Mnemonic Discrimination Deficits in First-Episode Psychosis and a Ketamine Model Suggest Dentate Gyrus Pathology Linked to NMDA Receptor Hypofunction

Open AccessPublished:October 11, 2021DOI:https://doi.org/10.1016/j.bpsc.2021.09.008

      Abstract

      Background

      Converging evidence from neuroimaging and postmortem studies suggests that hippocampal subfields are differentially affected in schizophrenia. Recent studies report dentate gyrus dysfunction in chronic schizophrenia, but the underlying mechanisms remain to be elucidated. Here, we sought to examine if this deficit is already present in first-episode psychosis and if NMDA receptor hypofunction, a putative central pathophysiological mechanism in schizophrenia, experimentally induced by ketamine, would result in a similar abnormality.

      Methods

      We applied a mnemonic discrimination task selectively taxing pattern separation in two experiments: 1) a group of 23 patients with first-episode psychosis and 23 matched healthy volunteers and 2) a group of 19 healthy volunteers before and during a ketamine challenge (0.27 mg/kg over 10 min, then 0.25 mg/kg/hour for 50 min, 0.01 mL/s). We calculated response bias–corrected pattern separation and recognition scores. We also examined the relationships between task performance and symptom severity as well as ketamine levels.

      Results

      We reported a deficit in pattern separation performance in patients with first-episode psychosis compared with healthy volunteers (p = .04) and in volunteers during the ketamine challenge compared with baseline (p = .003). Pattern recognition was lower in patients with first-episode psychosis than in control subjects (p < .01). Exploratory analyses revealed no correlation between task performance and Repeatable Battery for the Assessment of Neuropsychological Status total scores or positive symptoms in patients with first-episode psychosis or with ketamine serum levels.

      Conclusions

      We observed a mnemonic discrimination deficit in both datasets. Our findings suggest a tentative mechanistic link between dentate gyrus dysfunction in first-episode psychosis and NMDA receptor hypofunction.

