERG as a tool that could aid the clinician in the differential diagnosis of SZ and BP in stabilized medicated patients.

  • Plasticity of the reward circuitry after early life adversity: mechanisms and significance
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-12-24
    Matthew T. Birnie; Cassandra L. Kooiker; Annabel K. Short; Jessica L. Bolton; Yuncai Chen; Tallie Z. Baram

    Disrupted operation of the reward circuitry underlies many aspects of affective disorders. Such disruption may manifest as aberrant behavior including risk taking, depression, anhedonia and addiction. Early life adversity is a common antecedent of adolescent and adult affective disorders involving the reward circuitry. However, whether early life adversity influences the maturation and operations of the reward circuitry, and the potential underlying mechanisms, remain unclear. Here we present novel information using cutting-edge technologies in animal models to dissect out the mechanisms by which early life adversity provokes dysregulation of the complex interactions of stress and reward circuitries. We propose that certain molecularly defined pathways within the reward circuitry are particularly susceptible to early life adversity. We examine regions and pathways expressing the stress sensitive peptide corticotropin releasing hormone (CRH), which has been identified in critical components of the reward circuitry and interacting stress circuits. Notably, CRH is strongly modulated by early life adversity in several of these brain regions. Focusing on amygdala nuclei and their projections, we provide evidence suggesting that aberrant CRH expression and function may underlie augmented connectivity of the nucleus accumbens with fear/anxiety regions, disrupting the function of this critical locus of pleasure and reward.

  • Approaches to Defining Common and Dissociable Neurobiological Deficits Associated with Psychopathology in Youth
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-12-23
    Antonia N. Kaczkurkin; Tyler M. Moore; Aristeidis Sotiras; Cedric Huchuan Xia; Russell T. Shinohara; Theodore D. Satterthwaite

    Psychiatric disorders show high rates of co-morbidity and non-specificity of presenting clinical symptoms, while at the same time demonstrating substantial heterogeneity within diagnostic categories. Notably, many of these psychiatric disorders first manifest in youth. Here we review progress and next steps in efforts to parse heterogeneity in psychiatric symptoms in youth by identifying abnormalities within neural circuits. To address this fundamental challenge in psychiatry, a number of methods have been proposed. We provide an overview of these methods, broadly organized into dimensional vs. categorical approaches and single-view vs. multi-view approaches. Dimensional approaches including factor analysis and canonical correlation analysis aim to capture dimensional associations between psychopathology and brain measures across a continuous spectrum from health to disease. In contrast, categorical approaches such as clustering and community detection aim to identify subtypes of individuals within a class of symptoms or brain features. We highlight several studies that apply these methods to samples of youth, and discuss issues to consider when using these approaches. Finally, we end by highlighting avenues for future research.

  • Psychosis risk and development: What do we know from population-based studies?
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-12-20
    Eva Mennigen; Carrie E. Bearden

    Recent years have seen an advent in population-based studies in children, adolescents, and adults that examine the prevalence, etiology, and developmental trajectories of diverse subclinical psychopathological symptoms that pose a risk for the later development of severe mental illnesses. It is increasingly recognized that most categorically defined psychiatric disorders (i) occur on a spectrum or continuum, (ii) show high heterogeneity and symptom overlap, and (iii) share genetic and environmental risk factors. Here, we discuss neurodevelopmental underpinnings of psychosis spectrum symptoms and review brain morphometric and functional alterations, as well as genetic liability for psychosis, in individuals experiencing psychotic symptoms (PS) in the general population. With regard to brain structure and function, findings of qualitatively similar alterations in individuals experiencing subthreshold PS and those with overt psychotic disorders support the notion of a psychosis continuum. However, genetic and epidemiological studies have emphasized the overlap of PS and other psychiatric illnesses. In particular, PS during adolescence appear to be a non-specific precursor of different psychopathological outcomes.

  • Genetic risk underlying psychiatric and cognitive symptoms in Huntington’s Disease
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-12-17
    Natalie Ellis; Amelia Tee; Branduff McAllister; Thomas Massey; Duncan McLauchlan; Timothy Stone; Kevin Correia; Jacob Loupe; Kyung-Hee Kim; Douglas Barker; Eun Pyo Hong; Michael J. Chao; Jeffrey D. Long; Diane Lucente; Jean Paul G. Vonsattel; Ricardo Mouro Pinto; Kawther Abu Elneel; Eliana Marisa Ramos; Peter Holmans

    Background Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized exam of motor control and often presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor symptoms in HD, but genetic factors influencing cognitive and psychiatric presentations are unknown. Methods We tested the hypothesis that psychiatric and cognitive symptoms in HD are influenced by the same common genetic variation as in the general population by constructing polygenic risk scores from large genome-wide association studies of psychiatric and neurodegenerative disorders, and of intelligence, and testing for correlation with the presence of psychiatric and cognitive symptoms in a large sample (n=5160) of HD patients. Results Polygenic risk score for major depression was associated specifically with increased risk of depression in HD, as was schizophrenia risk score with psychosis and irritability. Cognitive impairment and apathy were associated with reduced polygenic risk score for intelligence. Conclusions Polygenic risk scores for psychiatric disorders, particularly depression and schizophrenia, are associated with increased risk of the corresponding psychiatric symptoms in HD, suggesting a common genetic liability. However, the genetic liability to cognitive impairment and apathy appears to be distinct from other psychiatric symptoms in HD. No associations were observed between HD symptoms and risk scores for other neurodegenerative disorders. These data provide a rationale for treatments effective in depression and schizophrenia to be used to treat depression and psychotic symptoms in HD.

  • Teeth as Potential New Tools to Measure Early-Life Adversity and Subsequent Mental Health Risk: An Interdisciplinary Review and Conceptual Model
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-12-17
    Kathryn A. Davis; Rebecca V. Mountain; Olivia R. Pickett; Pamela K. Den Besten; Felicitas B. Bidlack; Erin C. Dunn

    Early-life adversity affects nearly half of all youths in the United States and is a known risk factor for psychiatric disorders across the life course. One strategy to prevent mental illness may be to target interventions toward children who are exposed to adversity, particularly during sensitive periods when these adversities may have even more enduring effects. However, a major obstacle impeding progress in this area is the lack of tools to reliably and validly measure the existence and timing of early-life adversity. In this review, we summarize empirical work across dentistry, anthropology, and archaeology on human tooth development and discuss how teeth preserve a time-resolved record of our life experiences. Specifically, we articulate how teeth have been examined in these fields as biological fossils in which the history of an individual’s early-life experiences is permanently imprinted; this area of research is related to, but distinct from, studies of oral health. We then integrate these insights with knowledge about the role of psychosocial adversity in shaping psychopathology risk to present a working conceptual model, which proposes that teeth may be an understudied yet suggestive new tool to identify individuals at risk for mental health problems following early-life psychosocial stress exposure. We end by presenting a research agenda and discussion of future directions for rigorously testing this possibility and with a call to action for interdisciplinary research to meet the urgent need for new biomarkers of adversity and psychiatric outcomes.

  • Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-06-29
    Brett V. Johnson; Raman Kumar; Sabrina Oishi; Suzy Alexander; Maria Kasherman; Michelle Sanchez Vega; Atma Ivancevic; Alison Gardner; Deepti Domingo; Mark Corbett; Euan Parnell; Sehyoun Yoon; Tracey Oh; Matthew Lines; Henrietta Lefroy; Usha Kini; Margot Van Allen; Sabine Grønborg; Lachlan A. Jolly

    Background The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative. Methods We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology. Results Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory. Conclusions Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function.

  • Clinical Phenotypes of Carriers of Mutations in CHD8 or Its Conserved Target Genes
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-07-30
    Jennifer S. Beighley; Caitlin M. Hudac; Anne B. Arnett; Jessica L. Peterson; Jennifer Gerdts; Arianne S. Wallace; Heather C. Mefford; Kendra Hoekzema; Tychele N. Turner; Brian J. O’Roak; Evan E. Eichler; Raphael A. Bernier

    Background Variants disruptive to CHD8 (which codes for the protein CHD8 [chromodomain-helicase-DNA-binding protein 8]) are among the most common mutations revealed by exome sequencing in autism spectrum disorder (ASD). Recent work has indicated that CHD8 plays a role in the regulation of other ASD-risk genes. However, it is unclear whether a possible shared genetic ontology extends to the phenotype. Methods This study (N = 143; 42.7% female participants) investigated clinical and behavioral features of individuals ascertained for the presence of a known disruptive ASD-risk mutation that is 1) CHD8 (CHD8 group) (n = 15), 2) a gene targeted by CHD8 (target group) (n = 22), or 3) a gene without confirmed evidence of being targeted by CHD8 (other gene group) (n = 106). Results Results indicated shared features between the CHD8 and target groups that included less severe adaptive deficits in communication skills, similar functional language, more social motivation challenges in those with ASD, larger head circumference, higher weight, and lower seizure prevalence relative to the other gene group. Conclusions These similarities suggest broader genetic ontology accounts for aspects of phenotypic heterogeneity. Improved understanding of the relationships between related disruptive gene events may lead us to improved understanding of shared mechanisms and lead to more focused treatments for individuals with known genetic mutations.

