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1
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Parker DA, Imes S, Ruban G, Ousley OY, Henshey B, Massa NM, Walker E, Cubells JF, Duncan E. Reduced amplitude and slowed latency of the acoustic startle response in adolescents and adults with 22q11.2 deletion syndrome. Schizophr Res 2024; 269:9-17. [PMID: 38703519 PMCID: PMC11180576 DOI: 10.1016/j.schres.2024.04.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 04/14/2024] [Accepted: 04/27/2024] [Indexed: 05/06/2024]
Abstract
BACKGROUND 22q11.2 deletion syndrome (22q11DS) is one of the most robust genetic predictors of psychosis and other psychiatric illnesses. In this study, we examined 22q11DS subjects' acoustic startle responses (ASRs), which putatively index psychosis risk. Latency of the ASR is a presumptive marker of neural processing speed and is prolonged (slower) in schizophrenia. ASR measures correlate with increased psychosis risk, depend on glutamate and dopamine receptor signaling, and could serve as translational biomarkers in interventions for groups at high psychosis risk. METHODS Startle magnitude, latency, and prepulse inhibition were assessed with a standard acoustic startle paradigm in 31 individuals with 22q11.2DS and 32 healthy comparison (HC) subjects. Surface electrodes placed on participants' orbicularis oculi recorded the electromyographic signal in ASR eyeblinks. Individuals without measurable startle blinks in the initial habituation block were classified as non-startlers. RESULTS Across the startle session, the ASR magnitude was significantly lower in 22q11DS subjects than HCs because a significantly higher proportion of 22q11DS subjects were non-startlers. Latency of the ASR to pulse-alone stimuli was significantly slower in 22q11DS than HC subjects. Due to the overall lower 22q11DS startle response frequency and magnitudes prepulse inhibition could not be analyzed. CONCLUSIONS Reduced magnitude and slow latency of 22q11DS subjects' responses suggest reduced central nervous system and neuronal responsiveness. These findings are consistent with significant cognitive impairments observed in 22q11DS subjects. Further research is needed to untangle the connections among basic neurotransmission dysfunction, psychophysiological responsiveness, and cognitive impairment.
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Affiliation(s)
- David Alan Parker
- Department of Human Genetics, Emory University School of Medicine, United States of America.
| | - Sid Imes
- Department of Human Genetics, Emory University School of Medicine, United States of America
| | - Gabrielle Ruban
- Department of Human Genetics, Emory University School of Medicine, United States of America
| | - Opal Yates Ousley
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, United States of America
| | | | - Nicholas M Massa
- Atlanta Veterans Administration Health Care System, United States of America
| | - Elaine Walker
- Department of Psychology, Emory University, United States of America
| | - Joseph F Cubells
- Department of Human Genetics, Emory Autism Center, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, United States of America
| | - Erica Duncan
- Atlanta Veterans Administration Health Care System and Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, United States of America
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2
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Maćkowiak M. Psychedelics action and schizophrenia. Pharmacol Rep 2023; 75:1350-1361. [PMID: 37899392 PMCID: PMC10661800 DOI: 10.1007/s43440-023-00546-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 10/09/2023] [Accepted: 10/16/2023] [Indexed: 10/31/2023]
Abstract
Psychedelics are compounds acting by serotonin 5-hydroxytryptamine (5-HT)2A receptor activation and induce several behavioral responses. They are of special interest because of their positive effects on neuropsychiatric disorders (depression and posttraumatic stress disorder). However, several findings revealed that some psychedelic actions are similar to symptoms observed in schizophrenia (psychosis, sensorimotor gating impairments, attention, and working memory deficits) which might limit their clinical applications. Psychedelics activate some neurotransmitters, i.e., serotonergic, and glutamatergic, that are also impaired in schizophrenia. Therefore, the neurobiological background of psychedelics and schizophrenia is partially similar. Another important aspect to discuss is the perspective of using psychedelics in schizophrenia therapy. Postmortem studies showed a loss of synapses in schizophrenia, and the positive effects of psychedelics on neuroplasticity (synaptogenesis, neurogenesis, and neuritogenesis) might be essential in the context of schizophrenia therapy. However, because of psychedelics' psychotic action, the recommended doses of psychedelics in schizophrenia treatment are not established, and subpsychedelic dosing or microdosing are considered. Exploratory studies are needed to determine the tolerability of treatment and appropriate dosing regimen. Another therapeutic option is using non-hallucinogenic psychedelic analogs that also induce neuroplastic outcomes but do not have psychotogenic effects. Further preclinical and clinical studies are needed to recognize the potential effectiveness of 5-HT2A agonists in schizophrenia therapy.
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Affiliation(s)
- Marzena Maćkowiak
- Laboratory of Pharmacology and Brain Biostructure, Pharmacology Department, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
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3
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Dixon T, Cadenhead KS. Cannabidiol versus placebo as adjunctive treatment in early psychosis: study protocol for randomized controlled trial. Trials 2023; 24:775. [PMID: 38037108 PMCID: PMC10691114 DOI: 10.1186/s13063-023-07789-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 11/07/2023] [Indexed: 12/02/2023] Open
Abstract
BACKGROUND Psychotic disorders are a leading cause of disability in young adults. Antipsychotics have been the primary intervention for psychosis for over 60 years, and yet, we have made little progress in treating negative symptoms, neurocognition, and functional disability. There is growing evidence that cannabidiol (CBD) is effective in treating positive psychotic symptoms, possibly also negative and neurocognitive symptoms, and moreover is well tolerated compared to other psychotropic medications. Anecdotally, patients participating in the Cognitive Assessment and Risk Evaluation (CARE) Early Psychosis Treatment Program at the University of California, San Diego, are self-administering CBD and report subjective improvement in stress, anxiety, and ability to cope with symptoms. The overarching aim of the trial is to explore the effectiveness of CBD augmentation on symptoms and neurocognition in early psychosis while also exploring the mechanism of action of CBD and predictors of response to treatment. The mechanism by which cannabidiol has a therapeutic effect on psychosis is poorly understood. Recent evidence has suggested that CBD may reduce stress and pro-inflammatory biomarker levels. Endocannabinoids also have powerful roles in eating behavior, reward, and mood, indicating these neurotransmitters may play a role in reducing hyperphagia and metabolic abnormalities that are present early in the course of psychotic illness and exacerbated by antipsychotic medication. The neurophysiological effects of CBD have been studied in animal models of psychosis that show improvements in information processing in response to CBD, but there are no studies in individuals with early psychosis. METHOD A total of 120 individuals in the early stages of psychosis will be randomized to 1000 mg of CBD versus placebo as an adjunct to existing treatment in a 8-week, double-blind superiority randomized control trial. The primary outcome measures are symptoms and neurocognition. DISCUSSION We hypothesized that CBD will improve symptoms and neurocognition as well as secondary outcome measures of neurohormones, inflammation, eating behaviors, and information processing. Importantly, predictors, moderators, and mediators of the CBD effects will be examined. A better understanding of which individuals are likely to respond to CBD can inform treatment planning and personalize treatment. TRIAL REGISTRATION ClinicalTrials.gov NCT04411225. Registered on June 2, 2020.
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Affiliation(s)
- T Dixon
- Department of Psychiatry, University of California San Diego, 9500 Gilman Drive 0810, La Jolla, CA, 92093-0810, USA
| | - K S Cadenhead
- Department of Psychiatry, University of California San Diego, 9500 Gilman Drive 0810, La Jolla, CA, 92093-0810, USA.
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4
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Caballero N, Machiraju S, Diomino A, Kennedy L, Kadivar A, Cadenhead KS. Recent Updates on Predicting Conversion in Youth at Clinical High Risk for Psychosis. Curr Psychiatry Rep 2023; 25:683-698. [PMID: 37755654 PMCID: PMC10654175 DOI: 10.1007/s11920-023-01456-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/05/2023] [Indexed: 09/28/2023]
Abstract
PURPOSE OF REVIEW This review highlights recent advances in the prediction and treatment of psychotic conversion. Over the past 25 years, research into the prodromal phase of psychotic illness has expanded with the promise of early identification of individuals at clinical high risk (CHR) for psychosis who are likely to convert to psychosis. RECENT FINDINGS Meta-analyses highlight conversion rates between 20 and 30% within 2-3 years using existing clinical criteria while research into more specific risk factors, biomarkers, and refinement of psychosis risk calculators has exploded, improving our ability to predict psychotic conversion with greater accuracy. Recent studies highlight risk factors and biomarkers likely to contribute to earlier identification and provide insight into neurodevelopmental abnormalities, CHR subtypes, and interventions that can target specific risk profiles linked to neural mechanisms. Ongoing initiatives that assess longer-term (> 5-10 years) outcome of CHR participants can provide valuable information about predictors of later conversion and diagnostic outcomes while large-scale international biomarker studies provide hope for precision intervention that will alter the course of early psychosis globally.
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Affiliation(s)
- Noe Caballero
- Department of Psychiatry, University of California San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0810, USA
| | - Siddharth Machiraju
- Department of Psychiatry, University of California San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0810, USA
| | - Anthony Diomino
- Department of Psychiatry, University of California San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0810, USA
| | - Leda Kennedy
- Department of Psychiatry, University of California San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0810, USA
| | - Armita Kadivar
- Department of Psychiatry, University of California San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0810, USA
| | - Kristin S Cadenhead
- Department of Psychiatry, University of California San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0810, USA.
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Mouro Ferraz Lima T, Castaldelli-Maia JM, Apter G, Leopoldo K. Neurobiological associations between smoking and internalizing disorders. Int Rev Psychiatry 2023; 35:486-495. [PMID: 38299645 DOI: 10.1080/09540261.2023.2252907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 08/24/2023] [Indexed: 02/02/2024]
Abstract
People with severe mental disorders have a higher mortality rate due to preventable conditions like cardiovascular diseases and respiratory diseases. Nicotine addiction is a preventable risk factor, with tobacco use being twice as high in people with mental disorders. An integrative model that divides mental disorders into externalising, internalising, and thought disorders could be useful for identifying common causalities and risk factors. This review aims to examine the interface between smoking and internalising disorders, specifically schizophrenia, depressive disorders, and anxiety disorders. The review finds that there is a clear association between smoking behaviour and these disorders. Schizophrenia is associated with polymorphisms that result in an imbalance between glutamate and GABA release and abnormalities of dopaminergic pathways. Nicotine improves dopaminergic signalling and balances glutamatergic and GABAergic pathways, improving symptoms and increasing the risk of nicotine dependence. In depressive disorders, smoking is associated with functional changes in brain regions affected by smoking and self-medication. In anxiety disorders, there is a bidirectional relationship with smoking, involving the amygdala and changes in dopaminergic pathways and cortisol production. Smoking poses a threat to people living with psychiatric disorders and calls for further research to assess the interactions between nicotine dependence and internalising and thought disorders.
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Affiliation(s)
| | - João Mauricio Castaldelli-Maia
- Department of Neuroscience, Medical School, FMABC University Center
- Cellule de Recherche Clinique, Groupe Hospitalier du Havre, Le Havre, France
- Department of Psychiatry, Medical School, University of São Paulo, Brazil
| | - Gisèle Apter
- Societé de l'Information Psychiatrique, France
- University of Rouen Normandy, France
| | - Kae Leopoldo
- Department of Psychiatry, Medical School, University of São Paulo, Brazil
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6
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Kaki S, DeRosa H, Timmerman B, Brummelte S, Hunter RG, Kentner AC. Developmental Manipulation-Induced Changes in Cognitive Functioning. Curr Top Behav Neurosci 2023; 63:241-289. [PMID: 36029460 PMCID: PMC9971379 DOI: 10.1007/7854_2022_389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
Schizophrenia is a complex neurodevelopmental disorder with as-yet no identified cause. The use of animals has been critical to teasing apart the potential individual and intersecting roles of genetic and environmental risk factors in the development of schizophrenia. One way to recreate in animals the cognitive impairments seen in people with schizophrenia is to disrupt the prenatal or neonatal environment of laboratory rodent offspring. This approach can result in congruent perturbations in brain physiology, learning, memory, attention, and sensorimotor domains. Experimental designs utilizing such animal models have led to a greatly improved understanding of the biological mechanisms that could underlie the etiology and symptomology of schizophrenia, although there is still more to be discovered. The implementation of the Research and Domain Criterion (RDoC) has been critical in taking a more comprehensive approach to determining neural mechanisms underlying abnormal behavior in people with schizophrenia through its transdiagnostic approach toward targeting mechanisms rather than focusing on symptoms. Here, we describe several neurodevelopmental animal models of schizophrenia using an RDoC perspective approach. The implementation of animal models, combined with an RDoC framework, will bolster schizophrenia research leading to more targeted and likely effective therapeutic interventions resulting in better patient outcomes.
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Affiliation(s)
- Sahith Kaki
- School of Arts and Sciences, Health Psychology Program, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA
| | - Holly DeRosa
- School of Arts and Sciences, Health Psychology Program, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA
- University of Massachusetts Boston, Boston, MA, USA
| | - Brian Timmerman
- Department of Psychology, Wayne State University, Detroit, MI, USA
| | - Susanne Brummelte
- Department of Psychology, Wayne State University, Detroit, MI, USA
- Translational Neuroscience Program, Wayne State University, Detroit, MI, USA
| | | | - Amanda C Kentner
- School of Arts and Sciences, Health Psychology Program, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA.
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7
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Hampel H, Caruso G, Nisticò R, Piccioni G, Mercuri NB, Giorgi FS, Ferrarelli F, Lemercier P, Caraci F, Lista S, Vergallo A. Biological Mechanism-based Neurology and Psychiatry: A BACE1/2 and Downstream Pathway Model. Curr Neuropharmacol 2023; 21:31-53. [PMID: 34852743 PMCID: PMC10193755 DOI: 10.2174/1570159x19666211201095701] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 11/26/2021] [Accepted: 11/28/2021] [Indexed: 02/04/2023] Open
Abstract
In oncology, comprehensive omics and functional enrichment studies have led to an extensive profiling of (epi)genetic and neurobiological alterations that can be mapped onto a single tumor's clinical phenotype and divergent clinical phenotypes expressing common pathophysiological pathways. Consequently, molecular pathway-based therapeutic interventions for different cancer typologies, namely tumor type- and site-agnostic treatments, have been developed, encouraging the real-world implementation of a paradigm shift in medicine. Given the breakthrough nature of the new-generation translational research and drug development in oncology, there is an increasing rationale to transfertilize this blueprint to other medical fields, including psychiatry and neurology. In order to illustrate the emerging paradigm shift in neuroscience, we provide a state-of-the-art review of translational studies on the β-site amyloid precursor protein cleaving enzyme (BACE) and its most studied downstream effector, neuregulin, which are molecular orchestrators of distinct biological pathways involved in several neurological and psychiatric diseases. This body of data aligns with the evidence of a shared genetic/biological architecture among Alzheimer's disease, schizoaffective disorder, and autism spectrum disorders. To facilitate a forward-looking discussion about a potential first step towards the adoption of biological pathway-based, clinical symptom-agnostic, categorization models in clinical neurology and psychiatry for precision medicine solutions, we engage in a speculative intellectual exercise gravitating around BACE-related science, which is used as a paradigmatic case here. We draw a perspective whereby pathway-based therapeutic strategies could be catalyzed by highthroughput techniques embedded in systems-scaled biology, neuroscience, and pharmacology approaches that will help overcome the constraints of traditional descriptive clinical symptom and syndrome-focused constructs in neurology and psychiatry.