      Keywords

      The brain continuously simplifies and integrates sensory experiences in the context of prior memories, engaging in parallel competition between new, discrete memory formation and generalization across prior experiences (
      • Johnston S.T.
      • Shtrahman M.
      • Parylak S.
      • Gonçalves J.T.
      • Gage F.H.
      Paradox of pattern separation and adult neurogenesis: A dual role for new neurons balancing memory resolution and robustness.
      ). This process is thought to be supported by complementary computational operations: 1) pattern separation, by which similar patterns of neuronal inputs are transformed into distinct neural representations (
      • Leutgeb J.K.
      • Leutgeb S.
      • Moser M.B.
      • Moser E.I.
      Pattern separation in the dentate gyrus and CA3 of the hippocampus.
      ,
      • Leutgeb S.
      • Leutgeb J.K.
      Pattern separation, pattern completion, and new neuronal codes within a continuous CA3 map.
      ), and 2) pattern completion, by which a full memory representation is evoked from a partial set of inputs (
      • Rolls E.T.
      Pattern separation, completion, and categorisation in the hippocampus and neocortex.
      ). Theoretical models (
      • Treves A.
      • Rolls E.T.
      Computational constraints suggest the need for two distinct input systems to the hippocampal CA3 network.
      ,
      • Rolls E.T.
      The mechanisms for pattern completion and pattern separation in the hippocampus.
      ) and growing empirical evidence (
      • Neunuebel J.P.
      • Knierim J.J.
      CA3 retrieves coherent representations from degraded input: Direct evidence for CA3 pattern completion and dentate gyrus pattern separation.
      ,
      • Bakker A.
      • Kirwan C.B.
      • Miller M.
      • Stark C.E.L.
      Pattern separation in the human hippocampal CA3 and dentate gyrus.
      ,
      • Lacy J.W.
      • Yassa M.A.
      • Stark S.M.
      • Muftuler L.T.
      • Stark C.E.L.
      Distinct pattern separation related transfer functions in human CA3/dentate and CA1 revealed using high-resolution fMRI and variable mnemonic similarity.
      ) suggest that functionally distinct hippocampal subfields differentially and simultaneously contribute to these processes. The dentate gyrus is thought to operate as a competitive neuronal network performing pattern separation, delivering relatively orthogonal representation to the CA3 via sparse mossy fiber projections, allowing episodic memories to be formed and stored within the CA3 network, which then can be retrieved from a neural cue (
      • Rolls E.T.
      Pattern separation, completion, and categorisation in the hippocampus and neocortex.
      ,
      • Rolls E.T.
      The mechanisms for pattern completion and pattern separation in the hippocampus.
      ). The balance of excitation and inhibition is likely to play an important role in this process (
      • English D.F.
      • Peyrache A.
      • Stark E.
      • Roux L.
      • Vallentin D.
      • Long M.A.
      • Buzsáki G.
      Excitation and inhibition compete to control spiking during hippocampal ripples: Intracellular study in behaving mice.
      ). Dentate gyrus granule cells functionally innervate GABA (gamma-aminobutyric acid) interneurons that are thought to heavily suppress dentate gyrus activity through feedback inhibition, which mediates sparsity and consequently also pattern separation by avoiding representational overlap (
      • Nitz D.
      • McNaughton B.
      Differential modulation of CA1 and dentate gyrus interneurons during exploration of novel environments.
      ). Furthermore, dentate gyrus NMDA receptors have been shown to mediate pattern separation in the hippocampal network in animal models (
      • McHugh T.J.
      • Jones M.W.
      • Quinn J.J.
      • Balthasar N.
      • Coppari R.
      • Elmquist J.K.
      • et al.
      Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network.
      ).
      Although the fundamental pathology underlying schizophrenia and its symptom domains remains elusive, abnormalities in the excitation/inhibition balance secondary to NMDA receptor hypofunction on GABAergic interneurons have been proposed as a central mechanism (