  • Polygenic Risk Scores for Developmental Disorders, Neuromotor Functioning During Infancy, and Autistic Traits in Childhood
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-06-18
    Fadila Serdarevic; Henning Tiemeier; Philip R. Jansen; Silvia Alemany; Yllza Xerxa; Alexander Neumann; Elise Robinson; Manon H.J. Hillegers; Frank C. Verhulst; Akhgar Ghassabian

    Background Impaired neuromotor development is often one of the earliest observations in children with autism spectrum disorder (ASD). We investigated whether a genetic predisposition to developmental disorders was associated with nonoptimal neuromotor development during infancy and examined the genetic correlation between nonoptimal neuromotor development and autistic traits in the general population. Methods In a population-based cohort in The Netherlands (2002–2006), we calculated polygenic risk scores (PRSs) for ASD and attention-deficit/hyperactivity disorder (ADHD) using genome-wide association study summary statistics. In 1921 children with genetic data, parents rated autistic traits at 6 years of age. Among them, 1174 children (61.1%) underwent neuromotor examinations (tone, responses, senses, and other observations) during infancy (9–20 weeks of age). We used linear regressions to examine associations of PRSs with neuromotor scores and autistic traits. We performed a bivariate genome-based restricted maximum likelihood analysis to explore whether genetic susceptibility underlies the association between neuromotor development and autistic traits. Results Higher PRSs for ASD were associated with less optimal overall infant neuromotor development, in particular low muscle tone. Higher PRSs for ADHD were associated with less optimal senses. PRSs for ASD and those for ADHD both were associated with autistic traits. The single nucleotide polymorphism–based heritability of overall motor development was 20% (SE = .21) and of autistic traits was 68% (SE = .26). The genetic correlation between overall motor development and autistic traits was .35 (SE = .21, p < .001). Conclusions We found that genetic liabilities for ASD and ADHD covary with neuromotor development during infancy. Shared genetic liability might partly explain the association between nonoptimal neuromotor development during infancy and autistic traits in childhood.

  • Synaptic Dysfunction in Human Neurons With Autism-Associated Deletions in PTCHD1-AS
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-07-29
    P. Joel Ross; Wen-Bo Zhang; Rebecca S.F. Mok; Kirill Zaslavsky; Eric Deneault; Lia D’Abate; Deivid C. Rodrigues; Ryan K.C. Yuen; Muhammad Faheem; Marat Mufteev; Alina Piekna; Wei Wei; Peter Pasceri; Rebecca J. Landa; Andras Nagy; Balazs Varga; Michael W. Salter; Stephen W. Scherer; James Ellis

    Background The Xp22.11 locus that encompasses PTCHD1, DDX53, and the long noncoding RNA PTCHD1-AS is frequently disrupted in male subjects with autism spectrum disorder (ASD), but the functional consequences of these genetic risk factors for ASD are unknown. Methods To evaluate the functional consequences of PTCHD1 locus deletions, we generated induced pluripotent stem cells (iPSCs) from unaffected control subjects and 3 subjects with ASD with microdeletions affecting PTCHD1-AS/PTCHD1, PTCHD1-AS/DDX53, or PTCHD1-AS alone. Function of iPSC-derived cortical neurons was assessed using molecular approaches and electrophysiology. We also compiled novel and known genetic variants of the PTCHD1 locus to explore the roles of PTCHD1 and PTCHD1-AS in genetic risk for ASD and other neurodevelopmental disorders. Finally, genome editing was used to explore the functional consequences of deleting a single conserved exon of PTCHD1-AS. Results iPSC-derived neurons from subjects with ASD exhibited reduced miniature excitatory postsynaptic current frequency and N-methyl-D-aspartate receptor hypofunction. We found that 35 ASD-associated deletions mapping to the PTCHD1 locus disrupted exons of PTCHD1-AS. We also found a novel ASD-associated deletion of PTCHD1-AS exon 3 and showed that exon 3 loss altered PTCHD1-AS splicing without affecting expression of the neighboring PTCHD1 coding gene. Finally, targeted disruption of PTCHD1-AS exon 3 recapitulated diminished miniature excitatory postsynaptic current frequency, supporting a role for the long noncoding RNA in the etiology of ASD. Conclusions Our genetic findings provide strong evidence that PTCHD1-AS deletions are risk factors for ASD, and human iPSC-derived neurons implicate these deletions in the neurophysiology of excitatory synapses and in ASD-associated synaptic impairment.

  • Synaptic and Gene Regulatory Mechanisms in Schizophrenia, Autism, and 22q11.2 Copy Number Variant–Mediated Risk for Neuropsychiatric Disorders
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-07-11
    Jennifer K. Forsyth; Daniel Nachun; Michael J. Gandal; Daniel H. Geschwind; Ariana E. Anderson; Giovanni Coppola; Carrie E. Bearden

    Background 22q11.2 copy number variants are among the most highly penetrant genetic risk variants for developmental neuropsychiatric disorders such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the specific mechanisms through which they confer risk remain unclear. Methods Using a functional genomics approach, we integrated transcriptomic data from the developing human brain, genome-wide association findings for SCZ and ASD, protein interaction data, and gene expression signatures from SCZ and ASD postmortem cortex to 1) organize genes into the developmental cellular and molecular systems within which they operate, 2) identify neurodevelopmental processes associated with polygenic risk for SCZ and ASD across the allelic frequency spectrum, and 3) elucidate pathways and individual genes through which 22q11.2 copy number variants may confer risk for each disorder. Results Polygenic risk for SCZ and ASD converged on partially overlapping neurodevelopmental modules involved in synaptic function and transcriptional regulation, with ASD risk variants additionally enriched for modules involved in neuronal differentiation during fetal development. The 22q11.2 locus formed a large protein network during development that disproportionately affected SCZ-associated and ASD-associated neurodevelopmental modules, including loading highly onto synaptic and gene regulatory pathways. SEPT5, PI4KA, and SNAP29 genes are candidate drivers of 22q11.2 synaptic pathology relevant to SCZ and ASD, and DGCR8 and HIRA are candidate drivers of disease-relevant alterations in gene regulation. Conclusions This approach offers a powerful framework to identify neurodevelopmental processes affected by diverse risk variants for SCZ and ASD and elucidate mechanisms through which highly penetrant, multigene copy number variants contribute to disease risk.

  • Atypical Functional Connectivity in Tourette Syndrome Differs Between Children and Adults
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-07-02
    Ashley N. Nielsen; Caterina Gratton; Jessica A. Church; Nico U.F. Dosenbach; Kevin J. Black; Steven E. Petersen; Bradley L. Schlaggar; Deanna J. Greene

    Background Tourette syndrome (TS) is a neuropsychiatric disorder with symptomatology that typically changes over development. Whether and how brain function in TS also differs across development has been largely understudied. Here, we used functional connectivity magnetic resonance imaging to examine whole-brain functional networks in children and adults with TS. Methods Multivariate classification methods were used to find patterns among functional connections that distinguish individuals with TS from control subjects separately for children and adults (N = 202). We tested whether the patterns of connections that classify diagnosis in one age group (e.g., children) could classify diagnosis in another age group (e.g., adults). We also tested whether the developmental trajectory of these connections was altered in TS. Results Diagnostic classification was successful in children and adults separately but expressly did not generalize across age groups, suggesting that the patterns of functional connections that best distinguished individuals with TS from control subjects were age specific. Developmental patterns among these functional connections used for diagnostic classification deviated from typical development. Brain networks in childhood TS appeared “older” and brain networks in adulthood TS appeared “younger” in comparison with typically developing individuals. Conclusions Our results demonstrate that brain networks are differentially altered in children and adults with TS. The observed developmental trajectory of affected connections is consistent with theories of accelerated and/or delayed maturation, but may also involve anomalous developmental pathways. These findings further our understanding of neurodevelopmental trajectories in TS and carry implications for future applications aimed at predicting the clinical course of TS in individuals over development.

  • Parsing the Heterogeneity of Brain Metabolic Disturbances in Autism Spectrum Disorder
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-06-21
    Joseph O’Neill; Ravi Bansal; Suzanne Goh; Martina Rodie; Siddhant Sawardekar; Bradley S. Peterson

    Background Despite rising prevalence of autism spectrum disorder (ASD), its brain bases remain uncertain. Abnormal levels of N-acetyl compounds, glutamate+glutamine, creatine+phosphocreatine, or choline compounds measured by proton magnetic resonance spectroscopy suggest that neuron or glial density, mitochondrial energetic metabolism, and/or inflammation contribute to ASD neuropathology. The neuroanatomic distribution of these metabolites could help evaluate leading theories of ASD. However, most prior magnetic resonance spectroscopy studies had small samples (all <60, most <20), interrogated only a small fraction of the brain, and avoided assessing effects of age, sex, and IQ. Methods We acquired near-whole-brain magnetic resonance spectroscopy of N-acetyl compounds, glutamate+glutamine, creatine+phosphocreatine, and choline compounds in 78 children and adults with ASD and 96 typically developing children and adults, rigorously evaluating effects of diagnosis and severity on metabolites, as moderated by age, sex, and IQ. Results Effects of ASD and its severity included reduced levels of multiple metabolites in white matter and the perisylvian cortex and elevated levels in the posterior cingulate, consistent with white matter and social-brain theories of ASD. Regionally, both slower and faster decreases of metabolites with age were observed in ASD versus TD. Male-female metabolite differences were widely smaller in ASD than typically developing children and adults. ASD-specific decreases in metabolites with decreasing IQ occurred in several brain areas. Conclusions Results support multifocal abnormal neuron or glial density, mitochondrial energetics, or neuroinflammation in ASD, alongside widespread starkly atypical moderating effects of age, sex, and IQ. These findings help parse the neurometabolic signature for ASD by phenotypic heterogeneity.

