2018
2. MICROCIRCUITS, MACROCIRCUITS, AND CORTICOL DYSFUNCTION IN SCHIZOPHRENIA: A COMPUTATIONAL AND TRANSLATIONAL NEUROSCIENCE PERSPECTIVE
Krystal J. 2. MICROCIRCUITS, MACROCIRCUITS, AND CORTICOL DYSFUNCTION IN SCHIZOPHRENIA: A COMPUTATIONAL AND TRANSLATIONAL NEUROSCIENCE PERSPECTIVE. Schizophrenia Bulletin 2018, 44: s1-s1. PMCID: PMC5887654, DOI: 10.1093/schbul/sby014.001.Peer-Reviewed Original ResearchNMDA glutamate receptorsNMDA receptor antagonistCortical functional connectivityPathophysiology of schizophreniaReceptor antagonistTranslational neuroscience perspectiveGlutamate receptorsHealthy humansAnimal modelsSchizophrenia patientsMemory impairmentNeuropsychiatric disordersSynaptic signalingFunctional connectivityNovel therapeuticsSchizophreniaDisordersPresentationPatientsPathophysiologyDysfunctionKetamineAntagonistSymptomsAbnormalitiesDose-Related Target Occupancy and Effects on Circuitry, Behavior, and Neuroplasticity of the Glycine Transporter-1 Inhibitor PF-03463275 in Healthy and Schizophrenia Subjects
D’Souza D, Carson RE, Driesen N, Johannesen J, Ranganathan M, Krystal JH, Ahn K, Bielen K, Carbuto M, Deaso E, D’Souza D, Ranganathan M, Naganawa M, Ranganathan M, D’Souza D, Nabulsi N, Zheng M, Lin S, Huang Y, Carson R, Driesen N, Ahn K, Morgan P, Suckow R, He G, McCarthy G, Krystal J, Johannesen J, Kenney J, Gelernter J, Gueorguieva R, Pittman B. Dose-Related Target Occupancy and Effects on Circuitry, Behavior, and Neuroplasticity of the Glycine Transporter-1 Inhibitor PF-03463275 in Healthy and Schizophrenia Subjects. Biological Psychiatry 2018, 84: 413-421. PMID: 29499855, PMCID: PMC6068006, DOI: 10.1016/j.biopsych.2017.12.019.Peer-Reviewed Original ResearchMeSH KeywordsAdultAzabicyclo CompoundsBrainCognitive DysfunctionDose-Response Relationship, DrugDouble-Blind MethodFemaleGlycine Plasma Membrane Transport ProteinsHumansImidazolesKetamineLong-Term PotentiationMagnetic Resonance ImagingMaleMemory, Short-TermMiddle AgedPositron-Emission TomographySchizophreniaYoung AdultConceptsHealthy control subjectsLong-term potentiationSchizophrenia patientsControl subjectsCognitive impairmentClinical trialsGlyT1 occupancyN-methyl-D-aspartate receptor functionGlycine transporter-1 inhibitorKetamine-induced disruptionKetamine-induced effectsFunctional magnetic resonance imagingMagnetic resonance imagingPositron emission tomographyMemory-related activationF-MKSubstudy 1Schizophrenia subjectsResonance imagingReceptor functionCortical regionsEmission tomographyTarget engagementPotentiationSchizophrenia
2016
Schizophrenia is associated with a pattern of spatial working memory deficits consistent with cortical disinhibition
Starc M, Murray JD, Santamauro N, Savic A, Diehl C, Cho YT, Srihari V, Morgan PT, Krystal JH, Wang XJ, Repovs G, Anticevic A. Schizophrenia is associated with a pattern of spatial working memory deficits consistent with cortical disinhibition. Schizophrenia Research 2016, 181: 107-116. PMID: 27745755, PMCID: PMC5901719, DOI: 10.1016/j.schres.2016.10.011.Peer-Reviewed Original ResearchConceptsHealthy comparison subjectsSpatial WM taskSchizophrenia patientsSevere cognitive deficitsSpecific spatial locationsComputational modelContinuous response measuresWM precisionWM representationsSpatial WMWM taskDistractor distanceWM impairmentWM tracesNeural mechanismsCognitive deficitsMemory deficitsBehavioral consequencesDelay periodDelay durationCortical disinhibitionSpatial locationComparison subjectsMicrocircuit modelDistractibilityRole of N-Methyl-D-Aspartate Receptors in Action-Based Predictive Coding Deficits in Schizophrenia