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Affiliation(s)
- Harald Hampel
- Sorbonne University, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France
| | | | - Robert Nisticò
- Laboratory of Pharmacology of Synaptic Plasticity, EBRI Rita Levi-Montalcini Foundation, Rome, Italy
- School of Pharmacy, University of Rome “Tor Vergata”, Rome, Italy
| | - Gaia Piccioni
- Laboratory of Pharmacology of Synaptic Plasticity, EBRI Rita Levi-Montalcini Foundation, Rome, Italy
- Department of Physiology and Pharmacology “V.Erspamer”, Sapienza University of Rome, Rome, Italy
| | - Nicola B. Mercuri
- Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy
- IRCCS Santa Lucia Foundation, Rome, Italy
| | - Filippo Sean Giorgi
- Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa, Italy
| | - Fabio Ferrarelli
- Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA
| | - Pablo Lemercier
- Sorbonne University, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France
| | - Filippo Caraci
- Oasi Research Institute-IRCCS, Troina, Italy
- Department of Drug Sciences, University of Catania, Catania, Italy
| | - Simone Lista
- Sorbonne University, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France
- Memory Resources and Research Center (CMRR), Neurology Department, Gui de Chauliac University Hospital, Montpellier, France
| | - Andrea Vergallo
- Sorbonne University, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France
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8
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Oliveras I, Soria-Ruiz OJ, Sampedro-Viana D, Cañete T, Río-Álamos C, Tobeña A, Fernández-Teruel A. Different maturation patterns for sensorimotor gating and startle habituation deficits in male and female RHA vs RLA rats. Behav Brain Res 2022; 434:114021. [PMID: 35872331 DOI: 10.1016/j.bbr.2022.114021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 05/17/2022] [Accepted: 07/19/2022] [Indexed: 11/28/2022]
Abstract
Neurodevelopmental anomalies are thought to play a crucial role in the emergence of schizophrenia. The Roman high-avoidance (RHA) rats exhibit impaired prepulse inhibition (PPI), as well as other behavioral and cognitive singularities related to schizophrenia syndromes compared to the Roman low-avoidance (RLA) rats. In the present study, we aimed at elucidating whether PPI deficits in the RHA rats take place during prepubescence, adolescence, or adulthood. Thus, we evaluated the levels of PPI of both strains and both sexes during these three developmental phases. Additionally, we also investigated the onset of startle habituation deficits in the same groups. The results showed that male RHA rats exhibit a clear-cut PPI reduction compared to their RLA counterparts in adulthood. In female RHA rats, we observed lower levels of PPI since adolescence and through adulthood. We also found no differences between PPI percentages among the three ages in RHA male rats. Contrarily, in male RLA rats, PPI levels were increased in adults compared to their adolescent and prepubescent counterparts. Finally, a deficit in startle habituation was observed in adulthood of both male and female RHA rats, although in the latter case the disturbance in startle habituation was more profound. These results further the description of the maturational trajectory of cognitive markers relevant to schizophrenia prodrome and they add face validity to the RHA rats as a model of schizophrenia-relevant phenotypes.
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Affiliation(s)
- Ignasi Oliveras
- Medical Psychology Unit, Department of Psychiatry and Forensic Medicine & Institute of Neurosciences, School of Medicine, Autonomous University of Barcelona, Bellaterra, Barcelona 08193, Spain.
| | - Oscar J Soria-Ruiz
- Medical Psychology Unit, Department of Psychiatry and Forensic Medicine & Institute of Neurosciences, School of Medicine, Autonomous University of Barcelona, Bellaterra, Barcelona 08193, Spain
| | - Daniel Sampedro-Viana
- Medical Psychology Unit, Department of Psychiatry and Forensic Medicine & Institute of Neurosciences, School of Medicine, Autonomous University of Barcelona, Bellaterra, Barcelona 08193, Spain
| | - Toni Cañete
- Medical Psychology Unit, Department of Psychiatry and Forensic Medicine & Institute of Neurosciences, School of Medicine, Autonomous University of Barcelona, Bellaterra, Barcelona 08193, Spain
| | | | - Adolf Tobeña
- Medical Psychology Unit, Department of Psychiatry and Forensic Medicine & Institute of Neurosciences, School of Medicine, Autonomous University of Barcelona, Bellaterra, Barcelona 08193, Spain
| | - Alberto Fernández-Teruel
- Medical Psychology Unit, Department of Psychiatry and Forensic Medicine & Institute of Neurosciences, School of Medicine, Autonomous University of Barcelona, Bellaterra, Barcelona 08193, Spain.
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9
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Naysmith LF, Kumari V, Williams SCR. Neural mapping of prepulse-induced startle reflex modulation as indices of sensory information processing in healthy and clinical populations: A systematic review. Hum Brain Mapp 2021; 42:5495-5518. [PMID: 34414633 PMCID: PMC8519869 DOI: 10.1002/hbm.25631] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/30/2021] [Accepted: 08/06/2021] [Indexed: 12/18/2022] Open
Abstract
Startle reflex is modulated when a weaker sensory stimulus ("prepulse") precedes a startling stimulus ("pulse"). Prepulse Inhibition (PPI) is the attenuation of the startle reflex (prepulse precedes pulse by 30-500 ms), whereas Prepulse Facilitation (PPF) is the enhancement of the startle reflex (prepulse precedes pulse by 500-6000 ms). Here, we critically appraise human studies using functional neuroimaging to establish brain regions associated with PPI and PPF. Of 10 studies, nine studies revealed thalamic, striatal and frontal lobe activation during PPI in healthy groups, and activation deficits in the cortico-striato-pallido-thalamic circuitry in schizophrenia (three studies) and Tourette Syndrome (two studies). One study revealed a shared network for PPI and PPF in frontal regions and cerebellum, with PPF networks recruiting superior medial gyrus and cingulate cortex. The main gaps in the literature are (i) limited PPF research and whether PPI and PPF operate on separate/shared networks, (ii) no data on sex differences in neural underpinnings of PPI and PPF, and (iii) no data on neural underpinnings of PPI and PPF in other clinical disorders.
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Affiliation(s)
- Laura F. Naysmith
- Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and NeuroscienceKing's College LondonLondonUK
| | - Veena Kumari
- Department of Psychology, Institute of Psychiatry, Psychology and NeuroscienceKing's College LondonLondonUK
- Centre for Cognitive Neuroscience, College of HealthMedicine and Life Sciences, Brunel University LondonUK
| | - Steven C. R. Williams
- Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and NeuroscienceKing's College LondonLondonUK
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10
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Li W, Mao Z, Bo Q, Sun Y, Wang Z, Wang C. Prepulse inhibition in first-degree relatives of schizophrenia patients: A systematic review. Early Interv Psychiatry 2021; 15:652-661. [PMID: 32567764 DOI: 10.1111/eip.13003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 04/15/2020] [Accepted: 05/24/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND Prepulse inhibition (PPI) is a measure of sensorimotor gating used to identify deficits in early-stage information processing and inhibitory function defects. Many studies support the presence of PPI deficits in schizophrenia patients. However, very few studies have explored PPI levels among first-degree relatives (FDR) of schizophrenia patients, and the results have been inconsistent. This review article explored PPI levels in FDR of schizophrenia patients. METHODS We performed a systematic literature review using the PubMed, Cochrane, Embase, EBSCO and Chinese databases from inception to January 2020. A series of related factors (eg, PPI paradigm, heritability and sample characteristics) and outcomes were summarized from the literature that met the inclusion criteria. The Newcastle-Ottawa Scale was used to assess the quality of the included studies. RESULTS A total of eight studies were eligible for systematic review after screening. A meta-analysis of the selected studies was not conducted due to the limitations of quantity and paradigm heterogeneity. A majority of the studies' subjects were siblings of schizophrenia patients and different paradigms were applied. Most of the included studies reported no difference in PPI values between FDR of schizophrenia patients and healthy controls. CONCLUSION Contrary to traditional certainty that unaffected FDR of schizophrenia patients have PPI defects, our review found no sufficient evidence supporting that the PPI level in FDR of schizophrenia patients was lower than in healthy controls. A prospective cohort study focusing on different outcomes such as developing schizophrenia is required to explore PPI levels in FDR of schizophrenia patients.
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Affiliation(s)
- Weidi Li
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China.,Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Zhen Mao
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China.,Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Qijing Bo
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China.,Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Yue Sun
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China.,Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Zhimin Wang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China.,Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Chuanyue Wang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China.,Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
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11
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Interference of commissural connections through the genu of the corpus callosum specifically impairs sensorimotor gating. Behav Brain Res 2021; 411:113383. [PMID: 34048871 DOI: 10.1016/j.bbr.2021.113383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 05/19/2021] [Accepted: 05/22/2021] [Indexed: 11/20/2022]
Abstract
White matter abnormalities in schizophrenic patients are characterized as regional tract-specific. Myelin loss at the genu of the corpus callosum (GCC) is one of the most consistent findings in schizophrenic patients across the different populations. We characterized the axons that pass through the GCC by stereotactically injecting an anterograde axonal tracing viral vector into the forceps minor of the corpus callosum in one hemisphere, and identified the homotopic brain structures that have commissural connections in the two hemispheres of the prefrontal cortex, including the anterior cingulate area, the prelimbic area, the secondary motor area, and the dorsal part of the agranular insular area, along with commissural connections with the primary motor area, caudoputamen, and claustrum. To investigate whether dysmyelination in these commissural connections is critical for the development of schizophrenia symptoms, we generated a mouse model with focal demyelination at the GCC by stereotactically injecting demyelinating agent lysolecithin into this site, and tested these mice in a battery of behavioral tasks that are used to model the schizophrenia-like symptom domains. We found that demyelination at the GCC influenced neither the social interest or mood state, nor the locomotive activity or motor coordination. Nevertheless, it specifically reduced the prepulse inhibition of acoustic startle that is a well-known measure of sensorimotor gating. This study advances our understanding of the pathophysiological contributions of the GCC-specific white matter lesion to the related disease, and demonstrates an indispensable role of interhemispheric communication between the frontal cortices for the top-down regulation of the sensorimotor gating.
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12
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Effects of prepulse format and lead interval on the assessment of automatic and attention-modulated prepulse inhibition. Cogn Process 2021; 22:559-567. [PMID: 33772712 DOI: 10.1007/s10339-021-01023-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 02/25/2021] [Indexed: 10/21/2022]
Abstract
Prepulse inhibition (PPI) of the acoustic startle response can index automatic and attention-modulated aspects of sensorimotor gating. Automatic sensorimotor gating is typically assessed by a no-task PPI protocol in which participants are presented with discrete white noise prepulse and startle stimuli over continuous background broadband noise at brief short-lead intervals (e.g., 60-120 ms). In contrast, attention-modulated sensorimotor gating is typically assessed through a task-based PPI protocol using continuous format pure tone prepulses and white noise startle stimuli presented over an ambient background at a lead interval of 120 ms. The present study sought to test the extent that the assessment of attention-modulated PPI is dependent on prepulse type and lead interval across two experiments. Experiment 1 assessed attention effects on PPI produced by discrete prepulses at lead intervals of 60 and 120 ms. Experiment 2 examined attention effects on PPI with matched stimulus conditions apart from continuous prepulses. Results indicated that the use of discrete prepulses failed to elicit attentional-modulation of PPI and that assessment therein was dependent on the use of continuous prepulses at a lead interval of 120 ms. These results highlight additional methods to concurrently assess automatic and attention-modulated PPI in a single testing session using a task-based tone counting task.
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13
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Banono NS, Gawel K, De Witte L, Esguerra CV. Zebrafish Larvae Carrying a Splice Variant Mutation in cacna1d: A New Model for Schizophrenia-Like Behaviours? Mol Neurobiol 2021; 58:877-894. [PMID: 33057948 PMCID: PMC7843589 DOI: 10.1007/s12035-020-02160-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 10/02/2020] [Indexed: 12/16/2022]
Abstract
Persons with certain single nucleotide polymorphisms (SNPs) in the CACNA1D gene (encoding voltage-gated calcium channel subunit alpha 1-D) have increased risk of developing neuropsychiatric disorders such as bipolar, schizophrenia and autism. The molecular consequences of SNPs on gene expression and protein function are not well understood. Thus, the use of animal models to determine genotype-phenotype correlations is critical to understanding disease pathogenesis. Here, we describe the behavioural changes in larval zebrafish carrying an essential splice site mutation (sa17298) in cacna1da. Heterozygous mutation resulted in 50% reduction of splice variants 201 and 202 (haploinsufficiency), while homozygosity increased transcript levels of variant 201 above wild type (WT; gain-of-function, GOF). Due to low homozygote viability, we focused primarily on performing the phenotypic analysis on heterozygotes. Indeed, cacna1dasa17298/WT larvae displayed hyperlocomotion-a behaviour characterised in zebrafish as a surrogate phenotype for epilepsy, anxiety or psychosis-like behaviour. Follow-up tests ruled out anxiety or seizures, however, as neither thigmotaxis defects nor epileptiform-like discharges in larval brains were observed. We therefore focused on testing for potential "psychosis-like" behaviour by assaying cacna1dasa17298/WT larval locomotor activity under constant light, during light-dark transition and in startle response to dark flashes. Furthermore, exposure of larvae to the antipsychotics, risperidone and haloperidol reversed cacna1da-induced hyperactivity to WT levels while valproate decreased but did not reverse hyperactivity. Together, these findings demonstrate that cacna1da haploinsufficiency induces behaviours in larval zebrafish analogous to those observed in rodent models of psychosis. Future studies on homozygous mutants will determine how cacna1d GOF alters behaviour in this context.
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Affiliation(s)
- Nancy Saana Banono
- Chemical Neuroscience Group, Centre for Molecular Medicine Norway (NCMM), Faculty of Medicine, University of Oslo, Gaustadalléen 21, Forskningsparken, 0349, Oslo, Norway
| | - Kinga Gawel
- Chemical Neuroscience Group, Centre for Molecular Medicine Norway (NCMM), Faculty of Medicine, University of Oslo, Gaustadalléen 21, Forskningsparken, 0349, Oslo, Norway
- Department of Experimental and Clinical Pharmacology, Medical University of Lublin, Jaczewskiego Str. 8b, 20-090, Lublin, Poland
| | - Linus De Witte
- Pharmaceutical and Biological Sciences, AP Hogeschool Antwerpen, Antwerp, Belgium
| | - Camila V Esguerra
- Chemical Neuroscience Group, Centre for Molecular Medicine Norway (NCMM), Faculty of Medicine, University of Oslo, Gaustadalléen 21, Forskningsparken, 0349, Oslo, Norway.
- School of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Sem Sælandsvei 24, 0371, Oslo, Norway.