      • Olney J.W.
      • Farber N.B.
      Glutamate receptor dysfunction and schizophrenia.
      ,
      • Coyle J.T.
      • Tsai G.
      NMDA receptor function, neuroplasticity, and the pathophysiology of schizophrenia.
      ). Because of its neuronal composition, with a greater ratio of excitatory to inhibitory neurons than in the neocortex, the hippocampus may be especially vulnerable to shifts in the excitation/inhibition balance (
      • Heckers S.
      • Konradi C.
      GABAergic mechanisms of hippocampal hyperactivity in schizophrenia.
      ). In addition to reduced structural (
      • Reid M.A.
      • White D.M.
      • Kraguljac N.V.
      • Lahti A.C.
      A combined diffusion tensor imaging and magnetic resonance spectroscopy study of patients with schizophrenia.
      ), functional (
      • Hutcheson N.L.
      • Reid M.A.
      • White D.M.
      • Kraguljac N.V.
      • Avsar K.B.
      • Bolding M.S.
      • et al.
      Multimodal analysis of the hippocampus in schizophrenia using proton magnetic resonance spectroscopy and functional magnetic resonance imaging.
      ,
      • Hutcheson N.L.
      • Sreenivasan K.R.
      • Deshpande G.
      • Reid M.A.
      • Hadley J.
      • White D.M.
      • et al.
      Effective connectivity during episodic memory retrieval in schizophrenia participants before and after antipsychotic medication.
      ), and neurometabolic (
      • Kraguljac N.V.
      • Reid M.A.
      • White D.M.
      • den Hollander J.
      • Lahti A.C.
      Regional decoupling of N-acetyl-aspartate and glutamate in schizophrenia.
      ,
      • Kraguljac N.V.
      • Reid M.
      • White D.
      • Jones R.
      • den Hollander J.
      • Lowman D.
      • Lahti A.C.
      Neurometabolites in schizophrenia and bipolar disorder—A systematic review and meta-analysis.
      ) integrity of the hippocampus in medicated patients with schizophrenia, our group has reported excess hippocampal glutamate (
      • Kraguljac N.V.
      • White D.M.
      • Reid M.A.
      • Lahti A.C.
      Increased hippocampal glutamate and volumetric deficits in unmedicated patients with schizophrenia.
      ) and resting-state functional dysconnectivity (
      • Kraguljac N.V.
      • White D.M.
      • Hadley J.
      • Reid M.A.
      • Lahti A.C.
      Hippocampal-parietal dysconnectivity and glutamate abnormalities in unmedicated patients with schizophrenia.
      ,
      • Kraguljac N.V.
      • White D.M.
      • Hadley N.
      • Hadley J.A.
      • Ver Hoef L.
      • Davis E.
      • Lahti A.C.
      Aberrant hippocampal connectivity in unmedicated patients with schizophrenia and effects of antipsychotic medication: A longitudinal resting state functional MRI study.
      ) in unmedicated patients. We suggested that NMDA receptor hypofunction may be a common pathological substrate, which we empirically supported in an experiment using ketamine (
      • Kraguljac N.V.
      • Frölich M.A.
      • Tran S.
      • White D.M.
      • Nichols N.
      • Barton-McArdle A.
      • et al.
      Ketamine modulates hippocampal neurochemistry and functional connectivity: A combined magnetic resonance spectroscopy and resting-state fMRI study in healthy volunteers.
      ), a noncompetitive drug that preferentially blocks NMDA receptors on GABAergic interneurons (
      • Sapkota K.
      • Mao Z.
      • Synowicki P.
      • Lieber D.
      • Liu M.
      • Ikezu T.
      • et al.
      GluN2D N-methyl-d-aspartate receptor subunit contribution to the stimulation of brain activity and gamma oscillations by ketamine: Implications for schizophrenia.
      ,
      • Yamamoto T.
      • Nakayama T.
      • Yamaguchi J.
      • Matsuzawa M.
      • Mishina M.
      • Ikeda K.
      • Yamamoto H.
      Role of the NMDA receptor GluN2D subunit in the expression of ketamine-induced behavioral sensitization and region-specific activation of neuronal nitric oxide synthase.
      ,
      • von Engelhardt J.
      • Bocklisch C.
      • Tönges L.
      • Herb A.
      • Mishina M.
      • Monyer H.
      GluN2D-containing NMDA receptors-mediate synaptic currents in hippocampal interneurons and pyramidal cells in juvenile mice.
      ,