Kort NS, Ford JM, Roach BJ, Gunduz-Bruce H, Krystal JH, Jaeger J, Reinhart RM, Mathalon DH. Role of N-Methyl-D-Aspartate Receptors in Action-Based Predictive Coding Deficits in Schizophrenia. Biological Psychiatry 2016, 81: 514-524. PMID: 27647218, PMCID: PMC5203970, DOI: 10.1016/j.biopsych.2016.06.019.Peer-Reviewed Original ResearchConceptsEvent-related potentialsPredictive codingN1 suppressionN1 amplitudePredictive coding deficitsSelf-generated speechSchizophrenia patientsAuditory cortical responsesAuditory predictive codingSelf-produced vocalizationsNMDAR hypofunctionEffects of schizophreniaSpeech soundsTheorized contributionN1 componentHealthy volunteersPassive playbackCognitive deficitsN-methyl-D-aspartate receptorsPutative measureTalk/Cortical responsesHealthy control volunteersCase-control studySaline daysAmygdala volume is reduced in early course schizophrenia
Rich AM, Cho YT, Tang Y, Savic A, Krystal JH, Wang F, Xu K, Anticevic A. Amygdala volume is reduced in early course schizophrenia. Psychiatry Research Neuroimaging 2016, 250: 50-60. PMID: 27035063, PMCID: PMC4904038, DOI: 10.1016/j.pscychresns.2016.02.006.Peer-Reviewed Original ResearchConceptsMagnetic resonance imagingAmygdala volumeSchizophrenia patientsSubcortical structuresEarly course schizophrenia patientsEarly illness courseChronic schizophrenia patientsNeuropathology of schizophreniaMajor subcortical structuresSmaller amygdala volumesEarly course schizophreniaHealthy comparison subjectsBonferroni correctionGray matter volumeAcute stress responseMedication useIllness coursePathophysiologic changesGlobus pallidusIllness phaseNucleus accumbensHigh riskComparison subjectsMatter volumeHR subjects
2015
Functional hierarchy underlies preferential connectivity disturbances in schizophrenia
Yang GJ, Murray JD, Wang XJ, Glahn DC, Pearlson GD, Repovs G, Krystal JH, Anticevic A. Functional hierarchy underlies preferential connectivity disturbances in schizophrenia. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 113: e219-e228. PMID: 26699491, PMCID: PMC4720350, DOI: 10.1073/pnas.1508436113.Peer-Reviewed Original ResearchConceptsFunctional connectivityResting-state functional MRIExcitation/inhibition ratioElevated functional connectivityLarge-scale functional connectivityFronto-parietal control networkI elevationConnectivity disturbancesHealthy subjectsPreferential vulnerabilityAssociation cortexSchizophrenia patientsBipolar disorderFunctional MRIPatientsSymptom levelsSchizophreniaCortical microcircuitsInhibition ratioNeural modelControl networkNeuronal dynamicsHierarchical differencesParsimonious mechanismDysconnectivityRole of GABA Deficit in Sensitivity to the Psychotomimetic Effects of Amphetamine
Ahn KH, Sewell A, Elander J, Pittman B, Ranganathan M, Gunduz-Bruce H, Krystal J, D'Souza DC. Role of GABA Deficit in Sensitivity to the Psychotomimetic Effects of Amphetamine. Neuropsychopharmacology 2015, 40: 2822-2831. PMID: 25953357, PMCID: PMC4864658, DOI: 10.1038/npp.2015.132.Peer-Reviewed Original ResearchConceptsGABA deficitHealthy subjectsPsychotomimetic effectsIntravenous infusionSchizophrenia patientsPANSS positive symptoms subscaleDouble-blind crossover designStriatal dopamine releasePositive symptom subscaleAdministration of drugsDose of AMPHPartial inverse agonistSubclinical responsePharmacokinetic interactionsSubthreshold doseDopamine releaseBenzodiazepine receptorsSymptom subscalesCrossover designCADSS scoresPositive symptomsAMPHInverse agonistSubjective effectsTest day