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San-Martin R, Castro LA, Menezes PR, Fraga FJ, Simões PW, Salum C. Meta-Analysis of Sensorimotor Gating Deficits in Patients With Schizophrenia Evaluated by Prepulse Inhibition Test. Schizophr Bull 2020; 46:1482-1497. [PMID: 32506125 PMCID: PMC8061122 DOI: 10.1093/schbul/sbaa059] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Prepulse inhibition (PPI) of startle is an operational measure of sensorimotor gating that is often impaired in patients with schizophrenia. Despite the large number of studies, there is considerable variation in PPI outcomes reported. We conducted a systematic review and meta-analysis investigating PPI impairment in patients with schizophrenia compared with healthy control subjects, and examined possible explanations for the variation in results between studies. Major databases were screened for observational studies comparing healthy subjects and patients with schizophrenia for the prepulse and pulse intervals of 60 and 120 ms as primary outcomes, ie, PPI-60 and PPI-120. Standardized mean difference (SMD) and 95% confidence intervals (CI) were extracted and pooled using random effects models. We then estimated the mean effect size of these measures with random effects meta-analyses and evaluated potential PPI heterogeneity moderators, using sensitivity analysis and meta-regressions. Sixty-seven primary studies were identified, with 3685 healthy and 4290 patients with schizophrenia. The schizophrenia group showed reduction in sensorimotor gating for both PPI-60 (SMD = -0.50, 95% CI = [-0.61, -0.39]) and PPI-120 (SMD = -0.44, 95% CI = [-0.54, -0.33]). The sensitivity and meta-regression analysis showed that sample size, gender proportion, imbalance for gender, source of control group, and study continent were sources of heterogeneity (P < .05) for both PPI-60 and PPI-120 outcomes. Our findings confirm a global sensorimotor gating deficit in schizophrenia patients, with overall moderate effect size for PPI-60 and PPI-120. Methodological consistency should decrease the high level of heterogeneity of PPI results between studies.
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Affiliation(s)
- Rodrigo San-Martin
- Center for Mathematics, Computation and Cognition, Universidade Federal do ABC, Santo André, Brazil
| | - Leonardo Andrade Castro
- Center for Mathematics, Computation and Cognition, Universidade Federal do ABC, Santo André, Brazil
| | - Paulo Rossi Menezes
- Department of Preventive Medicine, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
- Population Mental Health Research Center, Universidade de São Paulo, São Paulo, Brazil
| | - Francisco José Fraga
- Engineering, Modeling and Applied Social Sciences Center, Universidade Federal do ABC, Santo André, Brazil
| | - Priscyla Waleska Simões
- Engineering, Modeling and Applied Social Sciences Center, Universidade Federal do ABC, Santo André, Brazil
| | - Cristiane Salum
- Center for Mathematics, Computation and Cognition, Universidade Federal do ABC, Santo André, Brazil
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15
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Rovný R, Besterciová D, Riečanský I. Genetic Determinants of Gating Functions: Do We Get Closer to Understanding Schizophrenia Etiopathogenesis? Front Psychiatry 2020; 11:550225. [PMID: 33324248 PMCID: PMC7723973 DOI: 10.3389/fpsyt.2020.550225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 10/12/2020] [Indexed: 11/13/2022] Open
Abstract
Deficits in the gating of sensory stimuli, i.e., the ability to suppress the processing of irrelevant sensory input, are considered to play an important role in the pathogenesis of several neuropsychiatric disorders, in particular schizophrenia. Gating is disrupted both in schizophrenia patients and their unaffected relatives, suggesting that gating deficit may represent a biomarker associated with a genetic liability to the disorder. To assess the strength of the evidence for the etiopathogenetic links between genetic variation, gating efficiency, and schizophrenia, we carried out a systematic review of human genetic association studies of sensory gating (suppression of the P50 component of the auditory event-related brain potential) and sensorimotor gating (prepulse inhibition of the acoustic startle response). Sixty-three full-text articles met the eligibility criteria for inclusion in the review. In total, 117 genetic variants were reported to be associated with gating functions: 33 variants for sensory gating, 80 variants for sensorimotor gating, and four variants for both sensory and sensorimotor gating. However, only five of these associations (four for prepulse inhibition-CHRNA3 rs1317286, COMT rs4680, HTR2A rs6311, and TCF4 rs9960767, and one for P50 suppression-CHRNA7 rs67158670) were consistently replicated in independent samples. Although these variants and genes were all implicated in schizophrenia in research studies, only two polymorphisms (HTR2A rs6311 and TCF4 rs9960767) were also reported to be associated with schizophrenia at a meta-analytic or genome-wide level of evidence. Thus, although gating is widely considered as an important endophenotype of schizophrenia, these findings demonstrate that evidence for a common genetic etiology of impaired gating functions and schizophrenia is yet unsatisfactory, warranting further studies in this field.
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Affiliation(s)
- Rastislav Rovný
- Department of Behavioural Neuroscience, Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Dominika Besterciová
- Department of Behavioural Neuroscience, Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Igor Riečanský
- Department of Behavioural Neuroscience, Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
- Social, Cognitive and Affective Neuroscience Unit, Department of Cognition, Emotion, and Methods in Psychology, Faculty of Psychology, University of Vienna, Vienna, Austria
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16
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Greenwood TA, Swerdlow NR, Sprock J, Calkins ME, Freedman R, Green MF, Gur RE, Gur RC, Lazzeroni LC, Light GA, Nuechterlein KH, Radant AD, Silverman JM, Stone WS, Sugar CA, Tsuang DW, Tsuang MT, Turetsky BI, Braff DL, Duncan E. Heritability of acoustic startle magnitude and latency from the consortium on the genetics of schizophrenia. Schizophr Res 2020; 224:33-39. [PMID: 33189519 PMCID: PMC7728376 DOI: 10.1016/j.schres.2020.11.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 09/18/2020] [Accepted: 11/02/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND Latency of the acoustic startle reflex is the time from presentation of the startling stimulus until the response, and provides an index of neural processing speed. Schizophrenia subjects exhibit slowed latency compared to healthy controls. One prior publication reported significant heritability of latency. The current study was undertaken to replicate and extend this solitary finding in a larger cohort. METHODS Schizophrenia probands, their relatives, and control subjects from the Consortium on the Genetics of Schizophrenia (COGS-1) were tested in a paradigm to ascertain magnitude, latency, and prepulse inhibition of startle. Trial types in the paradigm were: pulse-alone, and trials with 30, 60, or 120 ms between the prepulse and pulse. Comparisons of subject groups were conducted with ANCOVAs to assess startle latency and magnitude. Heritability of startle magnitude and latency was analyzed with a variance component method implemented in SOLAR v.4.3.1. RESULTS 980 subjects had analyzable startle results: 199 schizophrenia probands, 456 of their relatives, and 325 controls. A mixed-design ANCOVA on startle latency in the four trial types was significant for subject group (F(2,973) = 4.45, p = 0.012) such that probands were slowest, relatives were intermediate and controls were fastest. Magnitude to pulse-alone trials differed significantly between groups by ANCOVA (F(2,974) = 3.92, p = 0.020) such that controls were lowest, probands highest, and relatives intermediate. Heritability was significant (p < 0.0001), with heritability of 34-41% for latency and 45-59% for magnitude. CONCLUSION Both startle latency and magnitude are significantly heritable in the COGS-1 cohort. Startle latency is a strong candidate for being an endophenotype in schizophrenia.
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Affiliation(s)
| | - Neal R. Swerdlow
- Department of Psychiatry, University of California San Diego, La Jolla, CA
| | - Joyce Sprock
- Department of Psychiatry, University of California San Diego, La Jolla, CA
| | - Monica E. Calkins
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
| | - Robert Freedman
- Department of Psychiatry, University of Colorado Health Sciences Center, Denver, CO
| | - Michael F. Green
- VA Greater Los Angeles Healthcare System, Los Angeles, CA,Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA
| | - Raquel E. Gur
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
| | - Ruben C. Gur
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
| | - Laura C. Lazzeroni
- Departments of Psychiatry and Behavioral Sciences and of Biomedical Data Science, Stanford University, Stanford, CA,Department of Veterans Affairs Health Care System, Palo Alto, CA
| | - Gregory A. Light
- Department of Psychiatry, University of California San Diego, La Jolla, CA,VISN-22 Mental Illness, Research, Education and Clinical Center (MIRECC), VA San Diego Healthcare System, San Diego, CA
| | - Keith H. Nuechterlein
- Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA
| | - Allen D. Radant
- VA Puget Sound Health Care System, Seattle, WA,Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA
| | - Jeremy M. Silverman
- James J. Peters VA Medical Center, New York, NY,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY
| | - William S. Stone
- Department of Psychiatry, Harvard Medical School, Boston, MA,Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston, MA
| | - Catherine A. Sugar
- Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA,Department of Biostatistics, University of California Los Angeles School of Public Health, Los Angeles, CA
| | - Debby W. Tsuang
- VA Puget Sound Health Care System, Seattle, WA,Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA
| | - Ming T. Tsuang
- Department of Psychiatry, University of California San Diego, La Jolla, CA
| | - Bruce I. Turetsky
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
| | - David L. Braff
- Department of Psychiatry, University of California San Diego, La Jolla, CA
| | - Erica Duncan
- Atlanta Veterans Affairs Healthcare System, Decatur, GA, United States of America; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States of America.
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17
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Cadenhead KS, Duncan E, Addington J, Bearden C, Cannon TD, Cornblatt BA, Mathalon D, McGlashan TH, Perkins DO, Seidman LJ, Tsuang M, Walker EF, Woods SW, Bauchman P, Belger A, Carrión RE, Donkers F, Johannesen J, Light G, Niznikiewicz M, Nunag J, Roach B. Evidence of Slow Neural Processing, Developmental Differences and Sensitivity to Cannabis Effects in a Sample at Clinical High Risk for Psychosis From the NAPLS Consortium Assessed With the Human Startle Paradigm. Front Psychiatry 2020; 11:833. [PMID: 33005152 PMCID: PMC7479820 DOI: 10.3389/fpsyt.2020.00833] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 07/31/2020] [Indexed: 01/19/2023] Open
Abstract
ABSTRACT Biomarkers are important in the study of the prodromal period of psychosis because they can help to identify individuals at greatest risk for future psychotic illness and provide insights into disease mechanism underlying neurodevelopmental abnormalities. The biomarker abnormalities can then be targeted with treatment, with an aim toward prevention or mitigation of disease. The human startle paradigm has been used in translational studies of psychopathology including psychotic illness to assess preattentive information processing for over 50 years. In one of the largest studies to date in clinical high risk (CHR) for psychosis participants, we aimed to evaluate startle indices as biomarkers of risk along with the role of age, sex, treatment, and substance use in this population of high risk individuals. METHODS Startle response reactivity, latency, and prepulse inhibition (PPI) were assessed in 543 CHR and 218 Normal Comparison (NC) participants between the ages of 12 and 35. RESULTS At 1 year follow-up, 58 CHR participants had converted to psychosis. CHR and NC groups did not differ across any of the startle measures but those CHR participants who later converted to psychosis had significantly slower startle latency than did those who did not convert to psychosis, and this effect was driven by female CHR participants. PPI was significantly associated with age in the CHR, but not the NC, participants with the greatest positive age correlations present in those CHR participants who later converted to psychosis, consistent with a prior report. Finally, there was a significant group by cannabis use interaction due to greater PPI in cannabis users and opposite PPI group effects in users (CHR>NC) and non-users (NC>CHR). DISCUSSION This is the first study to demonstrate a relationship of startle response latency to psychotic conversion in a CHR population. PPI is an important biomarker that may be sensitive to the neurodevelopmental abnormalities thought to be present in psychosis prone individuals and the effects of cannabis. The significant correlations with age in this sample as well as the finding of greater PPI in CHR cannabis users replicate findings from another large sample of CHR participants.
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Affiliation(s)
- Kristin S. Cadenhead
- Department of Psychiatry, University of California San Diego (UCSD), La Jolla, CA, United States
| | - Erica Duncan
- Department of Psychiatry, Atlanta Veterans Affairs Healthcare System, Decatur, GA, United States
- Department of Psychiatry, Emory University School of Medicine, Atlanta, GA, United States
| | - Jean Addington
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Carrie Bearden
- Department of Psychiatry and Psychology, University of California Los Angeles (UCLA), Los Angeles, CA, United States
| | - Tyrone D. Cannon
- Department of Psychiatry and Psychology, Yale University, New Haven, CT, United States
| | - Barbara A. Cornblatt
- Department of Psychiatry and Psychology, The Feinstein Institute for Medical Research, Manhasset, NY, United States
- Department of Psychology, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, United States
- The Zucker Hillside Hospital, New York, NY, United States
| | - Dan Mathalon
- University of California, San Francisco, San Francisco, CA, United States
- San Francisco VA Medical Center, San Francisco, VA, United States
| | - Thomas H. McGlashan
- Department of Psychiatry and Psychology, Yale University, New Haven, CT, United States
| | - Diana O. Perkins
- Department of Psychology, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, United States
- University of North Carolina (UNC), Chapel Hill, NC, United States
| | - Larry J. Seidman
- Department of Psychiatry, Harvard University, Boston, MA, United States
| | - Ming Tsuang
- Department of Psychiatry, University of California San Diego (UCSD), La Jolla, CA, United States
| | - Elaine F. Walker
- Department of Psychiatry, Atlanta Veterans Affairs Healthcare System, Decatur, GA, United States
| | - Scott W. Woods
- Department of Psychiatry and Psychology, Yale University, New Haven, CT, United States
| | - Peter Bauchman
- San Francisco VA Medical Center, San Francisco, VA, United States
| | - Ayse Belger
- University of North Carolina (UNC), Chapel Hill, NC, United States
| | - Ricardo E. Carrión
- Department of Psychiatry and Psychology, The Feinstein Institute for Medical Research, Manhasset, NY, United States
- Department of Psychology, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, United States
- The Zucker Hillside Hospital, New York, NY, United States
| | - Franc Donkers
- University of North Carolina (UNC), Chapel Hill, NC, United States
| | - Jason Johannesen
- Department of Psychiatry and Psychology, Yale University, New Haven, CT, United States
| | - Gregory Light
- Department of Psychiatry, University of California San Diego (UCSD), La Jolla, CA, United States
| | | | - Jason Nunag
- Department of Psychiatry, University of California San Diego (UCSD), La Jolla, CA, United States
| | - Brian Roach
- University of California, San Francisco, San Francisco, CA, United States
- San Francisco VA Medical Center, San Francisco, VA, United States
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18
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Bo Q, Mao Z, Tian Q, Yang N, Li X, Dong F, Zhou F, Li L, Wang C. Impaired Sensorimotor Gating Using the Acoustic Prepulse Inhibition Paradigm in Individuals at a Clinical High Risk for Psychosis. Schizophr Bull 2020; 47:128-137. [PMID: 32743658 PMCID: PMC7825103 DOI: 10.1093/schbul/sbaa102] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Many robust studies have investigated prepulse inhibition (PPI) in patients with schizophrenia. Recent evidence indicates that PPI may help identify individuals who are at clinical high risk for psychosis (CHR). Selective attention to prepulse stimulus can specifically enhance PPI in healthy subjects; however, this enhancement effect is not observed in patients with schizophrenia. Modified PPI measurement with selective attentional modulation using perceived spatial separation (PSS) condition may be a more robust and sensitive index of PPI impairment in CHR individuals. The current study investigated an improved PSSPPI condition in CHR individuals compared with patients with first-episode schizophrenia (FES) and healthy controls (HC) and evaluated the accuracy of PPI in predicting CHR from HC. We included 53 FESs, 55 CHR individuals, and 53 HCs. CHRs were rated on the Structured Interview for Prodromal Syndromes. The measures of perceived spatial co-location PPI (PSCPPI) and PSSPPI conditions were applied using 60- and 120-ms lead intervals. Compared with HC, the CHR group had lower PSSPPI level (Inter-stimulus interval [ISI] = 60 ms, P < .001; ISI = 120 ms, P < .001). PSSPPI showed an effect size (ES) between CHR and HC (ISI = 60 ms, Cohen's d = 0.91; ISI = 120 ms, Cohen's d = 0.98); on PSSPPI using 60-ms lead interval, ES grade increased from CHR to FES. The area under the receiver operating characteristic curve for PSSPPI was greater than that for PSCPPI. CHR individuals showed a PSSPPI deficit similar to FES, with greater ES and sensitivity. PSSPPI appears a promising objective approach for preliminary identification of CHR individuals.