  • Schizotypy-related magnetization of cortex in healthy adolescence is co-located with expression of schizophrenia-related genes
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-12-13
    Rafael Romero-Garcia; Jakob Seidlitz; Kirstie J. Whitaker; Sarah E. Morgan; Peter Fonagy; Raymond J. Dolan; Peter B. Jones; Ian M. Goodyer; John Suckling; Petra E. Vértes; Edward T. Bullmore

    Background Genetic risk is thought to drive clinical variation on a spectrum of schizophrenia-like traits but the underlying changes in brain structure that mechanistically link genomic variation to schizotypal experience and behaviour are unclear. Methods We assessed schizotypy using a self-reported questionnaire, and measured magnetization transfer (MT), as a putative micro-structural MRI marker of intra-cortical myelination, in 68 brain regions, in 248 healthy young people (aged 14-25 years). We used normative adult brain gene expression data, and partial least squares (PLS) analysis, to find the weighted gene expression pattern that was most co-located with the cortical map of schizotypy-related magnetization (SRM). Results Magnetization was significantly correlated with schizotypy in bilateral posterior cingulate cortex and precuneus (and for disorganized schizotypy also in medial prefrontal cortex; all FDR-corrected P < 0.05), which are regions of the default mode network specialized for social and memory functions. The genes most positively weighted on the whole genome expression map co-located with SRM were enriched for genes that were significantly down-regulated in two prior case-control histological studies of brain gene expression in schizophrenia. Conversely, the most negatively weighted genes were enriched for genes that were transcriptionally up-regulated in schizophrenia. Positively weighted (down-regulated) genes were enriched for neuronal, specifically inter-neuronal, affiliations and coded a network of proteins comprising a few highly interactive “hubs” such as parvalbumin and calmodulin. Conclusions Microstructural MRI maps of intracortical magnetization can be linked to both the behavioural traits of schizotypy and to prior histological data on dysregulated gene expression in schizophrenia.

  • Persistently high levels of maternal antenatal inflammation are associated with and mediate the effect of prenatal environmental adversities on neurodevelopmental delay in the offspring
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-12-13
    Polina Girchenko; Marius Lahti-Pulkkinen; Kati Heinonen; Rebecca M. Reynolds; Hannele Laivuori; Jari Lipsanen; Pia M. Villa; Esa Hämäläinen; Eero Kajantie; Jari Lahti; Katri Räikkönen

    Background Prenatal exposure to environmental adversities, including maternal overweight/obesity, diabetes/hypertensive or mood/anxiety disorders, increases the risk for adverse neurodevelopmental outcomes in children. However, the underlying biological mechanisms remain elusive. We tested whether maternal antenatal inflammation associated with the number of neurodevelopmental delay areas in children and mediated the association between exposure to any prenatal environmental adversity and child neurodevelopmental delay. Methods Mother-child dyads (N=418) from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) study were followed-up to 10.8 years. We analyzed maternal plasma high-sensitivity C-reactive-protein (hsCRP) and glycoprotein acetyls at three consecutive antenatal time points, extracted data on maternal body mass index in early pregnancy, and diabetes/hypertensive disorders in pregnancy from medical records, and mood/anxiety disorders until childbirth from the Care Register for Health Care (HILMO). To estimate the number of neurodevelopmental delay areas in children across cognitive, motor and social functioning, we pooled data from HILMO on psychological development disorders with mother-reported Ages and Stages Questionnaire data on developmental milestones. Results Higher levels of maternal hsCRP and glycoprotein acetyls at and across all three antenatal time points were associated with 1.30 to 2.36-fold (p-values<0.02) increased relative risk for higher number of areas of child neurodevelopmental delay. Higher maternal inflammation across the three time points also mediated the effect of any prenatal environmental adversity on child neurodevelopmental delay. Conclusions Higher levels of maternal inflammation, especially when persisting throughout pregnancy, increase child’s risk of neurodevelopmental delay and mediate the effect of prenatal environmental adversity on child neurodevelopmental delay.

  • Medication for Attention-Deficit/Hyperactivity Disorder and Risk for Suicide Attempts
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-12-13
    Zheng Chang; Patrick D. Quinn; Lauren O'Reilly; Arvid Sjölander; Kwan Hur; Robert Gibbons; Henrik Larsson; Brian M. D’Onofrio

    Background Attention-deficit/hyperactivity disorder (ADHD) is a risk factor for suicidal behavior, but the effect of ADHD medication on suicidal behavior remains unclear. This study aimed to examine the associations between medication treatment for ADHD and risk of suicide attempts. Methods We identified a large cohort of patients with ADHD (N=3,874,728, 47.8% female) using data from commercial healthcare claims 2005-2014 in the US. We used population-level and within-individual analyses to compare risk of suicide attempts during months when individuals received prescribed stimulant or non-stimulant medication relative to months when they did not receive medication. Results In both population-level and within-individual analyses, ADHD medication was associated with lower odds of suicide attempts (odds ratio [OR] =0.69, 95% CI: 0.66- 0.73, and OR=0.61, 95% CI: 0.57- 0.66, respectively). Similar reductions were found in children to middle-aged adults and in clinically relevant subgroups, including ADHD patients with pre-existing depression or substance use disorder. The reduction was mainly seen for stimulant medication (OR=0.72, 95% CI: 0.66-0.77); non-stimulant medication was not associated with statistically significant changes in risk of suicide attempts (OR=0.94, 95% CI: 0.74-1.19). Sensitivity analyses assessing the influence of different exposure definitions, different outcome definitions, subsets of the cohort, and different analytic approaches provided comparable results. Conclusions Stimulant medication was associated with a reduced risk of suicide attempts in patients with ADHD, and non-stimulant medication is unlikely to increase the risk of suicide attempts.

  • Multiple hold-outs with stability: improving the generalizability of machine learning analyses of brain-behaviour relationships
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-12-10
    Agoston Mihalik, Fabio S. Ferreira, Michael Moutoussis, Gabriel Ziegler, Rick A. Adams, Maria J. Rosa, Gita Prabhu, Leticia de Oliveira, Mirtes Pereira, Edward T. Bullmore, Peter Fonagy, Ian M. Goodyer, Peter B. Jones, John Shawe-Taylor, Raymond Dolan, Janaina Mourao-Miranda

    Background In 2009, the National Institute of Mental Health launched the Research Domain Criteria (RDoC), an attempt to move beyond diagnostic categories and ground psychiatry within neurobiological constructs that combine different levels of measures (e.g. brain imaging and behaviour). Statistical methods that can integrate such multimodal data are often vulnerable to overfitting, poor generalization and difficulties in interpreting the results, however. Methods We propose an innovative machine learning framework combining multiple hold-outs and a stability criterion with regularized multivariate techniques, such as Sparse Partial Least Squares (SPLS) and Kernel Canonical Correlation Analysis (KCCA), for identifying hidden dimensions of cross-modality relationships. To illustrate the approach, we investigate structural brain-behaviour associations in an extensively phenotyped developmental sample of 345 participants (312 healthy, 33 clinically depressed). The brain data consisted of whole-brain voxel-based grey matter volumes, the behavioural data included item-level self-report questionnaires, IQ and demographic measures. Results SPLS and KCCA both captured two hidden dimensions of brain-behaviour relationships: one related to age and drinking and the other one to depression. The applied machine learning framework indicates that these results are stable and generalize well to new data. Indeed, the identified brain-behaviour associations are in agreement with previous findings in the literature concerning age, alcohol use and depression-related changes in brain volume. Conclusion Multivariate techniques (such as SPLS and KCCA) embedded in our novel framework are promising tools to link behaviour and/or symptoms to neurobiology, and thus have great potential to contribute to a biologically grounded definition of psychiatric disorders.

  • Retrieval-Driven Hippocampal NPTX2 Plasticity Facilitates the Extinction of Cocaine-Associated Context Memory
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-12-10
    Zhilin Wang, Tao Jin, Qiumin Le, Cao Liu, Xueying Wang, Feifei Wang, Lan Ma

    Background Postretrieval extinction attenuates the pathological memory associated with psychiatric states such as drug addiction in both humans and rodents. The extinction of a learned response requires gene transcription and protein synthesis after memory retrieval in a time-dependent manner, yet the precise physiological basis after retrieval to allow extinction to neutralize a learned behavior is not fully understood. Methods In a cocaine conditioned place preference paradigm, we used a ribosomal tagging strategy to measure the translational state of hippocampal pyramidal neurons after the retrieval of cocaine-associated context memory. Using approaches of electrophysiology, neuronal tracing, and a doxycycline-dependent robust activity marking system, we investigated the cellular and molecular basis of retrieval-induced plasticity that facilitated the extinction. Results Bioinformatics analysis discovered the specific translational regulation of signaling pathways by retrieval and revealed Nptx2 as the hub gene. Manipulating Nptx2 in dorsal hippocampus bidirectionally regulated the extinction of cocaine-associated context memory as well as the retrieval-driven synaptic remodeling. The pentraxin (PTX) domain of NPTX2 recruited GluA1-AMPA receptors and enhanced the extinction and excitatory synaptic transmission that was prevented by overexpressing carboxyl cytoplasmic tail of GluA1. Furthermore, Nptx2 in retrieval-activated neurons was required for the extinction. Conclusions The retrieval-driven upregulation of Nptx2 contributes to the synaptic remodeling in dorsal hippocampus and facilitates the extinction of cocaine-associated context memory, indicating a potential target for the treatment of cue-induced cocaine seeking.

  • Epigenetic Mechanisms of Opioid Addiction
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-07-08
    Caleb J. Browne, Arthur Godino, Marine Salery, Eric J. Nestler

    Opioid use kills tens of thousands of Americans each year, devastates families and entire communities, and cripples the health care system. Exposure to opioids causes long-term changes to brain regions involved in reward processing and motivation, leading vulnerable individuals to engage in pathological drug seeking and drug taking that can remain a lifelong struggle. The persistence of these neuroadaptations is mediated in part by epigenetic remodeling of gene expression programs in discrete brain regions. Although the majority of work examining how epigenetic modifications contribute to addiction has focused on psychostimulants such as cocaine, research into opioid-induced changes to the epigenetic landscape is emerging. This review summarizes our knowledge of opioid-induced epigenetic modifications and their consequential changes to gene expression. Current evidence points toward opioids promoting higher levels of permissive histone acetylation and lower levels of repressive histone methylation as well as alterations to DNA methylation patterns and noncoding RNA expression throughout the brain’s reward circuitry. Additionally, studies manipulating epigenetic enzymes in specific brain regions are beginning to build causal links between these epigenetic modifications and changes in addiction-related behavior. Moving forward, studies must leverage advanced chromatin analysis and next-generation sequencing approaches combined with bioinformatics pipelines to identify novel gene networks regulated by particular epigenetic modifications. Improved translational relevance also requires increased focus on volitional drug-intake models and standardization of opioid exposure paradigms. Such work will significantly advance our understanding of how opioids cause persistent changes to brain function and will provide a platform on which to develop interventions for treating opioid addiction.