2014
Preliminary analysis of positive and negative syndrome scale in ketamine-associated psychosis in comparison with schizophrenia
Xu K, Krystal JH, Ning Y, Chen da C, He H, Wang D, Ke X, Zhang X, Ding Y, Liu Y, Gueorguieva R, Wang Z, Limoncelli D, Pietrzak RH, Petrakis IL, Zhang X, Fan N. Preliminary analysis of positive and negative syndrome scale in ketamine-associated psychosis in comparison with schizophrenia. Journal Of Psychiatric Research 2014, 61: 64-72. PMID: 25560772, PMCID: PMC4445679, DOI: 10.1016/j.jpsychires.2014.12.012.Peer-Reviewed Original ResearchConceptsKetamine groupNegative Syndrome ScaleSchizophrenia groupSyndrome ScaleN-methyl-D-aspartate (NMDA) glutamate receptor antagonistGlutamate receptor antagonistsPotential confounding factorsEarly course schizophreniaSymptom dimensionsSymptoms of schizophreniaReceptor antagonistChronic schizophreniaHealthy subjectsKetamine abuseSchizophrenia psychosisSchizophrenia patientsConfounding factorsSymptom severitySymptomsInpatientsSchizophreniaPsychosisKetamine usersDissociation symptomsPrincipal component factor analysisVentral Anterior Cingulate Connectivity Distinguished Nonpsychotic Bipolar Illness From Psychotic Bipolar Disorder and Schizophrenia
Anticevic A, Savic A, Repovs G, Yang G, McKay DR, Sprooten E, Knowles EE, Krystal JH, Pearlson GD, Glahn DC. Ventral Anterior Cingulate Connectivity Distinguished Nonpsychotic Bipolar Illness From Psychotic Bipolar Disorder and Schizophrenia. Schizophrenia Bulletin 2014, 41: 133-143. PMID: 24782562, PMCID: PMC4266289, DOI: 10.1093/schbul/sbu051.Peer-Reviewed Original ResearchConceptsVentral anterior cingulate cortexBipolar illnessPsychosis historyWhole-brain connectivityBipolar patientsConnectivity alterationsBrain connectivityCo-occurring psychosisChronic schizophrenia patientsHealthy comparison subjectsBipolar disorder patientsPsychotic bipolar disorder patientsBipolar disorder groupAnterior cingulate cortexFunctional connectivity studiesPsychotic bipolar disorderLifetime psychosisChronic schizophreniaPsychotic symptomsDisorder patientsPatientsComparison subjectsSchizophrenia patientsBipolar disorderCingulate cortex
2013
Characterizing Thalamo-Cortical Disturbances in Schizophrenia and Bipolar Illness
Anticevic A, Cole MW, Repovs G, Murray JD, Brumbaugh MS, Winkler AM, Savic A, Krystal JH, Pearlson GD, Glahn DC. Characterizing Thalamo-Cortical Disturbances in Schizophrenia and Bipolar Illness. Cerebral Cortex 2013, 24: 3116-3130. PMID: 23825317, PMCID: PMC4224238, DOI: 10.1093/cercor/bht165.Peer-Reviewed Original ResearchConceptsThalamo-cortical systemThalamic connectivityBipolar illnessResting-state functional magnetic resonance imagingSensory-motor cortexSevere mental illnessFunctional magnetic resonance imagingMagnetic resonance imagingThalamic dysconnectivityThalamic seedsClinical presentationNeuropsychiatric syndromeBrain dysconnectivityThalamic nucleiBipolar patientsSchizophrenia patientsSensory gatingMental illnessResonance imagingDysconnectivityCerebellar regionsDiagnostic membershipPrefrontal cortexSchizophreniaIllness