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Affiliation(s)
- Qijing Bo
- The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders and Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China,Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Zhen Mao
- The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders and Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China,Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Qing Tian
- The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders and Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China,Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Ningbo Yang
- Department of Psychiatry, First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China
| | - Xianbin Li
- The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders and Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China,Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Fang Dong
- The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders and Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China,Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Fuchun Zhou
- The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders and Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China,Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Liang Li
- School of Psychological and Cognitive Sciences and Beijing Key Laboratory of Behavior and Mental Health, Peking University, Beijing, China
| | - Chuanyue Wang
- The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders and Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China,Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China,To whom correspondence should be addressed; Beijing Anding Hospital, Capital Medical University, No. 5 Ankang Lane, Dewai Avenue, Xicheng District, Beijing 100088, China; tel: +86-10-58303195, fax: +86-10-58303133, e-mail:
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19
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Kumari V, Ettinger U. Controlled sleep deprivation as an experimental medicine model of schizophrenia: An update. Schizophr Res 2020; 221:4-11. [PMID: 32402603 DOI: 10.1016/j.schres.2020.03.064] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/27/2020] [Accepted: 03/29/2020] [Indexed: 12/22/2022]
Abstract
In recent years there has been a surge of interest and corresponding accumulation of knowledge about the role of sleep disturbance in schizophrenia. In this review, we provide an update on the current status of experimentally controlled sleep deprivation (SD) as an experimental medicine model of psychosis, and also consider, given the complexity and heterogeneity of schizophrenia, whether this (state) model can be usefully combined with other state or trait model systems to more powerfully model the pathophysiology of psychosis. We present evidence of dose-dependent aberrations that qualitatively resemble positive, negative and cognitive symptoms of schizophrenia as well as deficits in a range of translational biomarkers for schizophrenia, including prepulse inhibition, smooth pursuit and antisaccades, following experimentally controlled SD, relative to standard sleep, in healthy volunteers. Studies examining the combination of SD and schizotypy, a trait model of schizophrenia, revealed only occasional, task-dependent superiority of the combination model, relative to either of the two models alone. Overall, we argue that experimentally controlled SD is a valuable experimental medicine model of schizophrenia to advance our understanding of the pathophysiology of the clinical disorder and discovery of more effective or novel treatments. Future studies are needed to test its utility in combination with other, especially state, model systems of psychosis such as ketamine.
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Affiliation(s)
- Veena Kumari
- Centre for Cognitive Neuroscience, College of Health and Life Sciences, Brunel University London, Uxbridge, UK.
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20
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Kumari V, Antonova E, Geyer MA. Prepulse inhibition and “psychosis-proneness” in healthy individuals: An fMRI study. Eur Psychiatry 2020; 23:274-80. [DOI: 10.1016/j.eurpsy.2007.11.006] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2007] [Revised: 11/20/2007] [Accepted: 11/20/2007] [Indexed: 10/22/2022] Open
Abstract
AbstractObjectivePrepulse inhibition (PPI) of the startle response provides an operational index of sensorimotor gating that is reliably demonstrable in both human and animal subjects. Patients with schizophrenia, first-degree relatives of patients with schizophrenia, patients with schizotypal personality disorder and healthy individuals scoring high on psychometric measures of psychosis-proneness display reduced PPI. This study examined associations between individual differences in “psychosis-proneness” and brain activity during a tactile prepulse inhibition paradigm previously found to reveal activation in controls and deficient activation in schizophrenia patients in the striatum, thalamus, insula, hippocampal, temporal, inferior frontal, and inferior parietal regions.MethodsFourteen right-handed healthy men underwent psychophysiological testing and functional magnetic resonance imaging (fMRI) during a 15-min tactile PPI paradigm involving the use of tactile stimuli as both the pulse (a 40-ms presentation of 30 psi air-puff) and the prepulse (a 20-ms presentation of 6 psi air-puff presented 30-ms or 120-ms before the pulse). Individual differences in “psychosis-proneness” were assessed with Psychoticism scale of the Eysenck Personality Questionnaire-Revised (EPQ-R).ResultsHigh psychosis-proneness was associated with lower PPI and reduced activity in the inferior frontal gyrus, insula extending to putamen and thalamus, parahippocampal gyrus, and inferior parietal and middle temporal regions. No regional activity correlated positively with psychosis-proneness.ConclusionsThe present observations extend the findings observed previously in people with schizophrenia to people with high psychosis-proneness, providing support to continuum theories of psychosis with implications for understanding trait-related neural deficits in schizophrenia.
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21
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Togay B, Çıkrıkçılı U, Bayraktaroglu Z, Uslu A, Noyan H, Üçok A. Lower prepulse inhibition in clinical high-risk groups but not in familial risk groups for psychosis compared with healthy controls. Early Interv Psychiatry 2020; 14:196-202. [PMID: 31264797 DOI: 10.1111/eip.12845] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 04/18/2019] [Accepted: 06/09/2019] [Indexed: 10/26/2022]
Abstract
AIM Although the lower level of prepulse inhibition (PPI) of the startle response is well known in schizophrenia, the onset of this difference is not clear. The aim of the present study was to compare PPI in individuals with clinical and familial high risk for psychosis, and healthy controls. METHODS We studied PPI in individuals within three groups: ultra-high risk for psychosis (UHR, n = 29), familial high risk for psychosis (FHR, n = 24) and healthy controls (HC, n = 28). The FHR group was chosen among siblings of patients with schizophrenia, whereas UHR was defined based on the Comprehensive Assessment of At-Risk Mental States (CAARMS). We collected clinical data using the BPRS-E, SANS and SAPS when individuals with UHR were antipsychotic-naïve. A cognitive battery that assessed attention, cognitive flexibility, working memory, verbal learning and memory domains was applied to all participants. RESULTS PPI was lower in the UHR group compared with both the FHR and HC groups. Those with a positive family history for schizophrenia had lower PPI than others in the UHR group. There was no difference in PPI between the FHR and HC groups. We found no relationship between PPI and cognitive performance in the three groups. Startle reactivity was not different among the three groups. Positive and negative symptoms were not related to PPI and startle reactivity in the UHR group. CONCLUSIONS Our findings suggest that clinical and familial high-risk groups for psychosis have different patterns of PPI.
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Affiliation(s)
- Bilge Togay
- University of Health Sciences, Tepecik Training and Research Hospital, Clinic of Psychiatry, Izmir, Turkey
| | | | - Zubeyir Bayraktaroglu
- Istanbul Medipol University, International School of Medicine, Department of Physiology, Beykoz, Istanbul, Turkey.,Istanbul Medipol University, Regenerative and Restorative Medicine Research Center (REMER), Beykoz, Istanbul, Turkey
| | - Atilla Uslu
- Istanbul Faculty of Medicine, Department of Physiology, Istanbul University, Istanbul, Turkey
| | - Handan Noyan
- Institute of Experimental Medicine and Research, Istanbul University, Istanbul, Turkey
| | - Alp Üçok
- Istanbul Faculty of Medicine, Department of Psychiatry, Istanbul University, Istanbul, Turkey
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22
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Rydkjaer J, Jepsen JRM, Pagsberg AK, Fagerlund B, Glenthoej BY, Oranje B. Do young adolescents with first-episode psychosis or ADHD show sensorimotor gating deficits? Psychol Med 2020; 50:607-615. [PMID: 30873927 DOI: 10.1017/s0033291719000412] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND Early identification is important for patients with early-onset schizophrenia (SZ). Assessment of (candidate) endophenotypic markers for SZ, such as prepulse inhibition of the startle reflex (PPI), may help distinguish between the early-onset SZ and other psychiatric disorders. We explored whether PPI deficits usually seen in adult-onset SZ are present in young adolescents with either early-onset psychosis or attention deficit/hyperactivity disorder (ADHD). METHODS Twenty-five adolescents with first-episode, non-affective psychosis (FEP), 28 adolescents with ADHD and 43 healthy controls (HC), aged 12-17 years, were assessed with an auditory PPI paradigm. RESULTS No significant group differences were found in PPI. However, when the FEP group was divided into those already diagnosed with SZ (n = 13) and those without (N-SZ) (n = 12), and all four groups (SZ, N-SZ, ADHD and HC) were compared on percentage PPI in the 85/60 trials, significantly less PPI was found in patients with SZ than in the HC as well as the ADHD group. No significant group differences were found in explorative analyses on the other trial types. Additionally, startle magnitude was significantly higher in SZ than in N-SZ patients. CONCLUSION Young adolescents with SZ showed sensorimotor gating deficits similar to those usually found in adults with SZ and had larger startle magnitude than patients with other types of non-affective early-onset psychosis. No sensorimotor gating deficits were found in adolescents with ADHD. Our findings support the theory that deficient PPI is endophenotypic for SZ.
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Affiliation(s)
- Jacob Rydkjaer
- Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS) and Center for Neuropsychiatric Schizophrenia Research (CNSR), Mental Health Center Glostrup, University of Copenhagen, Copenhagen, Denmark
- Child and Adolescent Mental Health Center, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark
| | - Jens Richardt Moellegaard Jepsen
- Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS) and Center for Neuropsychiatric Schizophrenia Research (CNSR), Mental Health Center Glostrup, University of Copenhagen, Copenhagen, Denmark
- Child and Adolescent Mental Health Center, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark
| | - Anne Katrine Pagsberg
- Child and Adolescent Mental Health Center, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Birgitte Fagerlund
- Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS) and Center for Neuropsychiatric Schizophrenia Research (CNSR), Mental Health Center Glostrup, University of Copenhagen, Copenhagen, Denmark
- Department of Psychology, University of Copenhagen, Copenhagen, Denmark
| | - Birte Yding Glenthoej
- Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS) and Center for Neuropsychiatric Schizophrenia Research (CNSR), Mental Health Center Glostrup, University of Copenhagen, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bob Oranje
- Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS) and Center for Neuropsychiatric Schizophrenia Research (CNSR), Mental Health Center Glostrup, University of Copenhagen, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands
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23
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Massa N, Owens AV, Harmon W, Bhattacharya A, Ivleva EI, Keedy S, Sweeney JA, Pearlson GD, Keshavan MS, Tamminga CA, Clementz BA, Duncan E. Relationship of prolonged acoustic startle latency to diagnosis and biotype in the bipolar-schizophrenia network on intermediate phenotypes (B-SNIP) cohort. Schizophr Res 2020; 216:357-366. [PMID: 31796306 PMCID: PMC7239737 DOI: 10.1016/j.schres.2019.11.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 10/21/2019] [Accepted: 11/06/2019] [Indexed: 01/19/2023]
Abstract
BACKGROUND Latency of the acoustic startle reflex is the time from presentation of the startling stimulus until the response and provides an index of neural processing speed. Latency is prolonged in schizophrenia, is 90% heritable, and predicts conversion to schizophrenia in a high-risk population. The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) consortium investigates neurobiological features found in psychotic disorders spanning diagnostic criteria for schizophrenia (SCZ), schizoaffective disorder (SAD), and psychotic bipolar disorder (BP). We investigated whether differences in startle latency and prepulse inhibition (PPI) occur in probands, their first-degree relatives, and neurobiologically defined subgroups of the probands (Biotypes). METHODS 1143 subjects were included from the B-SNIP cohort: 143 with SCZ, 178 SCZ relatives (SCZ-Fam), 123 with SAD, 152 SAD relatives (SAD-Fam), 138 BP, 183 BP relatives (BP-Fam), and 226 controls (CON). A Biopac system recorded the eyeblink component of the startle reflex during startle testing. RESULTS Latency differed by diagnosis (F(3,620) = 5.10, p = 0.002): SCZ, SAD, and BP probands had slower latency than CON, with relatives intermediate. Biotypes 1 and 2 had slower latency than CON (p < 0.031) but Biotype 3 did not differ from CON. PPI did not separate CON from other subjects when analyzed by diagnoses nor when analyzed by biotype. Biotype 1 relatives had slower latency (F(3,663) = 3.49, p = 0.016) and more impaired PPI than Biotype 2 and 3 relatives (F(3,663) = 2.77, p = 0.041). CONCLUSION Startle latency is prolonged in psychotic disorders that cross traditional diagnostic categories. These data suggest a genetic difference between biotypes that span across clinically defined diagnoses.
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Affiliation(s)
- Nicholas Massa
- Atlanta Veterans Affairs Medical Center, Decatur, GA 30033,Rollins School of Public Health, Emory University, Atlanta, GA 30322
| | - Andrew V. Owens
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30329
| | | | | | | | | | | | | | | | | | - Brett A. Clementz
- Departments of Psychology and Neuroscience, Bio-Imaging Research Center, University of Georgia
| | - Erica Duncan
- Atlanta Veterans Affairs Medical Center, Decatur, GA, 30033, USA; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30329, USA.
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24
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Ashbrook DG, Cahill S, Hager R. A Cross-Species Systems Genetics Analysis Links APBB1IP as a Candidate for Schizophrenia and Prepulse Inhibition. Front Behav Neurosci 2019; 13:266. [PMID: 31920576 PMCID: PMC6914690 DOI: 10.3389/fnbeh.2019.00266] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 11/22/2019] [Indexed: 12/20/2022] Open
Abstract
Background: Prepulse inhibition (PPI) of the startle response is a highly conserved form of sensorimotor gating, disruption of which is found in schizophrenia patients and their unaffected first-degree relatives. PPI can be measured in many species, and shows considerable phenotypic variation between and within rodent models. This makes PPI a useful endophenotype. Genome-wide association studies (GWAS) have been carried out to identify genetic variants underlying schizophrenia, and these suggest that schizophrenia is highly polygenic. GWAS have been unable to account for the high heritability of schizophrenia seen in family studies, partly because of the low power of GWAS due to multiple comparisons. By contrast, complementary mouse model linkage studies often have high statistical power to detect variants for behavioral traits but lower resolution, producing loci that include tens or hundreds of genes. To capitalize on the advantages of both GWAS and genetic mouse models, our study uses a cross-species approach to identify novel genes associated with PPI regulation, which thus may contribute to the PPI deficits seen in schizophrenia. Results: Using experimental data from the recombinant inbred (RI) mouse panel BXD, we identified two significant loci affecting PPI. These genomic regions contain genetic variants which influence PPI in mice and are therefore candidates that may be influencing aspects of schizophrenia in humans. We next investigated these regions in whole-genome data from the Psychiatric Genomics Consortium (PGC) schizophrenia GWAS and identify one novel candidate gene (ABPP1IP) that was significantly associated with PPI in mice and risk of schizophrenia in humans. A systems genetics approach demonstrates that APBB1IP coexpresses with several other genes related to schizophrenia in several brain regions. Gene coexpression and enrichment analysis shows clear links between APBB1IP and the immune system. Conclusion: The combination of human GWAS and mouse quantitative trait loci (QTL) from some of the largest study systems available has enabled us to identify a novel gene, APBB1IP, which influences schizophrenia in humans and PPI in mice.