      Canadian Agency for Drugs and Technologies in Health
      Intravenous Ketamine for the Treatment of Mental Health Disorders: A Review of Clinical Effectiveness and Guidelines.
      ) and is used as a pharmacological model for schizophrenia (
      • Lahti A.C.
      • Weiler M.A.
      • Tamara Michaelidis B.A.
      • Parwani A.
      • Tamminga C.A.
      Effects of ketamine in normal and schizophrenic volunteers.
      ,
      • Lahti A.C.
      • Koffel B.
      • LaPorte D.
      • Tamminga C.A.
      Subanesthetic doses of ketamine stimulate psychosis in schizophrenia.
      ,
      • Lahti A.C.
      • Holcomb H.H.
      Schizophrenia, VIII: Pharmacologic models.
      ,
      • Anticevic A.
      • Corlett P.R.
      • Cole M.W.
      • Savic A.
      • Gancsos M.
      • Tang Y.
      • et al.
      N-methyl-D-aspartate receptor antagonist effects on prefrontal cortical connectivity better model early than chronic schizophrenia [published correction appears in Biol Psychiatry 2016; 79:620–621].
      ). However, because of limitations in spatial resolution of conventional magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging (fMRI), we were unable to make inferences on subfield-specific alterations, which is important because volumetric studies suggest differential alterations (
      • Mathew I.
      • Gardin T.M.
      • Tandon N.
      • Eack S.
      • Francis A.N.
      • Seidman L.J.
      • et al.
      Medial temporal lobe structures and hippocampal subfields in psychotic disorders: Findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study.
      ,
      • Haukvik U.K.
      • Westlye L.T.
      • Mørch-Johnsen L.
      • Jørgensen K.N.
      • Lange E.H.
      • Dale A.M.
      • et al.
      In vivo hippocampal subfield volumes in schizophrenia and bipolar disorder.
      ) or even progression from selective to generalized involvement of hippocampal subfields in schizophrenia (
      • Kawano M.
      • Sawada K.
      • Shimodera S.
      • Ogawa Y.
      • Kariya S.
      • Lang D.J.
      • et al.
      Hippocampal subfield volumes in first episode and chronic schizophrenia.
      ,
      • Ho N.F.
      • Iglesias J.E.
      • Sum M.Y.
      • Kuswanto C.N.
      • Sitoh Y.Y.
      • De Souza J.
      • et al.
      Progression from selective to general involvement of hippocampal subfields in schizophrenia.
      ).
      Alternatively, cognitive tasks that differentially engage hippocampal subfields can help elucidate mechanisms of hippocampal pathology. Two studies using pattern separation and pattern completion tasks in patients with chronic schizophrenia found deficits in pattern separation but not pattern completion (
      • Martinelli C.
      • Shergill S.S.
      Clarifying the role of pattern separation in schizophrenia: The role of recognition and visual discrimination deficits.
      ,
      • Das T.
      • Ivleva E.I.
      • Wagner A.D.
      • Stark C.E.L.
      • Tamminga C.A.
      Loss of pattern separation performance in schizophrenia suggests dentate gyrus dysfunction.
      ), suggesting dentate gyrus dysfunction. They concluded that this alteration likely contributes to memory deficits and psychotic symptoms (
      • Tamminga C.A.
      Psychosis is emerging as a learning and memory disorder.
      ) but failed to establish a relationship with positive symptom severity or memory performance. While a lack of statistical power in these preliminary experiments may explain findings, it is possible that a pattern separation deficit is the result of disease progression.
      Here, we examined performance on a mnemonic discrimination task selectively taxing pattern separation (referred to as pattern separation task hereafter) in 1) a group of patients with first-episode psychosis and matched healthy volunteers and 2) a group of healthy volunteers with similar demographics before and during a pharmacological challenge with ketamine. We hypothesized that impairments in pattern separation are already present early in the illness and that ketamine administration results in a similar deficit. In an exploratory fashion, we also examined possible relationships between task performance and positive symptoms as well as cognitive deficits.