2012
Impaired Visual Cortical Plasticity in Schizophrenia
Çavuş I, Reinhart RM, Roach BJ, Gueorguieva R, Teyler TJ, Clapp WC, Ford JM, Krystal JH, Mathalon DH. Impaired Visual Cortical Plasticity in Schizophrenia. Biological Psychiatry 2012, 71: 512-520. PMID: 22364738, PMCID: PMC3292767, DOI: 10.1016/j.biopsych.2012.01.013.Peer-Reviewed Original ResearchConceptsHigh-frequency stimulationVisual cortical plasticityCortical plasticityVisual steady-state responseN-methyl-D-aspartate receptor functionHealthy control subjectsLong-term potentiation paradigmLong-term potentiationForm of neuroplasticityRepetitive visual stimulationSustained potentiationControl subjectsVEP assessmentSchizophrenia patientsStandard visual stimuliInfrequent target stimuliCore pathophysiologyReceptor functionPotentiationSchizophreniaVisual stimulationComponent scoresStimulationVisual stimuliBaseline
2011
Glutamatergic Modulation of Auditory Information Processing in the Human Brain
Gunduz-Bruce H, Reinhart RM, Roach BJ, Gueorguieva R, Oliver S, D'Souza DC, Ford JM, Krystal JH, Mathalon DH. Glutamatergic Modulation of Auditory Information Processing in the Human Brain. Biological Psychiatry 2011, 71: 969-977. PMID: 22036036, PMCID: PMC3290754, DOI: 10.1016/j.biopsych.2011.09.031.Peer-Reviewed Original ResearchConceptsN-acetylcysteineAuditory mismatch negativityReceptor antagonistN-methyl-D-aspartate receptor antagonistAspartate glutamate receptor antagonistOral N-acetylcysteinePlacebo-controlled studyGlutamate receptor antagonistsEffects of ketamineInfusion of salineMismatch negativityTest dayMMN amplitudeCystine-glutamate exchangerAuditory information processingP300 event-related potentialGlutamatergic modulationCognitive enhancing agentsEvent-related potentialsKetamine effectsHealthy volunteersHealthy humansSchizophrenia patientsPositive symptomsKetamine
2007
Lamotrigine as Add-On Therapy in Schizophrenia
Goff DC, Keefe R, Citrome L, Davy K, Krystal JH, Large C, Thompson TR, Volavka J, Webster EL. Lamotrigine as Add-On Therapy in Schizophrenia. Journal Of Clinical Psychopharmacology 2007, 27: 582-589. PMID: 18004124, DOI: 10.1097/jcp.0b013e31815abf34.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnticonvulsantsAntipsychotic AgentsClozapineDiagnostic and Statistical Manual of Mental DisordersDose-Response Relationship, DrugDouble-Blind MethodDrug Administration ScheduleDrug ResistanceDrug Therapy, CombinationFemaleHumansLamotrigineMaleMiddle AgedPatient CompliancePatient DropoutsPsychiatric Status Rating ScalesSchizophreniaSeverity of Illness IndexSuicide, AttemptedTreatment OutcomeTriazinesConceptsNegative Syndrome Scale total scoreScale total scoreAntipsychotic medicationTotal scoreTreatment groupsSchizophrenia patientsPlacebo-controlled trialPrimary end pointParallel-group trialUse of lamotrigineClinical Global ImpressionAtypical antipsychotic medicationsResidual psychotic symptomsSymptom total scoreNegative Symptoms total scoreLamotrigine augmentationLamotrigine trialsRefractory psychosisAtypical antipsychoticsCognitive composite scoreWeek 12Global ImpressionTreat samplePsychotic symptomsLamotrigine
2006
Enhanced Sensitivity to the Euphoric Effects of Alcohol in Schizophrenia