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Affiliation(s)
- David G Ashbrook
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Stephanie Cahill
- Evolution and Genomic Sciences, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom
| | - Reinmar Hager
- Evolution and Genomic Sciences, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom
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25
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Bilel S, Tirri M, Arfè R, Ossato A, Trapella C, Serpelloni G, Neri M, Fattore L, Marti M. Novel halogenated synthetic cannabinoids impair sensorimotor functions in mice. Neurotoxicology 2019; 76:17-32. [PMID: 31610187 DOI: 10.1016/j.neuro.2019.10.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 09/18/2019] [Accepted: 10/07/2019] [Indexed: 02/06/2023]
Abstract
JWH-018-Cl, JWH-018-Br and AM-2201 (JWH-018 halogenated-derivatives; JWH-018-R compounds) are synthetic cannabinoid agonists illegally marketed as "Spice", "K2", "herbal blend" and research chemicals for their cannabis-like psychoactive effects. In rodents, JWH-018 and its halogenated derivatives reproduce the typical effects of Δ9-tetrahydrocannabinol (Δ9-THC), i.e. hypothermia, analgesia, hypolocomotion and akinesia. Yet, the effects of JWH-018-R compounds on sensorimotor functions are still unknown. This study was designed to investigate the effect of an acute intraperitoneal (i.p.) administration of JWH-018-R compounds (0.01-6 mg/kg) on sensorimotor functions in mice and to compare them to those caused by the reference compound JWH-018 and Δ9-THC. A well validated battery of behavioral tests was used to investigate the effects of these synthetic cannabinoids on the visual, auditory and tactile responses in mice, while the pre-pulse inhibition (PPI) test was used to investigate their effect on sensorimotor gating. The effect of the synthetic cannabinoids on spontaneous locomotion was also measured by a video tracking analysis to assess potential cannabinoid-induced motor impairment. Results showed that, similarly to JWH-018, systemic administration of JWH-018-R compounds inhibits sensorimotor and PPI responses at lower doses (0.01-0.1 mg/kg) and reduced spontaneous locomotion at intermediate/high doses (1-6 mg/kg). All effects were prevented by the administration of the selective cannabinoid CB1 receptor antagonist/inverse agonist AM-251 thus confirming a CB1 receptor-mediated action. Finding that lower doses of JWH-018-R compounds selectively impair sensorimotor and PPI responses without affecting locomotion should be carefully considered to better understand the potential danger that halogenated-derivatives of JWH-018 may pose to public health, with particular reference to decreased performance in driving and hazardous works.
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Affiliation(s)
- Sabrine Bilel
- Department of Life Sciences and Biotechnology (SVeB), University of Ferrara, Italy
| | - Micaela Tirri
- Department of Morphology, Experimental Medicine and Surgery, Section of Legal Medicine, University of Ferrara, Ferrara, Italy
| | - Raffaella Arfè
- Institute of Public Health, Section of Legal Medicine, Catholic University of Rome, Rome, Italy
| | - Andrea Ossato
- Institute of Public Health, Section of Legal Medicine, Catholic University of Rome, Rome, Italy
| | - Claudio Trapella
- Department of Chemistry and Pharmaceutical Sciences, University of Ferrara, Italy
| | - Giovanni Serpelloni
- Drug Policy Institute, Department of Psychiatry in the College of Medicine, University of Florida, USA
| | - Margherita Neri
- Department of Morphology, Experimental Medicine and Surgery, Section of Legal Medicine, University of Ferrara, Ferrara, Italy
| | - Liana Fattore
- Institute of Neuroscience-Cagliari, National Research Council, Italy.
| | - Matteo Marti
- Department of Morphology, Experimental Medicine and Surgery, Section of Legal Medicine, University of Ferrara, Ferrara, Italy; Center for Neuroscience and National Institute of Neuroscience, Italy; Collaborative Center for the Italian National Early Warning System, Department of Anti-Drug Policies, Presidency of the Council of Ministers, Italy
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26
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Ni P, Tian Y, Gu X, Yang L, Wei J, Wang Y, Zhao L, Zhang Y, Zhang C, Li L, Tang X, Ma X, Hu X, Li T. Plasma neuropeptides as circulating biomarkers of multifactorial schizophrenia. Compr Psychiatry 2019; 94:152114. [PMID: 31401216 DOI: 10.1016/j.comppsych.2019.152114] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 06/26/2019] [Accepted: 07/17/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Promising biomarkers would be used to improve the determination of diagnosis and severity, as well as the prediction of symptomatic and functional outcomes of schizophrenia. BASIC PROCEDURES In this study, we used three different mouse models induced by a genetic factor (PV-Cre; ErbB4-/-, G group), an environmental stressor (adolescent social isolation, G group), and a combination of genetic factor and environmental stressor (PV-Cre; ErbB4-/- mice with isolation, G × E group). Attenuated PPI (%) confirmed the successful establishment of three schizophrenia-like mouse models. To evaluate whether neuropeptide levels in plasma would be potential biomarkers of different schizophrenia models in our work, we used MILLIPLEX® MAP method to simultaneously measure 6 critical neuropeptides in plasma. MAIN FINDINGS Among the evaluated neuropeptides, increased neurotensin tends to be associated with genetic factors of schizophrenia, increased orexin A seems to be a biomarker of an interplay between genetic and social isolation, while higher plasma oxytocin might be more apt to be responsive to social isolation. The potential biomarkers are mostly independent of sex. CONCLUSIONS This research would provide novel clues to develop circulating biomarkers of plasma neuropeptides for multifactorial schizophrenia.
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Affiliation(s)
- Peiyan Ni
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, PR China; Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, PR China
| | - Yang Tian
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, PR China; Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, PR China
| | - Xiaochu Gu
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, PR China; Clinical Laboratory, Suzhou Psychiatric Hospital, Suzhou, PR China
| | - Linghui Yang
- The Laboratory of Anesthesiology and Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, PR China
| | - Jinxue Wei
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, PR China; Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, PR China
| | - Yingcheng Wang
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, PR China; Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, PR China
| | - Liansheng Zhao
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, PR China; Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, PR China
| | - Yamin Zhang
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, PR China; Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, PR China
| | - Chengcheng Zhang
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, PR China; Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, PR China
| | - Liping Li
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, PR China
| | - Xiangdong Tang
- Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, PR China; Sleep Medicine Center, Mental Health Center, and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, PR China
| | - Xiaohong Ma
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, PR China; Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, PR China
| | - Xun Hu
- Biobank, West China Hospital, Sichuan University, Chengdu, PR China
| | - Tao Li
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, PR China; Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, PR China.
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27
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Mao Z, Bo Q, Li W, Wang Z, Ma X, Wang C. Prepulse inhibition in patients with bipolar disorder: a systematic review and meta-analysis. BMC Psychiatry 2019; 19:282. [PMID: 31510965 PMCID: PMC6737635 DOI: 10.1186/s12888-019-2271-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Accepted: 09/03/2019] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Prepulse inhibition (PPI) is a measurement method for the sensory gating process, which helps the brain adapt to complex environments. PPI may be reduced in patients with bipolar disorder (BD). This study investigated PPI deficits in BD and pooled the effect size of PPI in patients with BD. METHODS We conducted a literature search on PPI in patients with BD from inception to July 27, 2019 in PubMed, Embase, Cochrane Library databases, and Chinese databases. No age, sex, and language restriction were set. The calculation formula was PPI = 100 - [100*((prepulse - pulse amplitude) / pulse amplitude)]. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of studies. RESULTS Ten eligible papers were identified, of which five studies including a total of 141 euthymic patients and 132 healthy controls (HC) were included in the meta-analysis. Compared with HC, euthymic patients with BD had significantly lower PPI at the 60 ms interstimulus interval (ISI) between pulse and prepulse (P = 0.476, I2 = 0.0%, SMD = - 0.32, 95% CI = - 0.54 - -0.10). Sensitivity analysis shows no significant change in the combined effect value after removing any single study. There was no publication bias using the Egger's test at 60 ms (P = 0.606). The meta-analysis of PPI at the 60 ms ISI could have significant clinical heterogeneity in mood episode state, as well as lack of data on BD I or II subtypes. CONCLUSIONS Euthymic patients with BD show PPI deficits at the 60 ms, suggesting a deficit in the early sensory gate underlying PPI. The PPI inhibition rate at a 60 ms interval is a stable index. More research is needed in the future to confirm this outcome, and to delve deeper into the mechanisms behind deficits.
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Affiliation(s)
- Zhen Mao
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, No.5 Ankang Lane, Dewai Avenue, Xicheng District, Beijing, 100088 China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069 China
| | - Qijing Bo
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, No.5 Ankang Lane, Dewai Avenue, Xicheng District, Beijing, 100088 China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069 China
| | - Weidi Li
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, No.5 Ankang Lane, Dewai Avenue, Xicheng District, Beijing, 100088 China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069 China
| | - Zhimin Wang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, No.5 Ankang Lane, Dewai Avenue, Xicheng District, Beijing, 100088 China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069 China
| | - Xin Ma
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, No.5 Ankang Lane, Dewai Avenue, Xicheng District, Beijing, 100088 China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069 China
| | - Chuanyue Wang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, No.5 Ankang Lane, Dewai Avenue, Xicheng District, Beijing, 100088 China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069 China
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28
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Zhang C, Ni P, Liu Y, Tian Y, Wei J, Xiang B, Zhao L, Li X, Ma X, Deng W, Guo W, Ni R, Zhang Y, Wang Q, Huang H, Zhang N, Li T. GABAergic Abnormalities Associated with Sensorimotor Cortico-striatal Community Structural Deficits in ErbB4 Knockout Mice and First-Episode Treatment-Naïve Patients with Schizophrenia. Neurosci Bull 2019; 36:97-109. [PMID: 31388929 DOI: 10.1007/s12264-019-00416-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 05/01/2019] [Indexed: 02/05/2023] Open
Abstract
The current study was designed to explore how disruption of specific molecular circuits in the cerebral cortex may cause sensorimotor cortico-striatal community structure deficits in both a mouse model and patients with schizophrenia. We used prepulse inhibition (PPI) and brain structural and diffusion MRI scans in 23 mice with conditional ErbB4 knockout in parvalbumin interneurons and 27 matched controls. Quantitative real-time PCR was used to assess the differential levels of GABA-related transcripts in brain regions. Concurrently, we measured structural and diffusion MRI and the cumulative contribution of risk alleles in the GABA pathway genes in first-episode treatment-naïve schizophrenic patients (n = 117) and in age- and sex-matched healthy controls (n = 86). We present the first evidence of gray and white matter impairment of right sensorimotor cortico-striatal networks and reproduced the sensorimotor gating deficit in a mouse model of schizophrenia. Significant correlations between gray matter volumes (GMVs) in the somatosensory cortex and PPI as well as glutamate decarboxylase 1 mRNA expression were found in controls but not in knockout mice. Furthermore, these findings were confirmed in a human sample in which we found significantly decreased gray and white matter in sensorimotor cortico-striatal networks in schizophrenic patients. The psychiatric risk alleles of the GABA pathway also displayed a significant negative correlation with the GMVs of the somatosensory cortex in patients. Our study identified that ErbB4 ablation in parvalbumin interneurons induced GABAergic dysregulation, providing valuable mechanistic insights into the sensorimotor cortico-striatal community structure deficits associated with schizophrenia.
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Affiliation(s)
- Chengcheng Zhang
- Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Peiyan Ni
- Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Yikang Liu
- Department of Biomedical Engineering, Pennsylvania State University, University Park, PA, 16802, USA
| | - Yang Tian
- Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Jinxue Wei
- Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Bo Xiang
- Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Liansheng Zhao
- Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Xiaojing Li
- Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Xiaohong Ma
- Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Wei Deng
- Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Wanjun Guo
- Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Rongjun Ni
- Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Yamin Zhang
- Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Qiang Wang
- Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Hailiang Huang
- Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
| | - Nanyin Zhang
- Department of Biomedical Engineering, Pennsylvania State University, University Park, PA, 16802, USA.
| | - Tao Li
- Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China. .,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
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Coors A, Brosch M, Kahl E, Khalil R, Michels B, Laub A, Franke K, Gerber B, Fendt M. Rhodiola rosea root extract has antipsychotic-like effects in rodent models of sensorimotor gating. JOURNAL OF ETHNOPHARMACOLOGY 2019; 235:320-328. [PMID: 30776471 DOI: 10.1016/j.jep.2019.02.031] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 02/14/2019] [Accepted: 02/14/2019] [Indexed: 06/09/2023]
Abstract
UNLABELLED ETHNOPHARMACOLOGICAL RELEVANCE: The plant arctic root (Rhodiola rosea, L.) is growing in northern regions of Europe, Asia and North America. Extracts of R. rosea are used in traditional medicine for various conditions related to nervous system function. According to scientific studies from the last decades, the plant might have potential for use in the treatment of memory impairments, stress and depression, but reports concerning other neuropsychiatric disorders are scarce. AIM OF THE STUDY In this context, our study aimed to examine potential antipsychotic-like effects of R. rosea root extract. MATERIALS AND METHODS We tested the effects of R. rosea root extract on prepulse inhibition in rats and mice. Prepulse inhibition is an established operational measure of sensorimotor gating, which is impaired in schizophrenia and other psychotic disorders. RESULTS R. rosea root extract increased prepulse inhibition in rats and mice. Interestingly, the R. rosea extract had stronger effects in those individual animals that had low baseline levels of prepulse inhibition. Therefore, we performed further experiments in which we pharmacologically induced a prepulse inhibition deficit by two different psychostimulants, either the dopamine D2 receptor agonist apomorphine or the NMDA receptor antagonist dizocilpine (MK-801). Pre-treatment with the R. rosea extract significantly restored both, apomorphine- and dizocilpine-induced prepulse inhibition deficits. CONCLUSIONS The present study demonstrates that R. rosea extract robustly reverses prepulse inhibition deficits in rodents. This suggests antipsychotic-like effects of R. rosea extract. Future studies should focus on the pharmacological mechanisms underlying these effects.
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Affiliation(s)
- Andreas Coors
- Neuroscience Program, University of Bremen, Germany; Institute for Pharmacology and Toxicology, Otto-von-Guericke University Magdeburg, Germany.
| | - Marcel Brosch
- Integrative Neuroscience Program, Otto-von-Guericke University Magdeburg, Germany.
| | - Evelyn Kahl
- Institute for Pharmacology and Toxicology, Otto-von-Guericke University Magdeburg, Germany.
| | - Radwa Khalil
- Institute for Pharmacology and Toxicology, Otto-von-Guericke University Magdeburg, Germany.
| | - Birgit Michels
- Genetics, Leibniz Institute for Neurobiology, Magdeburg, Germany.
| | - Annegret Laub
- Leibniz Institute of Plant Biochemistry, Halle, Germany.
| | - Katrin Franke
- Leibniz Institute of Plant Biochemistry, Halle, Germany.
| | - Bertram Gerber
- Genetics, Leibniz Institute for Neurobiology, Magdeburg, Germany; Institute of Biology, Otto-von-Guericke University Magdeburg, Germany; Center of Behavioral Brain Sciences, Otto-von-Guericke University Magdeburg, Germany.
| | - Markus Fendt
- Institute for Pharmacology and Toxicology, Otto-von-Guericke University Magdeburg, Germany; Center of Behavioral Brain Sciences, Otto-von-Guericke University Magdeburg, Germany.