      Methods and Materials

      Patients were recruited from the First Episode Program at the University of Alabama at Birmingham. Healthy volunteers were recruited via flyers and advertisements. Studies were approved by the University of Alabama at Birmingham Institutional Review Board, and written informed consent was obtained prior to enrollment (patients with first-episode psychosis had to be deemed competent to provide consent) (
      • Carpenter Jr., W.T.
      • Gold J.M.
      • Lahti A.C.
      • Queern C.A.
      • Conley R.R.
      • Bartko J.J.
      • et al.
      Decisional capacity for informed consent in schizophrenia research.
      ).
      Subjects were excluded if they had major neurologic or medical conditions, had a history of head trauma with loss of consciousness, had a substance use disorder (excluding nicotine) within 6 months of imaging, were pregnant or breastfeeding, or had MRI contraindications. Healthy volunteers with a history of an Axis I disorder or a psychotic disorder in a first-degree family member were also excluded.

       Clinical Assessment

      The Brief Psychiatric Rating Scale (BPRS) and its positive and negative subscales were used to assess symptom severity. Cognitive function was characterized using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

       Task

      We used a pattern separation task involving two phases (
      • Stark S.M.
      • Yassa M.A.
      • Lacy J.W.
      • Stark C.E.L.
      A task to assess behavioral pattern separation (BPS) in humans: Data from healthy aging and mild cognitive impairment.
      ). During the incidental encoding phase, subjects viewed 40 pictures of objects (presented for 2 s each followed by a 0.5-s interstimulus interval) on a computer screen and were asked to indicate with a key press whether the picture could be classified as an indoor or an outdoor item. To facilitate encoding, a 5-minute break was given prior to the second phase. During the recognition phase, subjects were shown 60 pictures for 2 seconds each; 20 were exactly the same as presented during encoding (targets), 20 were novel pictures not presented during encoding (foils), and 20 were pictures that were similar but not exactly the same as shown during encoding (lures). Subjects were asked to indicate with a key press if they considered the picture to be old, similar, or new in relation to those presented during encoding; they were given up to 2 seconds to respond (Figure 1A). Instructions were given according to the manual for the task. All subjects first completed a practical training run with one of three versions of the task (each using different sets of pictures) prior to completing the experiment with different versions of the task. The order of set presentation was randomized.
      Figure thumbnail gr1
      Figure 1Mnemonic discrimination task. (A) The task had two phases, an incidental encoding phase, where subjects were asked to indicate with a key press whether the picture could be classified as an indoor or an outdoor item, and a recognition phase, where subjects were asked to indicate with a key press if they considered the picture to be old, similar, or new. (B) Task performance in a group of patients with first-episode pschosis (FEP) and healthy volunteers (HVs); pattern separation scores and pattern completion scores were significantly lower in patients with FEP compared with HVs. Dots represent individual measurements, and bars represent the overall group’s performance. (C) Task performance in HVs at baseline and during a ketamine challenge. Pattern separation scores were significantly lower during the ketamine challenge compared with baseline (p = .003). Dots represent individual measurements, and bars represent the overall group’s performance. BPR, bias-corrected pattern recognition score; BPS, bias-corrected pattern separation score.