  • The Opioid-Addicted Tetrapartite Synapse
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-06-13
    Anna Kruyer, Vivian C. Chioma, Peter W. Kalivas

    Opioid administration in preclinical models induces long-lasting adaptations in reward and habit circuitry. The latest research demonstrates that in the nucleus accumbens, opioid-induced excitatory synaptic plasticity involves presynaptic and postsynaptic elements as well as adjacent astroglial processes and the perisynaptic extracellular matrix. We outline opioid-induced modifications within each component of the tetrapartite synapse and provide a neurobiological perspective on how these adaptations converge to produce addiction-related behaviors in rodent models. By incorporating changes observed at each of the excitatory synaptic compartments into a unified framework of opioid-induced glutamate dysregulation, we highlight new avenues for restoring synaptic homeostasis that might limit opioid craving and relapse vulnerability.

  • Neurobiology of Opioid Addiction: Opponent Process, Hyperkatifeia, and Negative Reinforcement
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-06-12
    George F. Koob

    Opioids are powerful drugs that usurp and overpower the reward function of endogenous opioids and engage dramatic tolerance and withdrawal via molecular and neurocircuitry neuroadaptations within the same reward system. However, they also engage the brain systems for stress and pain (somatic and emotional) while producing hyperalgesia and hyperkatifeia, which drive pronounced drug-seeking behavior via processes of negative reinforcement. Hyperkatifeia (derived from the Greek “katifeia” for dejection or negative emotional state) is defined as an increase in intensity of the constellation of negative emotional or motivational signs and symptoms of withdrawal from drugs of abuse. In animal models, repeated extended access to drugs or opioids results in negative emotion-like states, reflected by the elevation of reward thresholds, lower pain thresholds, anxiety-like behavior, and dysphoric-like responses. Such negative emotional states that drive negative reinforcement are hypothesized to derive from the within-system dysregulation of key neurochemical circuits that mediate incentive-salience and/or reward systems (dopamine, opioid peptides) in the ventral striatum and from the between-system recruitment of brain stress systems (corticotropin-releasing factor, dynorphin, norepinephrine, hypocretin, vasopressin, glucocorticoids, and neuroimmune factors) in the extended amygdala. Hyperkatifeia can extend into protracted abstinence and interact with learning processes in the form of conditioned withdrawal to facilitate relapse to compulsive-like drug seeking. Compelling evidence indicates that plasticity in the brain pain emotional systems is triggered by acute excessive drug intake and becomes sensitized during the development of compulsive drug taking with repeated withdrawal. It then persists into protracted abstinence and contributes to the development and persistence of compulsive opioid-seeking behavior.

  • The Mesolimbic Dopamine System in Chronic Pain and Associated Affective Comorbidities
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-12-02
    Randal A. Serafini, Kerri D. Pryce, Venetia Zachariou

    Chronic pain is a complex neuropsychiatric disorder characterized by sensory, cognitive, and affective symptoms. Over the past 2 decades, researchers have made significant progress toward understanding the impact of mesolimbic dopamine circuitry in acute and chronic pain. These efforts have provided insights into the circuits and intracellular pathways in the brain reward center that are implicated in sensory and affective manifestations of chronic pain. Studies have also identified novel therapeutic targets as well as factors that affect treatment responsiveness. Dysregulation of dopamine function in the brain reward center may further promote comorbid mood disorders and vulnerability to addiction. This review discusses recent clinical and preclinical findings on the neuroanatomical and neurochemical adaptations triggered by prolonged pain states in the brain reward pathway. Furthermore, this discussion highlights evidence of mechanisms underlying comorbidities among pain, depression, and addiction.

  • Capturing Novel Non-opioid Pain Targets
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-06-29
    Clifford J. Woolf

    The relatively high efficacy of opioids, which have associated risks of addiction, tolerance, and dependence, for the management of acute and terminal pain has been a major driver of the opioid crisis, together with the availability, overprescription, and diversion of these drugs. Eliminating opioids without an effective replacement is, however, no solution, as it substitutes one major problem with another. To deal successfully with the opioid crisis, we need to discover novel analgesics whose mechanisms do not involve the mu opioid receptor but that have high analgesic potency and low risk of adverse effects, particularly no abuse liability. The question is how to achieve this. There are several necessary elements; first, we need to understand the nature of pain and the mechanisms responsible for it, and second, we need to adopt novel and unbiased approaches to the identification and validation of pain targets.

  • Medication Treatment of Opioid Use Disorder
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-07-02
    James Bell, John Strang

    Opioid use disorder (OUD) is a chronic, relapsing condition, often associated with legal, interpersonal, and employment problems. Medications demonstrated to be effective for OUD are methadone (a full opioid agonist), buprenorphine (a partial agonist), and naltrexone (an opioid antagonist). Methadone and buprenorphine act by suppressing opioid withdrawal symptoms and attenuating the effects of other opioids. Naltrexone blocks the effects of opioid agonists. Oral methadone has the strongest evidence for effectiveness. Longer duration of treatment allows restoration of social connections and is associated with better outcomes. Treatments for OUD may be limited by poor adherence to treatment recommendations and by high rates of relapse and increased risk of overdose after leaving treatment. Treatment with methadone and buprenorphine has the additional risk of diversion and misuse of medication. New depot and implant formulations of buprenorphine and naltrexone have been developed to address issues of safety and problems of poor treatment adherence. For people with OUD who do not respond to these treatments, there is accumulating evidence for supervised injectable opioid treatment (prescribing pharmaceutical heroin). Another medication mode of minimizing risk of overdose is take-home naloxone. Naloxone is an opioid antagonist used to reverse opioid overdose, and take-home naloxone programs aim to prevent fatal overdose. All medication-assisted treatment is limited by lack of access and by stigma. In seeking to stem the rising toll from OUD, expanding access to approved treatment such as methadone, for which there remains the best evidence of efficacy, may be the most useful approach.

  • Peripheral blood cell-stratified subgroups of inflamed depression
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-12-02
    Mary-Ellen Lynall, Lorinda Turner, Junaid Bhatti, Jonathan Cavanagh, Peter de Boer, Valeria Mondelli, Declan Jones, Wayne C. Drevets, Philip Cowen, Neil A. Harrison, Carmine M. Pariante, Linda Pointon, Menna R. Clatworthy, Edward Bullmore

    Background Depression has been associated with increased inflammatory proteins but changes in circulating immune cells are less well defined. Methods We used multi-parametric flow cytometry to count 14 subsets of peripheral blood cells in 206 cases of depression and 77 age- and sex-matched controls (total N = 283). We used univariate and multivariate analyses to investigate the immunophenotypes associated with depression and depression severity. Results Depressed cases, compared to controls, had significantly increased immune cell counts, especially neutrophils, CD4+ T cells and monocytes, and increased inflammatory proteins (C-reactive protein, CRP, and interleukin-6, IL-6). Within-group analysis of cases demonstrated significant associations between the severity of depressive symptoms and increased myeloid and CD4+ T cell counts. Depressed cases were partitioned into two subgroups by forced binary clustering of cell counts: the inflamed depression subgroup (N=81 out of 206; 39%) had increased monocyte, CD4+ and neutrophil counts, increased CRP and IL-6, and was more depressed than the uninflamed majority of cases. Relaxing the presumption of a binary classification, data-driven analysis identified four subgroups of depressed cases: two of which (N=38 and N=100; 67% collectively) were associated with increased inflammatory proteins and more severe depression, but differed in terms of myeloid and lymphoid cell counts. Results were robust to potentially confounding effects of age, sex, body mass index, recent infection, and tobacco use. Conclusions Peripheral immune cell counts were used to distinguish inflamed and uninflamed subgroups of depression and to indicate that there may be mechanistically distinct subgroups of inflamed depression.

  • Identification of genetic loci shared between ADHD, intelligence and educational attainment
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-11-29
    Kevin S. O’Connell, Alexey Shadrin, Olav B. Smeland, Shahram Bahrami, Oleksandr Frei, Francesco Bettella, Florian Krull, Chun C. Fan, Ragna B. Askeland, Gun Peggy S. Knudsen, Anne Halmøy, Nils Eiel Steen, Torill Ueland, G. Bragi Walters, Katrín Davíðsdóttir, Gyða S. Haraldsdóttir, Ólafur Ó. Guðmundsson, Hreinn Stefánsson, Ole A. Andreassen

    Background Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder which is consistently associated with lower levels of educational attainment. A recent large genome-wide association study (GWAS) identified common gene variants associated with ADHD, but most of the genetic architecture remains unknown. Methods We analyzed independent GWAS summary statistics for ADHD (19,099 cases and 34,194 controls), educational attainment (EDU) (n = 842,499) and general intelligence (INT) (n = 269,867) using a conditional/conjunctional false discovery rate (condFDR/conjFDR) statistical framework that increases power of discovery by conditioning the FDR on overlapping associations. The genetic variants identified were characterized in terms of function, expression and biological processes. Results We identified 58 LD-independent ADHD-associated loci (condFDR < 0.01), of which 30 are shared between ADHD and EDU or INT (conjFDR < 0.01), and 46 are novel risk loci for ADHD. Conclusions These results expand on previous genetic and epidemiological studies and support the hypothesis of a shared genetic basis between these phenotypes. Although the clinical utility of the identified loci remains to be determined, they can be used as resources to guide future studies aiming to disentangle the complex etiologies of ADHD, educational attainment and general intelligence.