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Lucatch AM, Lowe DJE, Clark RC, Kozak K, George TP. Neurobiological Determinants of Tobacco Smoking in Schizophrenia. Front Psychiatry 2018; 9:672. [PMID: 30574101 PMCID: PMC6291492 DOI: 10.3389/fpsyt.2018.00672] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 11/21/2018] [Indexed: 12/22/2022] Open
Abstract
Purpose of review: To provide an overview of the underlying neurobiology of tobacco smoking in schizophrenia, and implications for treatment of this comorbidity. Recent findings: Explanations for heavy tobacco smoking in schizophrenia include pro-cognitive effects of nicotine, and remediation of the underlying pathophysiology of schizophrenia. Nicotine may ameliorate neurochemical deficits through nicotine acetylcholine receptors (nAChRs) located on the dopamine, glutamate, and GABA neurons. Neurophysiological indices including electroencephalography, electromyography, and smooth pursuit eye movement (SPEM) paradigms may be biomarkers for underlying neuronal imbalances that contribute to the specific risk of tobacco smoking initiation, maintenance, and difficulty quitting within schizophrenia. Moreover, several social factors including socioeconomic factors and permissive smoking culture in mental health facilities, may contribute to the smoking behaviors (initiation, maintenance, and inability to quit smoking) within this disorder. Summary: Tobacco smoking may alleviate specific symptoms associated with schizophrenia. Understanding the neurobiological underpinnings and psychosocial determinants of this comorbidity may better explain these potential beneficial effects, while also providing important insights into effective treatments for smoking cessation.
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Affiliation(s)
- Aliya M. Lucatch
- Addictions Division, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
| | - Darby J. E. Lowe
- Addictions Division, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
| | - Rachel C. Clark
- Addictions Division, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada
| | - Karolina Kozak
- Addictions Division, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
| | - Tony P. George
- Addictions Division, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
- Division and Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, ON, Canada
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Rovný R, Marko M, Katina S, Murínová J, Roháriková V, Cimrová B, Repiská G, Minárik G, Riečanský I. Association between genetic variability of neuronal nitric oxide synthase and sensorimotor gating in humans. Nitric Oxide 2018; 80:32-36. [PMID: 30096361 DOI: 10.1016/j.niox.2018.08.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 06/15/2018] [Accepted: 08/06/2018] [Indexed: 11/17/2022]
Abstract
Research increasingly suggests that nitric oxide (NO) plays a role in the pathogenesis of schizophrenia. One important line of evidence comes from genetic studies, which have repeatedly detected an association between the neuronal isoform of nitric oxide synthase (nNOS or NOS1) and schizophrenia. However, the pathogenetic pathways linking nNOS, NO, and the disorder remain poorly understood. A deficit in sensorimotor gating is considered to importantly contribute to core schizophrenia symptoms such as psychotic disorganization and thought disturbance. We selected three candidate nNOS polymorphisms (Ex1f-VNTR, rs6490121 and rs41279104), associated with schizophrenia and cognition in previous studies, and tested their association with the efficiency of sensorimotor gating in healthy human adults. We found that risk variants of Ex1f-VNTR and rs6490121 (but not rs41279104) were associated with a weaker prepulse inhibition (PPI) of the acoustic startle reflex, a standard measure of sensorimotor gating. Furthermore, the effect of presence of risk variants in Ex1f-VNTR and rs6490121 was additive: PPI linearly decreased with increasing number of risk alleles, being highest in participants with no risk allele, while lowest in individuals who carry three risk alleles. Our findings indicate that NO is involved in the regulation of sensorimotor gating, and highlight one possible pathogenetic mechanism for NO playing a role in the development of schizophrenia psychosis.
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Affiliation(s)
- Rastislav Rovný
- Department of Behavioural Neuroscience, Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Martin Marko
- Department of Behavioural Neuroscience, Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Stanislav Katina
- Department of Behavioural Neuroscience, Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia; Institute of Mathematics and Statistics, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Jana Murínová
- Department of Behavioural Neuroscience, Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Veronika Roháriková
- Department of Behavioural Neuroscience, Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Barbora Cimrová
- Department of Behavioural Neuroscience, Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Gabriela Repiská
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
| | - Gabriel Minárik
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia
| | - Igor Riečanský
- Department of Behavioural Neuroscience, Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia; Social, Cognitive and Affective Neuroscience Unit, Department of Basic Psychological Research and Research Methods, Faculty of Psychology, University of Vienna, Vienna, Austria.
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Role of mesial temporal lobe structures in sensory processing in humans: a prepulse modulation study in temporal lobe epilepsy. Exp Brain Res 2018; 236:3297-3305. [PMID: 30244377 DOI: 10.1007/s00221-018-5380-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Accepted: 09/18/2018] [Indexed: 10/28/2022]
Abstract
Prepulse modulation (PPM) is an electrophysiological method which enables to assess sensory processing in vivo. Reflex responses may be facilitated or inhibited (prepulse inhibition, PPI) after a weak stimulus. Theoretically, in animal studies, the generator of PPI involves pedunculopontine nucleus which is modulated by various structures, including amygdala. We aimed to investigate whether or not there was a role of limbic structures in the generation of PPM in humans. For this purpose, we studied PPM of the blink reflex (BR) in 10 patients with mesial temporal lobe epilepsy (MTLE group) and in nine patients who had previously undergone amygdala resection for medically resistant MTLE (surgery group). A control group including 19 healthy volunteers was formed. Blink reflex, BR-PPM and BR excitability recovery were recorded in all participants. Two components of BR, first early ipsilateral component (R1) and second late bilateral components (R2 and R2c) were identified. All BR parameters after single stimulation were normal in all groups. Compared to healthy subjects, R2-PPI was more pronounced in the surgery group whereas there was a R2-PPI deficit in the MTLE group. R2-PPI deficit in the MTLE group was more prominent on the lesion side. Ipsilesional R1 facilitation was more evident at ISI of 100 ms in both MTLE and surgery groups compared to healthy subjects. BR excitability recovery was not different between groups. MTLE in humans leads to a PPI deficit. Interestingly, removal of amygdala in humans with MTLE probably provides more efficient functioning of PPI network. Amygdala and hippocampus play roles in the human R2-PPI circuit. Modulation of R1 facilitation is unilateral whereas the modulation of R2-PPI is bilateral, though asymmetric.
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Quednow BB, Ejebe K, Wagner M, Giakoumaki SG, Bitsios P, Kumari V, Roussos P. Meta-analysis on the association between genetic polymorphisms and prepulse inhibition of the acoustic startle response. Schizophr Res 2018; 198:52-59. [PMID: 29287625 DOI: 10.1016/j.schres.2017.12.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 12/13/2017] [Accepted: 12/18/2017] [Indexed: 01/14/2023]
Abstract
Sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) has been proposed as one of the most promising electrophysiological endophenotypes of schizophrenia. During the past decade, a number of publications have reported significant associations between genetic polymorphisms and PPI in samples of schizophrenia patients and healthy volunteers. However, an overall evaluation of the robustness of these results has not been published so far. Therefore, we performed the first meta-analysis of published and unpublished associations between gene polymorphisms and PPI of ASR. Unpublished associations between genetic polymorphisms and PPI were derived from three independent samples. In total, 120 single observations from 16 independent samples with 2660 study participants and 43 polymorphisms were included. After correction for multiple testing based on false discovery rate and considering the number of analyzed polymorphisms, significant associations were shown for four variants, even though none of these associations survived a genome-wide correction (P<5∗10-8). These results imply that PPI might be modulated by four genotypes - COMT rs4680 (primarily in males), GRIK3 rs1027599, TCF4 rs9960767, and PRODH rs385440 - indicating a role of these gene variations in the development of early information processing deficits in schizophrenia. However, the overall impact of single genes on PPI is still rather small suggesting that PPI is - like the disease phenotype - highly polygenic. Future genome-wide analyses studies with large sample sizes will enhance our understanding on the genetic architecture of PPI.
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Affiliation(s)
- Boris B Quednow
- Experimental and Clinical Pharmacopsychology, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland.
| | - Kenechi Ejebe
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Michael Wagner
- Department for Neurodegenerative Diseases and GeriatricPsychiatry, University Hospital Bonn, Bonn, Germany
| | - Stella G Giakoumaki
- Department of Psychology, Gallos University campus, University of Crete, Rethymno, Greece
| | - Panos Bitsios
- Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, Voutes University campus, University of Crete, Heraklion, Greece
| | - Veena Kumari
- Department of Psychology, Institute of Psychiatry, King's College London, United Kingdom
| | - Panos Roussos
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA; Mental Illness Research, Education, and Clinical Center (VISN 2), James J. Peters VA Medical Center, New York, USA.
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Khan A, Powell SB. Sensorimotor gating deficits in "two-hit" models of schizophrenia risk factors. Schizophr Res 2018; 198:68-83. [PMID: 29070440 PMCID: PMC5911431 DOI: 10.1016/j.schres.2017.10.009] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Revised: 10/03/2017] [Accepted: 10/06/2017] [Indexed: 02/07/2023]
Abstract
Genetic and environmental models of neuropsychiatric disease have grown exponentially over the last 20years. One measure that is often used to evaluate the translational relevance of these models to human neuropsychiatric disease is prepulse inhibition of startle (PPI), an operational measure of sensorimotor gating. Deficient PPI characterizes several neuropsychiatric disorders but has been most extensively studied in schizophrenia. It has become a useful tool in translational neuropharmacological and molecular genetics studies because it can be measured across species using almost the same experimental parameters. Although initial studies of PPI in rodents were pharmacological because of the robust predictive validity of PPI for antipsychotic efficacy, more recently, PPI has become standard common behavioral measures used in genetic and neurodevelopmental models of schizophrenia. Here we review "two hit" models of schizophrenia and discuss the utility of PPI as a tool in phenotyping these models of relevant risk factors. In the review, we consider approaches to rodent models of genetic and neurodevelopmental risk factors and selectively review "two hit" models of gene×environment and environment×environment interactions in which PPI has been measured.
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Affiliation(s)
- Asma Khan
- Department of Psychiatry, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States; Research Service, VA San Diego Healthcare System, La Jolla, CA, United States
| | - Susan B Powell
- Department of Psychiatry, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States; Research Service, VA San Diego Healthcare System, La Jolla, CA, United States.
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Fargotstein M, Hasenkamp W, Gross R, Cuthbert B, Green A, Swails L, Lewison B, Boshoven W, Keyes M, Duncan E. The effect of antipsychotic medications on acoustic startle latency in schizophrenia. Schizophr Res 2018; 198:28-35. [PMID: 28732798 DOI: 10.1016/j.schres.2017.07.030] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2017] [Revised: 07/06/2017] [Accepted: 07/09/2017] [Indexed: 10/19/2022]
Abstract
Prepulse inhibition of the acoustic startle reflex (PPI) is extensively studied as a biomarker of schizophrenia (SCZ); however, antipsychotic medication can confound the measure. Latency, the time between the startling stimulus and the reflexive eye blink, provides an index of neural processing speed and is 90% heritable. SCZ subjects have slower latency than controls (CON). This study examined the effects of antipsychotic medication on startle latency. 108 CON and 132 SCZ subjects in three medication subgroups (94 on second-generation antipsychotics (SGA), 25 on first-generation antipsychotics (FGA), 13 unmedicated (NoMed)) were tested on a standard acoustic startle paradigm designed to measure startle magnitude, PPI, and latency. Latency was slower in SCZ compared to CON subjects (p=0.005). Latency did not differ between the three SCZ medication groups. When CON were added to that model, both the NoMed subjects (p=0.04) and the SGA subjects (p=0.003) were slower than CON subjects. For PPI, CON did not differ from SCZ analyzed as a single group. When SCZ subjects were divided into medication groups, PPI was lower in NoMed subjects than the CON group (p=0.03), the SGA group (p=0.02) and the FGA group (p=0.05). SCZ subjects on any medication did not differ from CON. Thus, latency was partially normalized by antipsychotic medication, but this did not obscure the slower latency in SCZ compared to CON. Therefore latency is both trait and state related, whereas medication normalized PPI and obscured any difference between SCZ and CON.
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Affiliation(s)
- Molly Fargotstein
- Atlanta Veterans Affairs Medical Center, 1670 Clairmont Road, Decatur, GA 30033, USA
| | - Wendy Hasenkamp
- Atlanta Veterans Affairs Medical Center, 1670 Clairmont Road, Decatur, GA 30033, USA
| | - Robin Gross
- Atlanta Veterans Affairs Medical Center, 1670 Clairmont Road, Decatur, GA 30033, USA; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 12 Executive Park Drive Northeast #200, Atlanta, GA 30329, USA
| | - Bruce Cuthbert
- Atlanta Veterans Affairs Medical Center, 1670 Clairmont Road, Decatur, GA 30033, USA; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 12 Executive Park Drive Northeast #200, Atlanta, GA 30329, USA
| | - Amanda Green
- Atlanta Veterans Affairs Medical Center, 1670 Clairmont Road, Decatur, GA 30033, USA
| | - Lisette Swails
- Atlanta Veterans Affairs Medical Center, 1670 Clairmont Road, Decatur, GA 30033, USA
| | - Barbara Lewison
- Atlanta Veterans Affairs Medical Center, 1670 Clairmont Road, Decatur, GA 30033, USA; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 12 Executive Park Drive Northeast #200, Atlanta, GA 30329, USA
| | - William Boshoven
- Atlanta Veterans Affairs Medical Center, 1670 Clairmont Road, Decatur, GA 30033, USA; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 12 Executive Park Drive Northeast #200, Atlanta, GA 30329, USA
| | - Megan Keyes
- Atlanta Veterans Affairs Medical Center, 1670 Clairmont Road, Decatur, GA 30033, USA
| | - Erica Duncan
- Atlanta Veterans Affairs Medical Center, 1670 Clairmont Road, Decatur, GA 30033, USA; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 12 Executive Park Drive Northeast #200, Atlanta, GA 30329, USA.