       Experiment 1

      We enrolled 23 patients with first-episode psychosis; diagnoses were established by review of medical records, the Diagnostic Interview for Genetic Studies (
      • Nurnberger Jr., J.I.
      • Blehar M.C.
      • Kaufmann C.A.
      • York-Cooler C.
      • Simpson S.G.
      • Harkavy-Friedman J.
      • et al.
      Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative.
      ), and consensus of 2 board-certified psychiatrists (ACL and NVK). Mean illness duration was 51.6 ± 66.4 weeks, with a median of 18 weeks. Of the 23 subjects, 20 were within the first 2 years of initial diagnosis, 2 were within the first 3 years, and 1 was diagnosed 5.5 years prior to enrollment. A total of 17 subjects were treated with risperidone, 2 with aripiprazole, 2 with clozapine, and 1 with fluphenazine and risperidone; 1 subject had been stably off antipsychotic medications. Concomitant psychotropic medication was permissible (6 subjects were prescribed benztropine, 2 sertraline, 2 fluoxetine, 1 citalopram, 2 trazodone, and 1 lithium). We also enrolled 23 healthy control subjects matched on sex, age, and parental socioeconomic status. After completing the training run, each subject completed one version of the task (different from the training set).

       Experiment 2

      We enrolled 19 healthy volunteers meeting eligibility criteria. A psychiatric assessment including the Diagnostic Interview for Genetic Studies, physical examination, urine drug screen, and if applicable, pregnancy test was completed during the initial screen and before the ketamine infusion.
      After completing a training run and one version of the task (different from the training set), subjects received an intravenous racemic ketamine challenge (0.27 mg/kg bolus over 10 min, followed by a continuous infusion of 0.25 mg/kg/hour for 50 min) in the Clinical Research Unit. Immediately after completion of the bolus and 50 minutes after start of the challenge, 10 mL of blood were collected. Blood samples were centrifuged to obtain plasma and stored at −40 °C. Ketamine plasma levels were assayed (Nathan Klein Institute) using a validated liquid chromatographic procedure, which included a liquid/liquid extraction with internal standard, followed by high-performance liquid chromatography/reversed phase column separation with ultraviolet detection. During the ketamine challenge, vital signs including heart rate, blood pressure, peripheral oxygen saturation, and respiratory rate were monitored by an anesthesiology fellow under supervision of a board-certified anesthesiologist. Subjects completed a third version of the task 15 minutes after the continuous infusion started. Monitoring was continued for 1 hour after infusion completion. Prior to discharge into the care of an accompanying driver, subjects were medically cleared by the anesthesiology fellow and psychiatrist. Two subjects withdrew prior to completing the task because of emesis.

       Statistical Analyses

      Statistical analyses were performed with SPSS 23.0. Independent-sample two-tailed t tests and χ2 tests were used to investigate group differences in demographics and cognitive variables. Paired-sample two-tailed t tests were conducted to assess change in BPRS scores between baseline and the ketamine infusion.
      The response bias–corrected pattern separation score (referred to as pattern separation hereafter) was calculated as P(similar|lure) − P(similar|foil), and the response bias––corrected recognition score (referred to as pattern recognition hereafter) was calculated as P(old|target) minus P(old|foil) (
      • Yassa M.A.
      • Lacy J.W.
      • Stark S.M.
      • Albert M.S.
      • Gallagher M.
      • Stark C.E.L.
      Pattern separation deficits associated with increased hippocampal CA3 and dentate gyrus activity in nondemented older adults.
      ). In an exploratory fashion, we also examined the relationships between pattern separation/pattern completion performance and symptom severity as well as ketamine plasma levels.