D'Souza DC, Gil RB, Madonick S, Perry EB, Forselius-Bielen K, Braley G, Donahue L, Tellioglu T, Zimolo Z, Gueorguieva R, Krystal JH. Enhanced Sensitivity to the Euphoric Effects of Alcohol in Schizophrenia. Neuropsychopharmacology 2006, 31: 2767-2775. PMID: 16985503, DOI: 10.1038/sj.npp.1301207.Peer-Reviewed Original ResearchConceptsEffects of alcoholHealthy subjectsBlood alcohol levelsPositive psychotic symptomsSmall transient increaseSelf-medication hypothesisPerceptual alterationsAlcohol administrationMotor functionAlcohol dosesElevated riskPsychotic symptomsLifetime exposureSchizophrenia patientsSchizophrenia symptomsEuphoric effectsNegative symptomsAlcohol levelsAlcohol useStimulatory effectSubjective effectsTransient increaseSchizophreniaStimulatory responseAlcohol responses
2005
Impact of Schizophrenia and Chronic Antipsychotic Treatment on [123I]CNS-1261 Binding to N-Methyl-D-Aspartate Receptors In Vivo
Bressan RA, Erlandsson K, Stone JM, Mulligan RS, Krystal JH, Ell PJ, Pilowsky LS. Impact of Schizophrenia and Chronic Antipsychotic Treatment on [123I]CNS-1261 Binding to N-Methyl-D-Aspartate Receptors In Vivo. Biological Psychiatry 2005, 58: 41-46. PMID: 15992521, DOI: 10.1016/j.biopsych.2005.03.016.Peer-Reviewed Original ResearchConceptsHealthy control subjectsTypical antipsychoticsControl subjectsN-methyl-D-aspartate receptor functionN-methyl-D-aspartate receptorsAntipsychotic drug discoveryChronic antipsychotic treatmentDrug-free patientsImpact of schizophreniaNMDA receptor activityHealthy normal volunteersClozapine treatmentAntipsychotic treatmentGlutamatergic systemPatient groupAntipsychotic drugsNonsignificant reductionNMDA receptorsNormal volunteersSchizophrenia patientsControl groupReceptor activityBrain regionsReceptor functionTomography radiotracerAbnormal hemodynamics in schizophrenia during an auditory oddball task
Kiehl KA, Stevens MC, Celone K, Kurtz M, Krystal JH. Abnormal hemodynamics in schizophrenia during an auditory oddball task. Biological Psychiatry 2005, 57: 1029-1040. PMID: 15860344, PMCID: PMC2771438, DOI: 10.1016/j.biopsych.2005.01.035.Peer-Reviewed Original ResearchConceptsAuditory oddball taskHealthy participantsOddball taskThree-stimulus auditory oddball taskDiffuse brain abnormalitiesHealthy control subjectsNovelty processingWidespread pathologic processCerebral areasControl subjectsBrain abnormalitiesMagnetic resonance imaging dataAbnormal hemodynamicsPathologic processesSchizophrenia patientsParietal cortexCognitive functionHeterogeneous disorderCerebellar circuitsSchizophreniaAbnormalitiesSignificant activationSubcortical systemsFunctional magnetic resonance imaging (fMRI) dataPatientsDelta-9-tetrahydrocannabinol effects in schizophrenia: Implications for cognition, psychosis, and addiction
D’Souza D, Abi-Saab WM, Madonick S, Forselius-Bielen K, Doersch A, Braley G, Gueorguieva R, Cooper TB, Krystal JH. Delta-9-tetrahydrocannabinol effects in schizophrenia: Implications for cognition, psychosis, and addiction. Biological Psychiatry 2005, 57: 594-608. PMID: 15780846, DOI: 10.1016/j.biopsych.2004.12.006.Peer-Reviewed Original ResearchMeSH KeywordsAdultAkathisia, Drug-InducedArousalCognitionDose-Response Relationship, DrugDouble-Blind MethodDronabinolEndocrine SystemFemaleHumansInjections, IntravenousMaleMental RecallMiddle AgedMotor ActivityNeuropsychological TestsPerceptionPsychiatric Status Rating ScalesPsychotic DisordersPsychotropic DrugsSchizophreniaVerbal LearningConceptsSchizophrenia patientsAntipsychotic-treated schizophrenia patientsDelta-9-tetrahydrocannabinol effectsLong-term adverse eventsCognitive deficitsPlacebo-controlled studyDelta-9-THCTransient exacerbationAdverse eventsReceptor dysfunctionEndocrine effectsHealthy subjectsStudy participationPsychotic disordersPlasma prolactinSchizophrenia symptomsPatientsSchizophreniaCognitive effectsPerceptual alterationsDeficitsCannabisSubjectsAkathisiaExacerbationMazindol Augmentation of Antipsychotic Treatment for Schizophrenic Patients with Comorbid Cocaine Abuse or Dependence