  • Direct septum-hippocampal cholinergic circuit attenuates seizure through driving somatostatin inhibition
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-11-26
    Ying Wang, Yi Wang, Cenglin Xu, Shuang Wang, Na Tan, Cong Chen, Liying Chen, Xiaohua Wu, Fan Fei, Heming Cheng, Wenkai Lin, Yingbei Qi, Bin Chen, Jiao Liang, Junli Zhao, Zhenghao Xu, Yi Guo, Shihong Zhang, Zhong Chen

    Background Previous studies indicated the involvement of cholinergic neurons in seizure, however the specific role of the medial septum (MS)-hippocampus cholinergic circuit in temporal lobe epilepsy (TLE) has not yet been completely elucidated. Methods In the present study, we used magnetic resonance imaging and diffusion tensor imaging to characterize the pathological change of MS-hippocampus circuit in 42 TLE patients, compared with 22 healthy volunteers. Using optogenetics and chemogenetics, combined with in vivo/vitro electrophysiology and retrograde rabies virus tracing, we revealed a direct MS-hippocampus cholinergic circuit that potently attenuates seizure through driving somatostatin inhibition in animal TLE models. Results We found that TLE patients with hippocampal sclerosis showed a decrease of neuronal fiber connectivity of MS-hippocampus compared with healthy people. In the mouse TLE model, MS cholinergic neurons ceased firing during hippocampal seizures. Optogenetic and chemogenetic activation of MS cholinergic neurons (but not glutamatergic or GABAergic neurons) significantly attenuated, while specific inhibition promoted hippocampal seizures. Electrophysiology combined with modified rabies virus tracing studies showed that direct, but not the indirect MS-hippocampal cholinergic projections, mediated the anti-seizure effect by preferentially targeting hippocampal GABAergic neurons. Further, chemogenetic inhibition of hippocampal somatostatin+ rather than parvalbumin+, subtype of GABAergic neurons reversed the anti-seizure effect of MS-hippocampus cholinergic circuit, which was mimicked by activating somatostatin+ neurons. Conclusions These findings underscore the notable anti-seizure role of the direct cholinergic MS-hippocampus circuit in TLE through driving downstream somatostatin effector. This may provide a better understanding of the changes of seizure circuit and the precise spatiotemporal control of epilepsy.

  • CDK5-dependent BAG3 degradation modulates synaptic protein turnover
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-11-21
    Jiechao Zhou, Hei-Man Chow, Yan Liu, Di Wu, Meng Shi, Jieyin Li, Lei Wen, Yuehong Gao, Guimiao Chen, Kai Zhuang, Hui Lin, Guanyun Zhang, Wenting Xie, Huifang Li, Lige Leng, Mengdan Wang, Naizhen Zheng, Hao Sun, Jie Zhang

    Background Synaptic protein dyshomeostasis and functional loss is an early invariant feature of Alzheimer’s disease (AD), yet the unifying etiological pathway remains largely unknown. Knowing that cyclin-dependent kinase 5 (CDK5) plays critical roles in synaptic formation and degeneration, its phosphorylation targets were re-examined in search for candidates with direct global impacts on synaptic protein dynamics, and the associated regulatory network was also analyzed. Methods Quantitative phospho-proteomics and bioinformatics analyses were performed to identify top-ranked candidates. A series of biochemical assays were used to investigate the associated regulatory signaling networks. Histological, electrochemical and behavioral assays were performed in conditional knockout, shRNA-mediated knockdown and AD-related mice models to evaluate its relevance to synaptic homeostasis and functions. Results Among candidates with known implications in synaptic modulations, BCL2-associated athanogene-3 (BAG3) ranked the highest. CDK5-mediated phosphorylation on Ser297/Ser291 (Mouse/Human) destabilized BAG3. Loss of BAG3 unleashed the selective protein degradative function of the HSP70 machinery. In neurons, this resulted in enhanced degradation of a number of glutamatergic synaptic proteins. Conditional neuronal knockout of Bag3 in vivo led to impairment of learning and memory functions. In human AD and related-mouse models, aberrant CDK5-mediated loss of BAG3 yielded similar effects on synaptic homeostasis. Detrimental effects of BAG3 loss on learning and memory functions were confirmed in these mice, and such were reversed by ectopic BAG3 re-expression. Conclusions Our results highlight that neuronal CDK5-BAG3-HSP70 signaling axis plays a critical role in modulating synaptic homeostasis. Dysregulation of the signaling pathway directly contributes to synaptic dysfunction and AD pathogenesis.

  • Dorsal Amygdala Neurotrophin-3 Decreases Anxious Temperament in Primates
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-07-02
    Andrew S. Fox, Tade Souaiaia, Jonathan A. Oler, Rothem Kovner, Jae Mun (Hugo) Kim, Joseph Nguyen, Delores A. French, Marissa K. Riedel, Eva M. Fekete, Matthew R. Rabska, Miles E. Olsen, Ethan K. Brodsky, Andrew L. Alexander, Walter F. Block, Patrick H. Roseboom, James A. Knowles, Ned H. Kalin

    Background An early-life anxious temperament (AT) is a risk factor for the development of anxiety, depression, and comorbid substance abuse. We validated a nonhuman primate model of early-life AT and identified the dorsal amygdala as a core component of AT's neural circuit. Here, we combine RNA sequencing, viral-vector gene manipulation, functional brain imaging, and behavioral phenotyping to uncover AT's molecular substrates. Methods In response to potential threat, AT and brain metabolism were assessed in 46 young rhesus monkeys. We identified AT-related transcripts using RNA-sequencing data from dorsal amygdala tissue (including central nucleus of the amygdala [Ce] and dorsal regions of the basal nucleus). Based on the results, we overexpressed the neurotrophin-3 gene, NTF3, in the dorsal amygdala using intraoperative magnetic resonance imaging–guided surgery (n = 5 per group). Results This discovery-based approach identified AT-related alterations in the expression of well-established and novel genes, including an inverse association between NTRK3 expression and AT. NTRK3 is an interesting target because it is a relatively unexplored neurotrophic factor that modulates intracellular neuroplasticity pathways. Overexpression of the transcript for NTRK3's endogenous ligand, NTF3, in the dorsal amygdala resulted in reduced AT and altered function in AT's neural circuit. Conclusions Together, these data implicate neurotrophin-3/NTRK3 signaling in the dorsal amygdala in mediating primate anxiety. More generally, this approach provides an important step toward understanding the molecular underpinnings of early-life AT and will be useful in guiding the development of treatments to prevent the development of stress-related psychopathology.

  • Angiotensin II Type 2 Receptor–Expressing Neurons in the Central Amygdala Influence Fear-Related Behavior
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-06-17
    Zhe Yu, Adam P. Swiercz, Cassandra M. Moshfegh, Lauren Hopkins, Jan Wiaderkiewicz, Robert C. Speth, Jeanie Park, Paul J. Marvar

    Background The renin-angiotensin system has been implicated in posttraumatic stress disorder; however, the mechanisms responsible for this connection and the therapeutic potential of targeting the renin-angiotensin system in posttraumatic stress disorder remain unknown. Using an angiotensin receptor bacterial artificial chromosome (BAC) and enhanced green fluorescent protein (eGFP) reporter mouse, combined with neuroanatomical, pharmacological, and behavioral approaches, we examined the role of angiotensin II type 2 receptor (AT2R) in fear-related behavior. Methods Dual immunohistochemistry with retrograde labeling was used to characterize AT2R-eGFP+ cells in the amygdala of the AT2R-eGFP-BAC reporter mouse. Pavlovian fear conditioning and behavioral pharmacological analyses were used to demonstrate the effects of AT2R activation on fear memory in male C57BL/6 mice. Results AT2R-eGFP+ neurons in the amygdala were predominantly expressed in the medial amygdala and the medial division of the central amygdala (CeM), with little AT2R-eGFP expression in the basolateral amygdala or lateral division of the central amygdala. Characterization of AT2R-eGFP+ neurons in the CeM demonstrated distinct localization to gamma-aminobutyric acidergic projection neurons. Mice receiving acute intra–central amygdala injections of the selective AT2R agonist compound 21 prior to tests for cued or contextual fear expression displayed less freezing. Retrograde labeling of AT2R-eGFP+ neurons projecting to the periaqueductal gray revealed AT2R-eGFP+ neuronal projections from the CeM to the periaqueductal gray, a key brain structure mediating fear-related freezing. Conclusions These findings suggest that CeM AT2R-expressing neurons can modulate central amygdala outputs that play a role in fear expression, providing new evidence for a novel angiotensinergic circuit in the regulation of fear.