      Results

       Experiment 1

      Groups did not differ in gender, age, or parental occupation. Healthy volunteers scored significantly higher on RBANS than patients with first-episode psychosis (Table 1).
      Table 1Demographics and Clinical Characteristics
      CharacteristicsExperiment 1Experiment 2
      FEP, n = 23HV, n = 23t/χ2p ValueHV, n = 19t/χ2p Value
      Gender, Male, %69.6%69.6%0.001.063.2%
      Age, Years22.65 (1.03)22.65 (0.93)0.001.023.84 (3.67)
      Parental Occupation Rank
      Ranks determined from Diagnostic Interview for Genetic Studies (scale, 1–18); higher rank (lower numerical value) corresponds to higher socioeconomic status.
      4.61 (4.62)3.78 (3.23)−8.56.483.05 (3.66)
      Diagnosis, n
       Schizophrenia16
       Schizoaffective disorder7
      RBANS
      FEP: n = 20; HV: n = 21.
       Total index70.30 (16.11)92.62 (11.8)5.08<.0197.79 (15.82)
       Immediate memory80.05 (16.95)101.33 (14.20)4.37<.01106.21 (16.45)
       Visuospatial76.45 (17.13)85.76 (15.32)1.84.0789.47 (16.63)
       Language78.45 (13.41)98.81 (14.82)4.60<.01103.47 (12.66)
       Attention span72.90 (16.69)94.62 (17.24)4.10<.01101.58 (16.35)
       Delayed memory72.90 (20.84)93.19 (8.70)4.03<.0191.32 (12.76)
      BaselineKetamine
      BPRS
      Scale, 1–7; positive: conceptual disorganization, hallucinatory behavior, and unusual thought content; negative: emotional withdrawal, motor retardation, and blunted affect. FEP: n = 22; ketamine: n = 17.
       Total score34.36 (11.91)20.84 (0.83)39.47 (6.97)11.12<.01
       Positive5.18 (2.82)3.00 (0.00)6.41 (1.54)9.11<.01
       Negative6.73 (2.96)3.32 (0.48)6.76 (2.51)6.03<.01
      Values shown are mean (SD) unless otherwise indicated.
      BPRS, Brief Psychiatric Rating Scale; FEP, first-episode psychosis; HV, healthy volunteer; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status.
      a Ranks determined from Diagnostic Interview for Genetic Studies (scale, 1–18); higher rank (lower numerical value) corresponds to higher socioeconomic status.
      b FEP: n = 20; HV: n = 21.
      c Scale, 1–7; positive: conceptual disorganization, hallucinatory behavior, and unusual thought content; negative: emotional withdrawal, motor retardation, and blunted affect. FEP: n = 22; ketamine: n = 17.
      Table 2Behavioral Pattern Separation Response Measures
      ExperimentTargetsLuresFoils
      OldSimilarNewOldSimilarNewOldSimilarNew
      Experiment 1
       HV, n = 2390.1% (9.0)7.7% (7.8)2.2% (4.0)47.5% (16.0)48.8% (18.1)3.7% (5.9)6.0% (7.3)12.6% (11.5)81.6% (14.0)
       FEP, n = 2371.8% (22.2)15.1% (12.7)13.1% (17.8)45.0% (18.7)35.3% (18.0)19.9% (19.4)8.1% (8.0)10.9% (10.1)81.1% (10.1)
      Experiment 2
       Saline, n = 1984.5% (20.1)9.4% (8.9)6.0% (20.2)33.3% (17.0)58.9% (21.1)7.8% (19.8)6.1% (10.4)7.9% (11.6)85.9% (17.5)
       Ketamine, n = 1783.6% (10.4)10.4% (8.0)6.2% (9.9)40.2% (16.2)42.5% (19.9)17.4% (15.8)10.0% (16.8)11.9% (11.7)78.1% (22.0)
      Values in parentheses are SD.
      FEP, first-episode psychosis; HV, healthy volunteer.
      Healthy volunteers had significantly better pattern separation scores (t = 2.16; p = .04), and better pattern recognition performance (t = 4.01; p < .01) than patients with first-episode psychosis (Figure 1B). Further comparisons (Table 2) revealed that patients gave fewer “similar” responses to lures (t = 2.53; p = .02), fewer “old” responses to targets (t = 3.66; p < .01), more “new” responses to lures (t = −3.83, p < .01) and targets (t = −2.86; p < .01), as well as more “similar” responses to targets (t = −2.39; p = .02). Exploratory analyses showed no correlations between RBANS scores and pattern separation or pattern completion scores; positive symptom severity and pattern separation scores were negatively correlated at trend level (r = −0.42; p = .054).