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Swerdlow NR, Light GA, Thomas ML, Sprock J, Calkins ME, Green MF, Greenwood TA, Gur RE, Gur RC, Lazzeroni LC, Nuechterlein KH, Radant AD, Seidman LJ, Siever LJ, Silverman JM, Stone WS, Sugar CA, Tsuang DW, Tsuang MT, Turetsky BI, Braff DL. Deficient prepulse inhibition in schizophrenia in a multi-site cohort: Internal replication and extension. Schizophr Res 2018; 198:6-15. [PMID: 28549722 PMCID: PMC5700873 DOI: 10.1016/j.schres.2017.05.013] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 05/08/2017] [Accepted: 05/10/2017] [Indexed: 11/29/2022]
Abstract
BACKGROUND The Consortium on the Genetics of Schizophrenia (COGS) collected case-control endophenotype and genetic information from 2457 patients and healthy subjects (HS) across 5 test sites over 3.5 years. Analysis of the first "wave" (W1) of 1400 subjects identified prepulse inhibition (PPI) deficits in patients vs. HS. Data from the second COGS "wave" (W2), and the combined W(1+2), were used to assess: 1) the replicability of PPI deficits in this design; 2) the impact of response criteria on PPI deficits; and 3) PPI in a large cohort of antipsychotic-free patients. METHODS PPI in W2 HS (n=315) and schizophrenia patients (n=326) was compared to findings from W1; planned analyses assessed the impact of diagnosis, "wave" (1 vs. 2), and startle magnitude criteria. Combining waves allowed us to assess PPI in 120 antipsychotic-free patients, including many in the early course of illness. RESULTS ANOVA of all W(1+2) subjects revealed robust PPI deficits in patients across "waves" (p<0.0004). Strict response criteria excluded almost 39% of all subjects, disproportionately impacting specific subgroups; ANOVA in this smaller cohort confirmed no significant effect of "wave" or "wave x diagnosis" interaction, and a significant effect of diagnosis (p<0.002). Antipsychotic-free, early-illness patients had particularly robust PPI deficits. DISCUSSION Schizophrenia-linked PPI deficits were replicable across two multi-site "waves" of subjects collected over 3.5years. Strict response criteria disproportionately excluded older, male, non-Caucasian patients with low-normal hearing acuity. These findings set the stage for genetic analyses of PPI using the combined COGS wave 1 and 2 cohorts.
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Affiliation(s)
- Neal R. Swerdlow
- Department of Psychiatry, University of California San Diego, La Jolla, CA,Corresponding Author: Neal R. Swerdlow, M.D., Ph.D., University of California San Diego, Dept. of Psychiatry, 9500 Gilman Drive, La Jolla, CA 92093-0804 619-543-6270 (office); 619-543-2493 (fax);
| | - Gregory A. Light
- Department of Psychiatry, University of California San Diego, La Jolla, CA,VISN 22, Mental Illness Research, Education & Clinical Center (MIRECC), VA San Diego Healthcare System, San Diego, CA
| | - Michael L. Thomas
- Department of Psychiatry, University of California San Diego, La Jolla, CA,VISN 22, Mental Illness Research, Education & Clinical Center (MIRECC), VA San Diego Healthcare System, San Diego, CA
| | - Joyce Sprock
- Department of Psychiatry, University of California San Diego, La Jolla, CA,VISN 22, Mental Illness Research, Education & Clinical Center (MIRECC), VA San Diego Healthcare System, San Diego, CA
| | - Monica E. Calkins
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
| | - Michael F. Green
- Department of Psychiatry and Biobehavioral Sciences, Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA,VA Greater Los Angeles Healthcare System, Los Angeles, CA
| | | | - Raquel E. Gur
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
| | - Ruben C. Gur
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
| | - Laura C. Lazzeroni
- Departments of Psychiatry and Behavioral Sciences and of Pediatrics, Stanford University, Stanford, CA
| | - Keith H. Nuechterlein
- Department of Psychiatry and Biobehavioral Sciences, Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Allen D. Radant
- Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA,VA Puget Sound Health Care System, Seattle, WA
| | - Larry J. Seidman
- Department of Psychiatry, Harvard Medical School, Boston, MA,Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston, MA
| | - Larry J. Siever
- Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY,James J. Peters VA Medical Center, New York, NY
| | - Jeremy M. Silverman
- Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY,James J. Peters VA Medical Center, New York, NY
| | - William S. Stone
- Department of Psychiatry, Harvard Medical School, Boston, MA,Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, MA
| | - Catherine A. Sugar
- Department of Psychiatry and Biobehavioral Sciences, Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA,VISN 22, Mental Illness Research, Education & Clinical Center (MIRECC), VA San Diego Healthcare System, San Diego, CA,Department of Biostatistics, University of California Los Angeles School of Public Health, Los Angeles, CA
| | - Debby W. Tsuang
- Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA,VA Puget Sound Health Care System, Seattle, WA
| | - Ming T. Tsuang
- Department of Psychiatry, University of California San Diego, La Jolla, CA,Institute for Genomic Medicine, University of California San Diego, La Jolla, CA,Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, MA
| | - Bruce I. Turetsky
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
| | - David L. Braff
- Department of Psychiatry, University of California San Diego, La Jolla, CA,VISN 22, Mental Illness Research, Education & Clinical Center (MIRECC), VA San Diego Healthcare System, San Diego, CA
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Høivik MS, Lydersen S, Ranøyen I, Berg-Nielsen TS. Maternal personality disorder symptoms in primary health care: associations with mother-toddler interactions at one-year follow-up. BMC Psychiatry 2018; 18:198. [PMID: 29914432 PMCID: PMC6006703 DOI: 10.1186/s12888-018-1789-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 06/12/2018] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Research is scarce on how mothers' symptoms of personality disorders are linked to the mother-toddler relationship. In this study we have explored the extent to which these symptoms are associated with mutual mother-toddler interactions assessed 1 year after the initial assessment. METHODS Mothers and their 0-24-month-old children (n = 112) were recruited by nurses at well-baby clinics due to either self-reported or observed mother-toddler interaction problems. At inclusion (T1), mothers filled out the DSM-IV and ICD-10 Personality Questionnaire (DIP-Q), which measures symptoms of ten personality disorders. A year later (T2), mother-toddler interactions were video-recorded and coded using a standardised observation measure, the Emotional Availability Scales. RESULTS Only maternal schizotypal personality disorder symptoms predicted both the mothers' and the toddlers' interactional styles. Mothers with schizotypal personality symptoms appeared less sensitive, less structuring and more intrusive in their interactions with their toddlers, while mothers' borderline personality disorder symptoms were associated with increased hostility. Furthermore, toddlers who had mothers with schizotypal personality symptoms were less responsive towards their mothers. CONCLUSION Measured dimensionally by self-report, maternal schizotypal personality symptoms were observed to predict the interaction styles of both mothers and their toddlers in the dyad, while borderline personality disorder symptoms predicted mothers' interactional behaviour only. TRIAL REGISTRATION Current Controlled Trials ISRCTN99793905 , retrospectively registered. Registered on (04/08/2014).
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Affiliation(s)
- Magnhild Singstad Høivik
- Department of Mental Health, Faculty of Medicine and Health Sciences, the Norwegian University of Science and Technology (NTNU), N-7491, Trondheim, Norway. .,Division of Psychiatry, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
| | - Stian Lydersen
- 0000 0001 1516 2393grid.5947.fRegional Centre for Child and Youth Mental Health and Child Welfare – Central Norway, Faculty of Medicine and Health Sciences, The Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Ingunn Ranøyen
- 0000 0001 1516 2393grid.5947.fRegional Centre for Child and Youth Mental Health and Child Welfare – Central Norway, Faculty of Medicine and Health Sciences, The Norwegian University of Science and Technology (NTNU), Trondheim, Norway
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Cheng CH, Chan PYS, Hsu SC, Liu CY. Meta-analysis of sensorimotor gating in patients with autism spectrum disorders. Psychiatry Res 2018; 262:413-419. [PMID: 28918862 DOI: 10.1016/j.psychres.2017.09.016] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 09/08/2017] [Accepted: 09/08/2017] [Indexed: 01/24/2023]
Abstract
Prepulse inhibition (PPI) of startle response is a well-established neurophysiological marker of sensorimotor gating ability in psychiatric patients including those with autism spectrum disorders (ASD). PPI has been utilized as an indicator of the central inhibitory function and is potentially linked to the clinical features of this disease. However, it remains inconclusive whether ASD patients exhibit PPI deficits compared with healthy controls. The present meta-analysis aimed to explore the pooled effect sizes of PPI in ASD patients. We searched major electronic databases from 1990 to January 2017. Seven studies, consisting of 21 individual investigations with 135 healthy controls and 99 ASD patients, were obtained. The effect size, calculated as Hedges's g and 95% confidence interval, were estimated. Overall, we found ASD patients exhibited an impaired PPI compared with healthy controls (p = 0.008). Specifically, significant PPI deficits were observed among ASD children/adolescents, compared with their healthy counterparts (p = 0.019). However, differences in PPI responses were not observed among adults. Conclusively, our results reconciled the previous studies and showed that ASD children/adolescents, but not adults, exhibit reduced sensorimotor gating function compared to healthy controls. We also suggest that the parameters of PPI are particularly important and the results should be interpreted with cautions.
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Affiliation(s)
- Chia-Hsiung Cheng
- Department of Occupational Therapy and Graduate Institute of Behavioral Sciences, Chang Gung University, Taoyuan, Taiwan; Laboratory of Brain Imaging and Neural Dynamics (BIND Lab), Chang Gung University, Taoyuan, Taiwan; Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan; Department of Psychiatry, Chang Gung Memorial Hospital, Linkou, Taiwan.
| | - Pei-Ying S Chan
- Department of Occupational Therapy and Graduate Institute of Behavioral Sciences, Chang Gung University, Taoyuan, Taiwan; Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan; Department of Psychiatry, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Shih-Chieh Hsu
- Department of Psychiatry, Chang Gung Memorial Hospital, Linkou, Taiwan; School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chia-Yih Liu
- Department of Psychiatry, Chang Gung Memorial Hospital, Linkou, Taiwan; School of Medicine, Chang Gung University, Taoyuan, Taiwan
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The role of N-methyl-d-aspartate receptors and metabotropic glutamate receptor 5 in the prepulse inhibition paradigms for studying schizophrenia: pharmacology, neurodevelopment, and genetics. Behav Pharmacol 2018; 29:13-27. [DOI: 10.1097/fbp.0000000000000352] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Storozheva ZI, Kirenskaya AV, Gordeev MN, Kovaleva ME, Novototsky-Vlasov VY. COMT Genotype and Sensory and Sensorimotor Gating in High and Low Hypnotizable Subjects. Int J Clin Exp Hypn 2018; 66:83-105. [PMID: 29319456 DOI: 10.1080/00207144.2018.1396120] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
We investigated the association between hypnotizability, COMT polymorphism, P50 suppression ratio, and prepulse inhibition of acoustic startle response (ASR) in 21 high (HH) and 19 low (LH) hypnotizable subjects. The frequency of Met/Met carriers of COMT polymorphysm was higher in HH than in LH group (33.3% versus 10.6%, p = .049). Increased ASR amplitude and latency and decreased prepulse inhibition at 120 ms lead interval were found in the HH compared to the LH group. The effect of COMT genotype on prepulse inhibition was observed in LH group only. No between-group differences in P50 measures were found. The obtained results suppose the participation of dopamine system in mechanisms of hypnotizability and different allocation of attentional resources in HH and LH subjects.
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Affiliation(s)
- Zinaida I Storozheva
- a V. Serbsky Federal Medical Research Centre for Psychiatry and Narcology , Moscow , Russia
| | - Anna V Kirenskaya
- a V. Serbsky Federal Medical Research Centre for Psychiatry and Narcology , Moscow , Russia
| | - Mikhail N Gordeev
- b Institute of Psychotherapy and Clinical Psychology , Moscow , Russia
| | - Maria E Kovaleva
- a V. Serbsky Federal Medical Research Centre for Psychiatry and Narcology , Moscow , Russia
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Notzon S, Vennewald N, Gajewska A, Klahn AL, Diemer J, Winter B, Fohrbeck I, Arolt V, Pauli P, Domschke K, Zwanzger P. Is prepulse modification altered by continuous theta burst stimulation? DAT1 genotype and motor threshold interact on prepulse modification following brain stimulation. Eur Arch Psychiatry Clin Neurosci 2017; 267:767-779. [PMID: 28337537 DOI: 10.1007/s00406-017-0786-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2016] [Accepted: 03/13/2017] [Indexed: 12/14/2022]
Abstract
Previous studies suggest an inhibitory top-down control of the amygdala by the prefrontal cortex (PFC). Both brain regions play a role in the modulation of prepulse modification (PPM) of the acoustic startle response by a pre-stimulus. Repetitive transcranial magnetic stimulation (rTMS) can modulate the activity of the PFC and might thus affect PPM. This study tested the effect of inhibitory rTMS on PPM accounting for a genetic variant of the dopamine transporter gene (DAT1). Healthy participants (N = 102) were stimulated with continuous theta burst stimulation (cTBS, an intense form of inhibitory rTMS) or sham treatment over the right PFC. Afterwards, during continuous presentation of a background white noise a louder noise burst was presented either alone (control startle) or preceded by a prepulse. Participants were genotyped for a DAT1 variable number tandem repeat (VNTR) polymorphism. Two succeeding sessions of cTBS over the right PFC (2 × 600 stimuli with a time lag of 15 min) attenuated averaged prepulse inhibition (PPI) in participants with a high resting motor threshold. An attenuation of PPI induced by prepulses with great distances to the pulse (480, 2000 ms) was observed following active cTBS in participants that were homozygous carriers of the 10-repeat-allele of the DAT1 genotype and had a high resting motor threshold. Our results confirm the importance of the prefrontal cortex for the modulation of PPM. The effects were observed in participants with a high resting motor threshold only, probably because they received a higher dose of cTBS. The effects in homozygous carriers of the DAT1 10-repeat allele confirm the relevance of dopamine for PPM. Conducting an exploratory study we decided against the use of a correction for multiple testing.
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Affiliation(s)
- S Notzon
- Department of Psychiatry and Psychotherapy, University of Münster, Albert-Schweitzer-Campus 1, Gebäude A9, 48149, Münster, Germany.
| | - N Vennewald
- School of Health, Münster University of Applied Sciences, Leonardo Campus 8, 48149, Münster, Germany
| | - A Gajewska
- Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany
| | - A L Klahn
- Department of Psychiatry and Psychotherapy, University of Münster, Albert-Schweitzer-Campus 1, Gebäude A9, 48149, Münster, Germany
| | - J Diemer
- kbo-Inn-Salzach-Hospital, Gabersee 7, 83512, Wasserburg am Inn, Germany
| | - B Winter
- Catholic University of Applied Sciences North Rhine-Westphalia, Münster, Piusallee 89, 48147, Münster, Germany
| | - I Fohrbeck
- Department of Psychiatry and Psychotherapy, University of Münster, Albert-Schweitzer-Campus 1, Gebäude A9, 48149, Münster, Germany
| | - V Arolt
- Department of Psychiatry and Psychotherapy, University of Münster, Albert-Schweitzer-Campus 1, Gebäude A9, 48149, Münster, Germany
| | - P Pauli
- Department of Biological Psychology, Clinical Psychology and Psychotherapy, University of Würzburg, Marcusstraße 9-11, 97070, Würzburg, Germany
| | - K Domschke
- Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany
- Department of Psychiatry and Psychotherapy, University of Freiburg, Hauptstrasse 5, 79104, Freiburg, Germany
| | - P Zwanzger
- Department of Psychiatry and Psychotherapy, University of Münster, Albert-Schweitzer-Campus 1, Gebäude A9, 48149, Münster, Germany
- kbo-Inn-Salzach-Hospital, Gabersee 7, 83512, Wasserburg am Inn, Germany
- Department of Psychiatry und Psychotherapy, Ludwig Maximilians University, Munich, Germany
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Zhang Z, Huang J, Shen Y, Li R. BACE1-Dependent Neuregulin-1 Signaling: An Implication for Schizophrenia. Front Mol Neurosci 2017; 10:302. [PMID: 28993723 PMCID: PMC5622153 DOI: 10.3389/fnmol.2017.00302] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 09/07/2017] [Indexed: 12/13/2022] Open
Abstract
Schizophrenia is a chronic psychiatric disorder with a lifetime prevalence of about 1% in the general population. Recent studies have shown that Neuregulin-1 (Nrg1) is a candidate gene for schizophrenia. At least 15 alternative splicing of NRG1 isoforms all contain an extracellular epidermal growth factor (EGF)-like domain, which is sufficient for Nrg1 biological activity including the formation of myelin sheaths and the regulation of synaptic plasticity. It is known that Nrg1 can be cleaved by β-secretase (BACE1) and the resulting N-terminal fragment (Nrg1-ntf) binds to receptor tyrosine kinase ErbB4, which activates Nrg1/ErbB4 signaling. While changes in Nrg1 expression levels in schizophrenia still remain controversial, understanding the BACE1-cleaved Nrg1-ntf and Nrg1/ErbB4 signaling in schizophrenia neuropathogenesis is essential and important. In this review paper, we included three major parts: (1) Nrg1 structure and cleavage pattern by BACE1; (2) BACE1-dependent Nrg1 cleavage associated with schizophrenia in human studies; and (3) Animal studies of Nrg1 and BACE1 mutations with behavioral observations. Our review will provide a better understanding of Nrg1 in schizophrenia and a potential strategy for using BACE1 cleavage of Nrg1 as a unique biomarker for diagnosis, as well as a new therapeutic target, of schizophrenia.