  • Human Extinction Learning Is Accelerated by an Angiotensin Antagonist via Ventromedial Prefrontal Cortex and Its Connections With Basolateral Amygdala
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-07-25
    Feng Zhou, Yayuan Geng, Fei Xin, Jialin Li, Pan Feng, Congcong Liu, Weihua Zhao, Tingyong Feng, Adam J. Guastella, Richard P. Ebstein, Keith M. Kendrick, Benjamin Becker

    Background Deficient extinction learning and threat adaptation in the ventromedial prefrontal cortex (vmPFC)-amygdala circuitry strongly impede the efficacy of exposure-based interventions in anxiety disorders. Recent animal models suggest a regulatory role of the renin-angiotensin system in both these processes. Against this background, the present randomized placebo-controlled pharmacologic functional magnetic resonance imaging experiment aimed at determining the extinction enhancing potential of the angiotensin II type 1 receptor antagonist losartan (LT) in humans. Methods Seventy healthy male subjects underwent Pavlovian threat conditioning and received single-dose LT (50 mg) or placebo administration before extinction. Psychophysiological threat reactivity (skin conductance response) and neural activity during extinction served as primary outcomes. Psychophysiological interaction, voxelwise mediation, and novel multivariate pattern classification analyses were used to determine the underlying neural mechanisms. Results LT significantly accelerated the decline of the psychophysiological threat response during within-session extinction learning. On the neural level, the acceleration was accompanied and critically mediated by threat-specific enhancement of vmPFC activation. Furthermore, LT enhanced vmPFC-basolateral amygdala coupling and attenuated the neural threat expression, particularly in the vmPFC, during early extinction. Conclusions Overall the results indicate that LT facilitates within-session threat memory extinction by augmenting threat-specific encoding in the vmPFC and its regulatory control over the amygdala. The findings document a pivotal role of angiotensin regulation of extinction learning in humans and suggest that adjunct LT administration has the potential to facilitate the efficacy of exposure-based interventions in anxiety disorders.

  • Deficient Amygdala Habituation to Threatening Stimuli in Borderline Personality Disorder Relates to Adverse Childhood Experiences
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-06-19
    Edda Bilek, Marlena L. Itz, Gabriela Stößel, Ren Ma, Oksana Berhe, Laura Clement, Zhenxiang Zang, Lydia Robnik, Michael M. Plichta, Corinne Neukel, Christian Schmahl, Peter Kirsch, Andreas Meyer-Lindenberg, Heike Tost

    Background Heightened amygdala response to threatening cues has been repeatedly observed in borderline personality disorder (BPD). A previous report linked hyperactivation to deficient amygdala habituation to repeated stimuli, but the biological underpinnings are incompletely understood. Methods We examined a sample of 120 patients with BPD and 115 healthy control subjects with a well-established functional magnetic resonance imaging emotional face processing task to replicate the previously reported amygdala habituation deficit in BPD and probed this neural phenotype for associations with symptom severity and early social risk exposure. Results Our results confirm a significant reduction in amygdala habituation to repeated negative stimuli in BPD (pFWE = .015, peak-level familywise error [FWE] corrected for region of interest). Post hoc comparison and regression analysis did not suggest a role for BPD clinical state (pFWE > .56) or symptom severity (pFWE > .45) for this phenotype. Furthermore, deficient amygdala habituation was significantly related to increased exposure to adverse childhood experiences (pFWE = .013, region of interest corrected). Conclusions Our data replicate a prior report on deficient amygdala habituation in BPD and link this neural phenotype to early adversity, a well-established social environmental risk factor for emotion dysregulation and psychiatric illness.

  • Socioeconomic Disparities in Chronic Physiologic Stress Are Associated With Brain Structure in Children
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-06-12
    Emily C. Merz, Pooja M. Desai, Elaine A. Maskus, Samantha A. Melvin, Rehan Rehman, Sarah D. Torres, Jerrold Meyer, Xiaofu He, Kimberly G. Noble

    Background Socioeconomic factors have been consistently linked with the structure of children’s hippocampus and anterior cingulate cortex (ACC). Chronic stress—as indexed by hair cortisol concentration—may represent an important mechanism underlying these associations. Here, we examined associations between hair cortisol and children’s hippocampal and ACC structure, including across hippocampal subfields, and whether hair cortisol mediated associations between socioeconomic background (family income-to-needs ratio, parental education) and the structure of these brain regions. Methods Participants were 5- to 9-year-old children (N = 94; 61% female) from socioeconomically diverse families. Parents and children provided hair samples that were assayed for cortisol. High-resolution, T1-weighted magnetic resonance imaging scans were acquired, and FreeSurfer 6.0 was used to compute hippocampal volume and rostral and caudal ACC thickness and surface area (n = 37 with both child hair cortisol and magnetic resonance imaging data; n = 41 with both parent hair cortisol and magnetic resonance imaging data). Results Higher hair cortisol concentration was significantly associated with smaller CA3 and dentate gyrus hippocampal subfield volumes but not with CA1 or subiculum volume. Higher hair cortisol was also associated with greater caudal ACC thickness. Hair cortisol significantly mediated associations between parental education level and CA3 and dentate gyrus volumes; lower parental education level was associated with higher hair cortisol, which in turn was associated with smaller volume in these subfields. Conclusions These findings point to chronic physiologic stress as a potential mechanism through which lower parental education level leads to reduced hippocampal volume. Hair cortisol concentration may be an informative biomarker leading to more effective prevention and intervention strategies aimed at childhood socioeconomic disadvantage.

  • Reconciling Dimensional and Categorical Models of Autism Heterogeneity: a Brain Connectomics & Behavioral Study
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-11-18
    Siyi Tang, Nanbo Sun, Dorothea L. Floris, Xiuming Zhang, Adriana Di Martino, B.T. Thomas Yeo

    Background Heterogeneity in autism spectrum disorder (ASD) has hindered the development of biomarkers, thus motivating subtyping efforts. Most subtyping studies divide ASD individuals into non-overlapping (categorical) subgroups. However, continuous inter-individual variation in ASD suggests the need for a dimensional approach. Methods A Bayesian model was employed to decompose resting-state functional connectivity (RSFC) of ASD individuals into multiple abnormal RSFC patterns, i.e., categorical subtypes henceforth referred to as “factors”. Importantly, the model allowed each individual to express one or more factors to varying degrees (dimensional subtyping). The model was applied to 306 ASD individuals (age 5.2-57 years) from two multisite repositories. Posthoc analyses associated factors with symptoms and demographics. Results Analyses yielded three factors with dissociable whole-brain hypo/hyper RSFC patterns. Most participants expressed multiple (categorical) factors, suggestive of a mosaic of subtypes within individuals. All factors shared abnormal RSFC involving the default network, but the directionality (hypo/hyper RSFC) differed across factors. Factor 1 was associated with core ASD symptoms. Factors 1 and 2 were associated with distinct comorbid symptoms. Older males preferentially expressed factor 3. Factors were robust across control analyses and not associated with IQ, nor head motion. Conclusions There exist at least three ASD factors with dissociable whole-brain RSFC patterns, behaviors and demographics. Heterogeneous default network hypo/hyper RSFC across the factors might explain previously reported inconsistencies. The factors differentiated between core ASD and comorbid symptoms - a less appreciated domain of heterogeneity in ASD. These factors are co-expressed in ASD individuals with different degrees, thus reconciling categorical and dimensional perspectives of ASD heterogeneity.

  • Heroin Cue–Evoked Astrocytic Structural Plasticity at Nucleus Accumbens Synapses Inhibits Heroin Seeking
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-07-08
    Anna Kruyer, Michael D. Scofield, Daniel Wood, Kathryn J. Reissner, Peter W. Kalivas

    Background Opioid addiction is a critical medical and societal problem characterized by vulnerability to relapse. Glutamatergic synapses in the nucleus accumbens regulate the motivation to relapse to opioid use, and downregulation of glutamate transporters on astroglial processes adjacent to accumbens synapses contributes to heroin seeking induced by cues. However, it is not known how astroglial processes themselves respond to heroin cues or if changes in astroglial morphology are necessary for heroin seeking. Methods Male Sprague Dawley rats (n = 62) were trained to self-administer heroin or sucrose and were reinstated by heroin-conditioned or sucrose-conditioned cues. Astroglial proximity to accumbens synapses was estimated using a confocal-based strategy, and the association between digitally isolated astroglia and the presynaptic marker synapsin I was quantified. To determine the functional consequence of astroglial morphological plasticity on cued heroin seeking, a morpholino antisense strategy was used to knock down expression of the actin binding protein ezrin, which is expressed almost exclusively in peripheral astroglial processes in the adult rat brain. Results After heroin extinction, there was an enduring reduction in synaptic proximity by astroglia. Synaptic proximity was restored during 15 minutes of cued heroin seeking but returned to extinction levels by 120 minutes. Extinction from sucrose self-administration and reinstated sucrose seeking induced no changes in astroglial synaptic association. Ezrin knockdown reduced astroglial association with synapses and potentiated cued heroin seeking. Conclusions Cue-induced heroin seeking transiently increased synaptic proximity of accumbens astrocytes. Surprisingly, the reassociation of astroglia with synapses was compensatory, and preventing cue-induced morphological plasticity in astrocytes potentiated heroin seeking.

  • Dopamine D1 and D2 Receptors Differentially Regulate Rac1 and Cdc42 Signaling in the Nucleus Accumbens to Modulate Behavioral and Structural Plasticity After Repeated Methamphetamine Treatment
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-03-15
    Genghong Tu, Li Ying, Liuzhen Ye, Jinlan Zhao, Nuyun Liu, Juan Li, Yutong Liu, Mengjuan Zhu, Yue Wu, Bin Xiao, Huidong Guo, Fukun Guo, Huijun Wang, Lin Zhang, Lu Zhang

    Background Methamphetamine (METH) is a highly addictive psychostimulant that strongly activates dopamine receptor signaling in the nucleus accumbens (NAc). However, how dopamine D1 and D2 receptors (D1Rs and D2Rs, respectively) as well as downstream signaling pathways, such as those involving Rac1 and Cdc42, modulate METH-induced behavioral and structural plasticity is largely unknown. Methods Using NAc conditional D1R and D2R deletion mice, Rac1 and Cdc42 mutant viruses, and a series of behavioral and morphological methods, we assessed the effects of D1Rs and D2Rs on Rac1 and Cdc42 in modulating METH-induced behavioral and structural plasticity in the NAc. Results D1Rs and D2Rs in the NAc consistently regulated METH-induced conditioned place preference, locomotor activation, and dendritic and spine remodeling of medium spiny neurons but differentially regulated METH withdrawal–induced spatial learning and memory impairment and anxiety. Interestingly, Rac1 and Cdc42 signaling were oppositely modulated by METH, and suppression of Rac1 signaling and activation of Cdc42 signaling were crucial to METH-induced conditioned place preference and structural plasticity but not to locomotor activation. D1Rs activated Rac1 and Cdc42 signaling, while D2Rs inhibited Rac1 signaling but activated Cdc42 signaling to mediate METH-induced conditioned place preference and structural plasticity but not locomotor activation. In addition, NAc D1R deletion aggravated METH withdrawal–induced spatial learning and memory impairment by suppressing Rac1 signaling but not Cdc42 signaling, while NAc D2R deletion aggravated METH withdrawal–induced anxiety without affecting Rac1 or Cdc42 signaling. Conclusions D1Rs and D2Rs differentially regulate Rac1 and Cdc42 signaling to modulate METH-induced behavioral plasticity and the structural remodeling of medium spiny neurons in the NAc.