Perry E, Gil R, Miles D, Brenner L, Macdougall L, Johnson R, Degen K, Gueorguieva R, Petrakis I, Krystal J, D'Souza D. Mazindol Augmentation of Antipsychotic Treatment for Schizophrenic Patients with Comorbid Cocaine Abuse or Dependence. Journal Of Dual Diagnosis 2005, 1: 37-47. DOI: 10.1300/j374v01n01_04.Peer-Reviewed Original ResearchCocaine abusePsychiatric symptomsCocaine cravingCatecholamine reuptake inhibitorCurrent antipsychotic medicationsCocaine consumptionPlacebo groupAntipsychotic pharmacotherapyReuptake inhibitorsAntipsychotic medicationAntipsychotic treatmentComorbid schizophreniaSchizoaffective patientsSubstance abuse issuesSchizophrenic patientsPatientsSchizoaffective disorderSchizophrenia patientsNatural historyMazindolPilot studyGroup therapySchizophreniaSymptomsAbuse issues
2004
Nicotine effects on brain function and functional connectivity in schizophrenia
Jacobsen LK, D'Souza DC, Mencl WE, Pugh KR, Skudlarski P, Krystal JH. Nicotine effects on brain function and functional connectivity in schizophrenia. Biological Psychiatry 2004, 55: 850-858. PMID: 15050867, DOI: 10.1016/j.biopsych.2003.12.023.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnalysis of VarianceAttentionBrainBrain MappingBrief Psychiatric Rating ScaleCase-Control StudiesFemaleHumansImage Processing, Computer-AssistedMagnetic Resonance ImagingMaleMemory, Short-TermMiddle AgedNeuropsychological TestsNicotineNicotinic AgonistsReaction TimeRegression AnalysisSchizophreniaSmokeTask Performance and AnalysisVerbal LearningConceptsTask performanceFunctional connectivityFunctional magnetic resonance imaging (fMRI) scanningBrain regionsN-back taskMultiple cognitive domainsNetwork of regionsDifficult task conditionsAnterior cingulate cortexAttention loadMemory loadSelective attentionCognitive domainsTask conditionsCognitive functionCingulate cortexThalamocortical functional connectivityNicotine effectsCognitive dysfunctionBrain functionSchizophrenia patientsControl subjectsSchizophrenic subjectsMagnetic resonance imaging (MRI) scanningMental illness
1999
Comparison of four components of sensory gating in schizophrenia and normal subjects: a preliminary report
Boutros N, Belger A, Campbell D, D’Souza C, Krystal J. Comparison of four components of sensory gating in schizophrenia and normal subjects: a preliminary report. Psychiatry Research 1999, 88: 119-130. PMID: 10622348, DOI: 10.1016/s0165-1781(99)00074-8.Peer-Reviewed Original ResearchConceptsNormal control subjectsSchizophrenia patientsSensory gatingControl subjectsNormal subjectsSex-matched normal control subjectsPathophysiology of schizophreniaStimulus repetitionStable schizophrenia patientsSchizophrenia subjectsSimilar abnormalitiesPatientsPreliminary reportDysfunctionDegree of attenuationSchizophreniaLate phaseSubjectsDeviant stimuliStimulus changeIrrelevant stimuliPathophysiologyStimuliPotential paradigmAbnormalities