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Affiliation(s)
- Zhengrong Zhang
- National Clinical Research Center for Mental Disorders, Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical UniversityBeijing, China
| | - Jing Huang
- National Clinical Research Center for Mental Disorders, Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical UniversityBeijing, China
| | - Yong Shen
- Neurodegenerative Disorder Research Center, School of Life Sciences, University of Science and Technology of ChinaHefei, China.,Center for Therapeutic Strategies for Brain Disorders, Roskamp Institute, SarasotaFL, United States.,Center for Hormone Advanced Science and Education, Roskamp Institute, SarasotaFL, United States
| | - Rena Li
- National Clinical Research Center for Mental Disorders, Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical UniversityBeijing, China.,Center for Therapeutic Strategies for Brain Disorders, Roskamp Institute, SarasotaFL, United States.,Center for Hormone Advanced Science and Education, Roskamp Institute, SarasotaFL, United States.,Beijing Institute for Brain Disorders, Capital Medical UniversityBeijing, China
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Managò F, Papaleo F. Schizophrenia: What's Arc Got to Do with It? Front Behav Neurosci 2017; 11:181. [PMID: 28979198 PMCID: PMC5611489 DOI: 10.3389/fnbeh.2017.00181] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 09/11/2017] [Indexed: 01/08/2023] Open
Abstract
Human studies of schizophrenia are now reporting a previously unidentified genetic convergence on postsynaptic signaling complexes such as the activity-regulated cytoskeletal-associated (Arc) gene. However, because this evidence is still very recent, the neurobiological implication of Arc in schizophrenia is still scattered and unrecognized. Here, we first review current and developing findings connecting Arc in schizophrenia. We then highlight recent and previous findings from preclinical mouse models that elucidate how Arc genetic modifications might recapitulate schizophrenia-relevant behavioral phenotypes following the novel Research Domain Criteria (RDoC) framework. Building on this, we finally compare and evaluate several lines of evidence demonstrating that Arc genetics can alter both glutamatergic and dopaminergic systems in a very selective way, again consistent with molecular alterations characteristic of schizophrenia. Despite being only initial, accumulating and compelling data are showing that Arc might be one of the primary biological players in schizophrenia. Synaptic plasticity alterations in the genetic architecture of psychiatric disorders might be a rule, not an exception. Thus, we anticipate that additional evidence will soon emerge to clarify the Arc-dependent mechanisms involved in the psychiatric-related dysfunctional behavior.
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Affiliation(s)
- Francesca Managò
- Department of Neuroscience and Brain Technologies, Istituto Italiano di TecnologiaGenova, Italy
| | - Francesco Papaleo
- Department of Neuroscience and Brain Technologies, Istituto Italiano di TecnologiaGenova, Italy
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Smith AK, Jovanovic T, Kilaru V, Lori A, Gensler L, Lee SS, Norrholm SD, Massa N, Cuthbert B, Bradley B, Ressler KJ, Duncan E. A Gene-Based Analysis of Acoustic Startle Latency. Front Psychiatry 2017; 8:117. [PMID: 28729842 PMCID: PMC5498475 DOI: 10.3389/fpsyt.2017.00117] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 06/19/2017] [Indexed: 12/16/2022] Open
Abstract
Latency of the acoustic startle response is the time required from the presentation of startling auditory stimulus until the startle response is elicited and provides an index of neural processing speed. Latency is prolonged in subjects with schizophrenia compared to controls in some but not all studies and is 68-90% heritable in baseline startle trials. In order to determine the genetic association with latency as a potential inroad into genetically based vulnerability to psychosis, we conducted a gene-based study of latency followed by an independent replication study of significant gene findings with a single-nucleotide polymorphism (SNP)-based analysis of schizophrenia and control subjects. 313 subjects from an urban population of low socioeconomic status with mixed psychiatric diagnoses were included in the gene-based study. Startle testing was conducted using a Biopac M150 system according to our published methods. Genotyping was performed with the Omni-Quad 1M or the Omni Express BeadChip. The replication study was conducted on 154 schizophrenia subjects and 123 psychiatric controls. Genetic analyses were conducted with Illumina Human Omni1-Quad and OmniExpress BeadChips. Twenty-nine SNPs were selected from four genes that were significant in the gene-based analysis and also associated with startle and/or schizophrenia in the literature. Linear regressions on latency were conducted, controlling for age, race, and diagnosis as a dichotomous variable. In the gene-based study, 2,870 genes demonstrated the evidence of association after correction for multiple comparisons (false discovery rate < 0.05). Pathway analysis of these genes revealed enrichment for relevant biological processes including neural transmission (p = 0.0029), synaptic transmission (p = 0.0032), and neuronal development (p = 0.024). The subsequent SNP-based replication analysis revealed a strong association of onset latency with the SNP rs901561 on the neuregulin gene (NRG1) in an additive model (beta = 0.21, p = 0.001), indicating that subjects with the AA and AG genotypes had slower mean latency than subjects with GG genotype. In conclusion, startle latency, a highly heritable measure that is slowed in schizophrenia, may be a useful biological probe for genetic contributions to psychotic disorders. Our analyses in two independent populations point to a significant prediction of startle latency by genetic variation in NRG1.
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Affiliation(s)
- Alicia K. Smith
- Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, United States
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
| | - Tanja Jovanovic
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
| | - Varun Kilaru
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
| | - Adriana Lori
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
| | - Lauren Gensler
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
| | - Samuel S. Lee
- Department of Emergency Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Seth Davin Norrholm
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
- Mental Health Service Line, Atlanta Veterans Affairs Medical Center, Decatur, GA, United States
| | - Nicholas Massa
- Mental Health Service Line, Atlanta Veterans Affairs Medical Center, Decatur, GA, United States
| | - Bruce Cuthbert
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
- Mental Health Service Line, Atlanta Veterans Affairs Medical Center, Decatur, GA, United States
| | - Bekh Bradley
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
- Mental Health Service Line, Atlanta Veterans Affairs Medical Center, Decatur, GA, United States
| | - Kerry J. Ressler
- Department of Psychiatry, Harvard Medical School, Boston, MA, United States
| | - Erica Duncan
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
- Mental Health Service Line, Atlanta Veterans Affairs Medical Center, Decatur, GA, United States
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McDiarmid TA, Bernardos AC, Rankin CH. Habituation is altered in neuropsychiatric disorders-A comprehensive review with recommendations for experimental design and analysis. Neurosci Biobehav Rev 2017; 80:286-305. [PMID: 28579490 DOI: 10.1016/j.neubiorev.2017.05.028] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 05/29/2017] [Indexed: 02/03/2023]
Abstract
Abnormalities in the simplest form of learning, habituation, have been reported in a variety of neuropsychiatric disorders as etiologically diverse as Autism Spectrum Disorder, Fragile X syndrome, Schizophrenia, Parkinson's Disease, Huntington's Disease, Attention Deficit Hyperactivity Disorder, Tourette's Syndrome, and Migraine. Here we provide the first comprehensive review of what is known about alterations in this form of non-associative learning in each disorder. Across several disorders, abnormal habituation is predictive of symptom severity, highlighting the clinical significance of habituation and its importance to normal cognitive function. Abnormal habituation is discussed within the greater framework of learning theory and how it may relate to disease phenotype either as a cause, symptom, or therapy. Important considerations for the design and interpretation of habituation experiments are outlined with the hope that these will aid both clinicians and basic researchers investigating how this simple form of learning is altered in disease.
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Affiliation(s)
- Troy A McDiarmid
- Graduate Program in Neuroscience, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada; Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Rm F221, 2211 Wesbrook Mall, Vancouver, British Columbia, V6T 2B5, Canada
| | - Aram C Bernardos
- Graduate Program in Neuroscience, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada; Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Rm F221, 2211 Wesbrook Mall, Vancouver, British Columbia, V6T 2B5, Canada
| | - Catharine H Rankin
- Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, British Columbia, V6T 1Z4, Canada; Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Rm F221, 2211 Wesbrook Mall, Vancouver, British Columbia, V6T 2B5, Canada.
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Inhibitory deficits in prepulse inhibition, sensory gating, and antisaccade eye movement in schizotypy. Int J Psychophysiol 2017; 114:47-54. [DOI: 10.1016/j.ijpsycho.2017.02.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 02/05/2017] [Accepted: 02/06/2017] [Indexed: 11/18/2022]
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48
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Iacono WG, Malone SM, Vrieze SI. Endophenotype best practices. Int J Psychophysiol 2017; 111:115-144. [PMID: 27473600 PMCID: PMC5219856 DOI: 10.1016/j.ijpsycho.2016.07.516] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 07/21/2016] [Accepted: 07/24/2016] [Indexed: 01/19/2023]
Abstract
This review examines the current state of electrophysiological endophenotype research and recommends best practices that are based on knowledge gleaned from the last decade of molecular genetic research with complex traits. Endophenotype research is being oversold for its potential to help discover psychopathology relevant genes using the types of small samples feasible for electrophysiological research. This is largely because the genetic architecture of endophenotypes appears to be very much like that of behavioral traits and disorders: they are complex, influenced by many variants (e.g., tens of thousands) within many genes, each contributing a very small effect. Out of over 40 electrophysiological endophenotypes covered by our review, only resting heart, a measure that has received scant advocacy as an endophenotype, emerges as an electrophysiological variable with verified associations with molecular genetic variants. To move the field forward, investigations designed to discover novel variants associated with endophenotypes will need extremely large samples best obtained by forming consortia and sharing data obtained from genome wide arrays. In addition, endophenotype research can benefit from successful molecular genetic studies of psychopathology by examining the degree to which these verified psychopathology-relevant variants are also associated with an endophenotype, and by using knowledge about the functional significance of these variants to generate new endophenotypes. Even without molecular genetic associations, endophenotypes still have value in studying the development of disorders in unaffected individuals at high genetic risk, constructing animal models, and gaining insight into neural mechanisms that are relevant to clinical disorder.
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Matsuo J, Ota M, Hori H, Hidese S, Teraishi T, Ishida I, Hiraishi M, Kunugi H. A large single ethnicity study of prepulse inhibition in schizophrenia: Separate analysis by sex focusing on effect of symptoms. J Psychiatr Res 2016; 82:155-62. [PMID: 27505440 DOI: 10.1016/j.jpsychires.2016.07.026] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 07/13/2016] [Accepted: 07/29/2016] [Indexed: 10/21/2022]
Abstract
Deficits in sensorimotor gating, as measured with prepulse inhibition (PPI), have been considered an endophenotype of schizophrenia. However, the question remains whether these deficits are related to current symptoms. This single site study aimed to explore clinical features related to the modulation of startle reflex in a large sample of Japanese patients with schizophrenia (DSM-IV). The subjects comprised 181 patients and 250 healthy controls matched for age and sex. Schizophrenia symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Startle reflex to acoustic stimuli was recorded using a startle stimulus of 115 dB and a prepulse of four different conditions (intensity: 86 dB or 90 dB; lead interval: 60 ms or 120 ms). Patients exhibited significantly reduced startle magnitude (p < 0.001), habituation (p = 0.001), and PPI (90 dB, 60 ms, p = 0.016; 90 dB, 120 ms, p = 0.001) compared with controls. Patients of both sexes exhibited significantly lower habituation and PPI (90 dB, 120 ms) compared with the same sex controls. We could not detect a significant correlation with any clinical variable in the entire patients, however, when men and women were examined separately, there was a negative correlation with the PANSS cognitive domain (ρ = -0.33, p = 0.008) in men, but not in women. Moreover, when patients were subdivided into four clusters, two clusters with high positive symptoms showed significant PPI deficits in men. Our results suggest that sensorimotor gating is impaired in schizophrenia of both sexes, and PPI deficits may be related to thought disturbance and disorganization in male patients with schizophrenia.
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Affiliation(s)
- Junko Matsuo
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
| | - Miho Ota
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
| | - Hiroaki Hori
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
| | - Shinsuke Hidese
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
| | - Toshiya Teraishi
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
| | - Ikki Ishida
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
| | - Moeko Hiraishi
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
| | - Hiroshi Kunugi
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
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Mena A, Ruiz-Salas JC, Puentes A, Dorado I, Ruiz-Veguilla M, De la Casa LG. Reduced Prepulse Inhibition as a Biomarker of Schizophrenia. Front Behav Neurosci 2016; 10:202. [PMID: 27803654 PMCID: PMC5067522 DOI: 10.3389/fnbeh.2016.00202] [Citation(s) in RCA: 142] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 10/04/2016] [Indexed: 01/24/2023] Open
Abstract
The startle response is composed by a set of reflex behaviors intended to prepare the organism to face a potentially relevant stimulus. This response can be modulated by several factors as, for example, repeated presentations of the stimulus (startle habituation), or by previous presentation of a weak stimulus (Prepulse Inhibition [PPI]). Both phenomena appear disrupted in schizophrenia that is thought to reflect an alteration in dopaminergic and glutamatergic neurotransmission. In this paper we analyze whether the reported deficits are indicating a transient effect restricted to the acute phase of the disease, or if it reflects a more general biomarker or endophenotype of the disorder. To this end, we measured startle responses in the same set of thirteen schizophrenia patients with a cross-sectional design at two periods: 5 days after hospital admission and 3 months after discharge. The results showed that both startle habituation and PPI were impaired in the schizophrenia patients at the acute stage as compared to a control group composed by 13 healthy participants, and that PPI but not startle habituation remained disrupted when registered 3 months after the discharge. These data point to the consideration of PPI, but not startle habituation, as a schizophrenia biomarker.
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Affiliation(s)
- Auxiliadora Mena
- Department of Experimental Psychology, University of Seville Seville, Spain
| | - Juan C Ruiz-Salas
- Department of Experimental Psychology, University of Seville Seville, Spain
| | - Andrea Puentes
- Neurosciences Institute, El Bosque University Bogotá, Colombia
| | - Inmaculada Dorado
- Institute of Biomedicine, University Hospital Virgen del Rocío Seville, Spain
| | | | - Luis G De la Casa
- Department of Experimental Psychology, University of Seville Seville, Spain
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