  • Nucleus Accumbens Fast-Spiking Interneurons Constrain Impulsive Action
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-07-10
    Marc T. Pisansky, Emilia M. Lefevre, Cassandra L. Retzlaff, Brian H. Trieu, David W. Leipold, Patrick E. Rothwell

    Background The nucleus accumbens (NAc) controls multiple facets of impulsivity but is a heterogeneous brain region with diverse microcircuitry. Prior literature links impulsive behavior in rodents to gamma-aminobutyric acid signaling in the NAc. Here, we studied the regulation of impulsive behavior by fast-spiking interneurons (FSIs), a strong source of gamma-aminobutyric acid–mediated synaptic inhibition in the NAc. Methods Male and female transgenic mice expressing Cre recombinase in FSIs allowed us to identify these sparsely distributed cells in the NAc. We used a 5-choice serial reaction time task to measure both impulsive action and sustained attention. During the 5-choice serial reaction time task, we monitored FSI activity with fiber photometry calcium imaging and manipulated FSI activity with chemogenetic and optogenetic methodology. We used electrophysiology, optogenetics, and fluorescent in situ hybridization to confirm these methods were robust and specific to FSIs. Results In mice performing the 5-choice serial reaction time task, NAc FSIs showed sustained activity on trials ending with correct responses, but FSI activity declined over time on trials ending with premature responses. The number of premature responses increased significantly after sustained chemogenetic inhibition or temporally delimited optogenetic inhibition of NAc FSIs, without any changes in response latencies or general locomotor activity. Conclusions These experiments provide strong evidence that NAc FSIs constrain impulsive actions, most likely through gamma-aminobutyric acid–mediated synaptic inhibition of medium spiny projection neurons. Our findings may provide insight into the pathophysiology of disorders associated with impulsivity and may inform the development of circuit-based therapeutic interventions.

  • Operant Social Reward Decreases Incubation of Heroin Craving in Male and Female Rats
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-05-30
    Marco Venniro, Trinity I. Russell, Michelle Zhang, Yavin Shaham

    Background We recently reported that operant social choice–induced voluntary abstinence prevents incubation of methamphetamine craving. Here, we determined whether social choice–induced voluntary abstinence would prevent incubation of heroin craving. We also introduce a fully automatic social reward self-administration model that eliminates the intense workload and rat–human interaction of the original semiautomatic model. Methods In experiment 1, we trained male and female rats for social self-administration (6 days) and then for heroin self-administration (12 days). Next, we assessed relapse to heroin seeking after 1 and 15 abstinence days. Between tests, the rats underwent either forced or social choice–induced abstinence. In experiment 2, we developed a fully automatic social self-administration procedure by introducing a screen between the self-administration chamber and the social-peer chamber; the screen allows physical contact but prevents rats from crossing chambers. Next, we compared incubation of craving in rats with a history of standard (no-screen) or automatic (screen) social self-administration and social choice–induced abstinence. Results The time-dependent increase in heroin seeking after cessation of drug self-administration (incubation of craving) was lower after social choice–induced abstinence than after forced abstinence. There were no differences in social self-administration, social choice–induced abstinence, and incubation of craving in rats trained in the standard semiautomatic procedure versus the novel fully automatic procedure. Conclusions Our study demonstrates the protective effect of rewarding social interaction on heroin self-administration and incubation of heroin craving and introduces a fully automatic social self-administration and choice procedure to investigate the role of volitional social interaction in drug addiction and other psychiatric disorders.

  • Neural Response Patterns During Pavlovian-to-Instrumental Transfer Predict Alcohol Relapse and Young Adult Drinking
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-07-11
    Maria Sekutowicz, Matthias Guggenmos, Sören Kuitunen-Paul, Maria Garbusow, Miriam Sebold, Patricia Pelz, Josef Priller, Hans-Ulrich Wittchen, Michael N. Smolka, Ulrich S. Zimmermann, Andreas Heinz, Philipp Sterzer, Katharina Schmack

    Background Pavlovian-to-instrumental transfer (PIT) describes the influence of conditioned stimuli on instrumental behaviors and is discussed as a key process underlying substance abuse. Here, we tested whether neural responses during alcohol-related PIT predict future relapse in alcohol-dependent patients and future drinking behavior in adolescents. Methods Recently detoxified alcohol-dependent patients (n = 52) and young adults without dependence (n = 136) underwent functional magnetic resonance imaging during an alcohol-related PIT paradigm, and their drinking behavior was assessed in a 12-month follow-up. To predict future drinking behavior from PIT activation patterns, we used a multivoxel classification scheme based on linear support vector machines. Results When training and testing the classification scheme in patients, PIT activation patterns predicted future relapse with 71.2% accuracy. Feature selection revealed that classification was exclusively based on activation patterns in medial prefrontal cortex. To probe the generalizability of this functional magnetic resonance imaging–based prediction of future drinking behavior, we applied the support vector machine classifier that had been trained on patients to PIT functional magnetic resonance imaging data from adolescents. An analysis of cross-classification predictions revealed that those young social drinkers who were classified as abstainers showed a greater reduction in alcohol consumption at 12-month follow-up than those classified as relapsers (Δ = −24.4 ± 6.0 g vs. −5.7 ± 3.6 g; p = .019). Conclusions These results suggest that neural responses during PIT could constitute a generalized prognostic marker for future drinking behavior in established alcohol use disorder and in at-risk states.

  • The Kappa Opioid Receptor Is Associated With Naltrexone-Induced Reduction of Drinking and Craving
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-06-08
    Bart de Laat, Alissa Goldberg, Julia Shi, Jeanette M. Tetrault, Nabeel Nabulsi, Ming-Qiang Zheng, Soheila Najafzadeh, Hong Gao, Michael Kapinos, Jim Ropchan, Stephanie S. O’Malley, Yiyun Huang, Evan D. Morris, Suchitra Krishnan-Sarin

    Background Naltrexone is a nonselective opioid receptor antagonist used as a treatment for alcohol use disorder. However, only modest clinical effects have been observed, possibly because of limited knowledge about the biological variables affecting the efficacy of naltrexone. We investigated the potential role of the kappa opioid receptor (KOR) in the therapeutic effect of naltrexone. Methods A total of 48 non-treatment-seeking heavy drinkers (16 women) who met DSM-IV criteria for alcohol dependence participated in two alcohol drinking paradigms (ADPs) separated by a week of open-label naltrexone (100 mg daily). Craving, assessed with the Alcohol Urge Questionnaire and the Yale Craving Scale, and drinking behavior were recorded in each ADP. Prior to naltrexone initiation, KOR availability was determined in the amygdala, hippocampus, pallidum, striatum, cingulate cortex, and prefrontal cortex using positron emission tomography with [11C]LY2795050. Results Participants reported lower levels of craving (Yale Craving Scale: −11 ± 1, p < .0001; Alcohol Urge Questionnaire: −6 ± 0.6, p < .0001) and consumed fewer drinks (−3.7 ± 4, p < .0001) during the second ADP following naltrexone therapy. The observed reduction in drinking was negatively associated with baseline KOR availability in the striatum (p = .005), pallidum (p = .023), and cingulate cortex (p = .018). Voxelwise analysis identified clusters in the bilateral insula, prefrontal, and cingulate cortex associated with the reduction in drinking (p < .0001). In addition, KOR availability in all evaluated brain regions was associated with craving measured in both ADPs. Conclusions The KOR is implicated in drinking and craving following naltrexone therapy in alcohol use disorder.

  • A pattern of cognitive deficits stratified for gene-and-environment risk reliably classifies patients with schizophrenia from healthy controls
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-11-15
    Linda A. Antonucci, Giulio Pergola, Alessandro Pigoni, Dominic Dwyer, Lana Kambeitz-Ilankovic, Nora Penzel, Raffaella Romano, Barbara Gelao, Silvia Torretta, Antonio Rampino, Maria Trojano, Grazia Caforio, Peter Falkai, Giuseppe Blasi, Nikolaos Koutsouleris, Alessandro Bertolino

    Background Schizophrenia risk is associated with both genetic and environmental risk factors. Furthermore, cognitive abnormalities are established core characteristics of schizophrenia. We aim to assess whether a classification approach encompassing risk factors, cognition and their associations can discriminate patients (SCZ) from healthy controls (HC). We hypothesized that cognition would demonstrate greater HC-SCZ classification accuracy, and that combined gene-environment stratification would improve the discrimination performance of cognition. Methods GWAS-based genetic, environmental, and neurocognitive classifiers were trained to separate 337 HC from 103 SCZ using support vector classification and repeated nested cross-validation. We validated classifiers on independent datasets using within-diagnostic (SCZ) and cross-diagnostic (Clinically Isolated Syndrome for Multiple Sclerosis – CIS, another condition with cognitive abnormalities) approaches. Then, we tested whether gene-and-environment multivariate stratification modulated the discrimination performance of the cognitive classifier in iterative subsamples. Results The cognitive classifier discriminated SCZ from HC with a Balanced Accuracy (BAC) of 88.7%, followed by environmental (BAC= 65.1%) and genetic classifiers (BAC=55.5%). Similar classification performance was measured in the within-diagnosis validation sample (HC-SCZ BACs, cognition=70.5%; environment=65.8%; genetics=49.9%). The cognitive classifier was relatively specific to schizophrenia (HC-CIS BAC=56.7%). Combined gene-environment stratification allowed cognitive features to classify HC from SCZ with 89.4% BAC. Conclusion Consistent with cognitive deficits being core features of the phenotype of SCZ, our results suggest that cognitive features alone bear the greatest amount of information for SCZ classification. Consistent with their being risk factors, gene-environment stratification modulates HC-SCZ classification performance of cognition, perhaps providing another target for refining early identification and intervention strategies.

  • Anticipatory Threat Responding: Associations with Anxiety, Development, and Brain Structure
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-11-15
    Rany Abend, Andrea L. Gold, Jennifer C. Britton, Kalina J. Michalska, Tomer Shechner, Jessica F. Sachs, Anderson M. Winkler, Ellen Leibenluft, Bruno B. Averbeck, Daniel S. Pine

    Background While translational theories link neurodevelopmental changes in threat learning to pathological anxiety, findings from studies in patients inconsistently support these theories. This may reflect difficulties in studying large patient samples with wide age-ranges using consistent methods. A dearth of imaging data in patients further limits translational advances. We address these gaps through a psychophysiology and structural brain imaging study in a large sample of patients across the lifespan. Methods A total of 351 participants (age 8-50 years; 209 females; 195 healthy participants and 156 medication-free, treatment-seeking anxious patients) completed a differential threat conditioning and extinction paradigm that has been validated in pediatric and adult populations. Skin conductance response indexed psychophysiological responding to conditioned (CS-, CS+) and unconditioned (UCS) threat stimuli. Structural magnetic resonance imaging data were available for 250 participants. Analyses tested anxiety and age associations with psychophysiological responding, as well as associations between psychophysiology and brain structure. Results Regardless of age, patients and healthy comparisons demonstrated comparable differential threat conditioning and extinction. Magnitude of skin-conductance responding to both CS types differentiated patients from comparisons and covaried with dorsal prefrontal cortical thickness; structure-response associations were moderated by anxiety and age in several regions. Unconditioned responding was unrelated to anxiety and brain structure. Conclusions Rather than impaired threat learning, pathological anxiety involves heightened skin-conductance response to potential but not immediately-present threats; this anxiety-related potentiation of anticipatory responding also relates to variation in brain structure. These findings inform theoretical considerations by highlighting anticipatory responding to potential threat in anxiety.

  • Posttraumatic stress disorder and inflammation: untangling issues of bidirectionality
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-11-14
    Jennifer A. Sumner, Kristen M. Nishimi, Karestan C. Koenen, Andrea L. Roberts, Laura D. Kubzansky

    Posttraumatic stress disorder (PTSD) has increasingly been linked to heightened systemic inflammation. Whether this association is causal and either bidirectional or unidirectional, or correlational matters. Investigators have hypothesized that chronic systemic low-grade inflammation may contribute to greater risk of developing PTSD after experiencing trauma and/or serve as a mechanism linking PTSD to adverse physical health outcomes. However, if the PTSD-inflammation relation is correlational, it may not warrant further research aimed at understanding inflammation as a PTSD risk factor or as a pathway linking PTSD with poor health. In this review, first we assess the longitudinal evidence related to PTSD and inflammation to understand more clearly the directionality and causal nature of this relation. Overall, few longitudinal studies rigorously assess the direction of the PTSD-inflammation relation. Some of the evidence indicates elevated inflammation assessed pre-trauma or in the acute aftermath of trauma increases risk for developing PTSD. Fewer studies evaluate the influence of PTSD on subsequent inflammation levels, and findings are mixed. Sample characteristics and study designs, and also type of inflammation-related measure, vary widely across studies. Based on current evidence, we then recommend several statistical and study design approaches that may help untangle issues of bidirectionality and aid in determining the direction of causality between PTSD and inflammation. Finally, we conclude with future research directions and consider potential implications for interventions or treatment approaches based on this growing body of literature.

  • Prefrontal regulation of punished ethanol self-administration
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-11-13
    Lindsay R. Halladay, Adrina Kocharian, Patrick T. Piantadosi, Michael E. Authement, Abby G. Lieberman, Nathen A. Spitz, Kendall Coden, Lucas R. Glover, Vincent D. Costa, Veronica A. Alvarez, Andrew Holmes

    Background A clinical hallmark of alcohol use disorder (AUD) is persistent drinking despite potential adverse consequences. The ventral (vmPFC) and dorsal (dmPFC) medial prefrontal cortex are positioned to exert top-down control over subcortical regions, such as the nucleus accumbens shell (NAcS) and basolateral amygdala (BLA), which encode positive and negative valence of EtOH-related stimuli. Prior rodent studies have implicated these regions in regulation of punished EtOH self-administration (EtOH-SA). Methods We conducted in vivo electrophysiological recordings in mouse vmPFC and dmPFC to obtain neuronal correlates of footshock-punished EtOH-SA. Ex vivo recordings were performed in NAcS D1-positive MSNs receiving vmPFC input to examine punishment-related plasticity in this pathway. Optogenetic photosilencing was employed to assess the functional contribution of the vmPFC and dmPFC, vmPFC projections to NAcS or BLA, to punished EtOH-SA. Results Punishment reduced EtOH-lever pressing and elicited aborted presses (lever approach followed by rapid retraction). Neurons in vmPFC and dmPFC exhibited phasic firing to EtOH-lever presses and aborts, but only in vmPFC was there a population-level shift in coding from lever presses to aborts with punishment. Closed-loop vmPFC, not dmPFC, photosilencing on a post-punishment probe test negated the reduction in EtOH-lever presses but not aborts. Punishment was associated with altered plasticity at vmPFC inputs to D1-MSNs in NAcS. Photosilencing vmPFC projections to NAcS, not BLA, partially reversed suppression of EtOH-lever presses on probe testing. Conclusions These findings demonstrate a key role for vmPFC in regulating EtOH-SA after punishment, with implications for understanding the neural basis of compulsive drinking in AUDs.

  • A Critical Role of Basolateral Amygdala to Nucleus Accumbens Projection in Sleep Regulation of Reward Seeking
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-11-09
    Yao Wang, Zheng Liu, Li Cai, Rong Guo, Yan Dong, Yanhua H. Huang

    Background Sleep impacts reward-motivated behaviors partly by retuning the brain reward circuits. The nucleus accumbens (NAc) is a reward processing hub sensitive to acute sleep deprivation. Glutamatergic transmission carrying reward-associated signals converges in the NAc and regulates various aspects of reward-motivated behaviors. The basal lateral amygdala projection (BLAp) innervates broad regions of the NAc, and critically regulates reward seeking. Methods Using slice electrophysiology, we measured how acute sleep deprivation alters transmission at BLAp-NAc synapses in male C57BL/6 mice. Moreover, using stabilized step function opsin (SSFO) and DREADDs (Gi) to amplify and reduce transmission, respectively, we tested behavioral consequences following bi-directional manipulations of BLAp-NAc transmission. Results Acute sleep deprivation increased sucrose self-administration in mice, and altered the BLAp-NAc transmission in a topographically specific manner. It selectively reduced glutamate release at rostral BLAp (rBLAp) onto ventral and lateral NAc (vlNAc) synapses, but spared caudal BLAp (cBLAp) onto medial NAc (mNAc) synapses. Furthermore, experimentally facilitating glutamate release at rBLAp-vlNAc synapses suppressed sucrose reward seeking. Conversely, mimicking sleep deprivation-induced reduction of rBLAp-vlNAc transmission increased sucrose reward seeking. Finally, facilitating rBLAp-vlNAc transmission per se did not promote either approach-motivation or aversion. Conclusions Sleep acts on rBLAp-vINAc transmission gain control to regulate established reward seeking, but does not convey approach-motivation or aversion on its own.

  • From signaling molecules to circuits and behaviors: cell-type-specific adaptations to psychostimulant exposure in the striatum
    Biol. Psychiatry (IF 11.501) Pub Date : 2019-11-09
    Marine Salery, Pierre Trifilieff, Jocelyne Caboche, Peter Vanhoutte

    Addiction is characterized by a compulsive pattern of drug seeking and consumption and a high risk of relapse after withdrawal, which are thought to result from persistent adaptations within brain reward circuits. Drugs of abuse increase dopamine (DA) concentration in these brain areas, including the striatum, which shapes an abnormal memory trace of drug consumption that virtually highjacks reward processing. Long-term neuronal adaptations of GABAergic striatal projection neurons (SPN) evoked by drugs of abuse are critical for the development of addiction. These neurons form two mostly segregated populations, depending on the DA receptor they express and their output projections, constituting the so-called direct (D1R-SPN) and indirect (D2R-SPN) pathways. Both SPN subtypes receive converging glutamate inputs from limbic and cortical regions, encoding contextual and emotional information, together with DA that mediates reward prediction and incentive values. DA differentially modulates the efficacy of glutamate synapses onto D1R-SPN and D2R-SPN by recruiting distinct striatal signaling pathways, epigenetic and genetic responses likely involved in the transition from casual drug use to addiction. Herein we focus on recent studies that have assessed psychostimulant-induced alterations in a cell-type-specific manner, from remodeling of input projections to the characterization of specific molecular events in each SPN subtypes and their impact on long-lasting behavioral adaptations. We discuss recent evidence revealing the complex and concerted action of both SPN populations on drug-induced behavioral responses as these studies can contribute to the design of future strategies to alleviate specific behavioral components of addiction.

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上海纽约大学William Glover