       Experiment 2

      None of the subjects had baseline BPRS scores in the clinical range. As expected, BPRS total scores increased during the ketamine challenge (Table 1). Ketamine plasma levels were 81.95 ± 32.44 ng/mL immediately after completion of the bolus and 98.32 ± 19.59 ng/mL 50 minutes after the start of the ketamine infusion.
      During the ketamine challenge, pattern separation (t = 3.57; p < .01) but not pattern recognition performance (t = 0.81; p = .43) was significantly lower when compared with baseline (Figure 1C). Task performance during the saline and ketamine infusions were significantly correlated for pattern separation (r = 0.64; p < .01). Exploratory analyses showed no correlations between pattern separation and pattern recognition scores during the ketamine challenge and BPRS total, positive, and negative symptom scores or ketamine plasma levels at either time point.

      Discussion

      Here, we present results from two complementary experiments characterizing hippocampal subfield–specific alterations with a pattern separation task in patients with first-episode psychosis and in a pharmacological model of schizophrenia. As hypothesized, we observed a deficit in pattern separation in the illness. Our findings extend prior studies reporting pattern separation abnormalities in chronic schizophrenia and suggest a tentative mechanistic link between dentate gyrus dysfunction in first-episode psychosis and NMDA receptor hypofunction.
      While hippocampal volume loss is one of the most replicated findings in the schizophrenia literature (
      • Adriano F.
      • Caltagirone C.
      • Spalletta G.
      Hippocampal volume reduction in first-episode and chronic schizophrenia: A review and meta-analysis.
      ), much less attention has been devoted to subfield-specific alterations in this structurally and functionally heterogeneous area, in part because of the technical challenges in accurately delineating subfields in vivo. Neuroimaging studies report widespread volume loss across hippocampal subfields in patients with chronic schizophrenia (
      • Mathew I.
      • Gardin T.M.
      • Tandon N.
      • Eack S.
      • Francis A.N.
      • Seidman L.J.
      • et al.
      Medial temporal lobe structures and hippocampal subfields in psychotic disorders: Findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study.
      ,
      • Haukvik U.K.
      • Westlye L.T.
      • Mørch-Johnsen L.
      • Jørgensen K.N.
      • Lange E.H.
      • Dale A.M.
      • et al.
      In vivo hippocampal subfield volumes in schizophrenia and bipolar disorder.
      ) and a negative relationship between CA1 and CA2/3 volumes and positive symptom severity (
      • Kühn S.
      • Musso F.
      • Mobascher A.
      • Warbrick T.
      • Winterer G.
      • Gallinat J.
      Hippocampal subfields predict positive symptoms in schizophrenia: First evidence from brain morphometry.
      ). Furthermore, a high-resolution 7T MRI study investigating the dentate gyrus granule cell layer found a trend-level decreased contrast in the right hippocampus in schizophrenia that was predictive of diagnosis (
      • Kirov I.I.
      • Hardy C.J.
      • Matsuda K.
      • Messinger J.
      • Cankurtaran C.Z.
      • Warren M.
      • et al.
      In vivo 7 Tesla imaging of the dentate granule cell layer in schizophrenia.
      ). Examinations of hippocampal surface shape report only CA1 and CA2 deformities in patients with first-episode schizophrenia (
      • Narr K.L.
      • Thompson P.M.
      • Szeszko P.
      • Robinson D.
      • Jang S.
      • Woods R.P.
      • et al.
      Regional specificity of hippocampal volume reductions in first-episode schizophrenia.
      ) and CA1 deformities in patients with chronic disorders (
      • Zierhut K.C.
      • Graßmann R.
      • Kaufmann J.
      • Steiner J.
      • Bogerts B.
      • Schiltz K.
      Hippocampal CA1 deformity is related to symptom severity and antipsychotic dosage in schizophrenia.
      ), but this method is not ideal to delineate subfields embedded deep in the hippocampal formation. A recent study reported evidence of progression from CA1 volume reduction in earlier stages of the illness (mean illness duration of 7 years) to a general involvement of hippocampal subfields in patients with chronic disorders (mean illness duration of 18 years), with the greatest volume decline in those with poor clinical outcomes (
      • Ho B.C.
      • Alicata D.
      • Ward J.
      • Moser D.J.
      • O’Leary D.S.
      • Arndt S.
      • Andreasen N.C.
      Untreated initial psychosis: Relation to cognitive deficits and brain morphology in first-episode schizophrenia.
      ). In contrast, Kawano et al. (
      • Kawano M.
      • Sawada K.
      • Shimodera S.
      • Ogawa Y.
      • Kariya S.
      • Lang D.J.
      • et al.
      Hippocampal subfield volumes in first episode and chronic schizophrenia.
      ) found an isolated dentate gyrus volume loss in patients with first-episode schizophrenia who had minimal prior exposure to antipsychotic medications. With illness progression, the authors noted increasing dentate gyrus atrophy along with volume deficits in the CA2/3 region, but not in CA1 (
      • Kawano M.
      • Sawada K.
      • Shimodera S.
      • Ogawa Y.
      • Kariya S.
      • Lang D.J.
      • et al.
      Hippocampal subfield volumes in first episode and chronic schizophrenia.
      ). It is important to note that the cellular substrates and pathophysiological mechanisms underlying this putatively progressive structural deficit across subfields remain to be elucidated. Postmortem evidence suggests no alteration in the total neuron number in any of the hippocampal subfields (
      • Walker M.A.
      • Highley J.R.
      • Esiri M.M.
      • McDonald B.
      • Roberts H.C.
      • Evans S.P.
      • Crow T.J.
      Estimated neuronal populations and volumes of the hippocampus and its subfields in schizophrenia.
      ,
      • Schmitt A.
      • Steyskal C.
      • Bernstein H.G.
      • Schneider-Axmann T.
      • Parlapani E.
      • Schaeffer E.L.
      • et al.
      Stereologic investigation of the posterior part of the hippocampus in schizophrenia.
      ), but rather a subtle decrease of parvalbumin-positive interneurons in the dentate gyrus and CA1 (
      • Konradi C.
      • Yang C.K.
      • Zimmerman E.I.
      • Lohmann K.M.
      • Gresch P.
      • Pantazopoulos H.
      • et al.
      Hippocampal interneurons are abnormal in schizophrenia.
      ) and reduction of adult-born hippocampal granule cell neurons (
      • Reif A.
      • Fritzen S.
      • Finger M.
      • Strobel A.
      • Lauer M.
      • Schmitt A.
      • Lesch K.P.
      Neural stem cell proliferation is decreased in schizophrenia, but not in depression.
      ). The recent finding of reduced CA1 glutamic acid decarboxylase immunoreactivity neutrophil density has been interpreted in support of hyperexcitation related to GABAergic impairment (
      • Steiner J.
      • Brisch R.
      • Schiltz K.
      • Dobrowolny H.
      • Mawrin C.
      • Krzyżanowska M.
      • et al.
      GABAergic system impairment in the hippocampus and superior temporal gyrus of patients with paranoid schizophrenia: A post-mortem study.
      ). Consistent with this, two functional investigations of hippocampal subfields identified selectively increased cerebral blood volumes in CA1 in patients with chronic disorders (
      • Schobel S.A.
      • Lewandowski N.M.
      • Corcoran C.M.
      • Moore H.
      • Brown T.
      • Malaspina D.
      • Small S.A.
      Differential targeting of the CA1 subfield of the hippocampal formation by schizophrenia and related psychotic disorders.
      ,
      • Talati P.
      • Rane S.
      • Kose S.
      • Blackford J.U.
      • Gore J.
      • Donahue M.J.
      • Heckers S.
      Increased hippocampal CA1 cerebral blood volume in schizophrenia.
      ), an abnormality that also appears to be a marker of conversion to syndromal psychosis in prodromal patients (
      • Schobel S.A.
      • Lewandowski N.M.
      • Corcoran C.M.
      • Moore H.
      • Brown T.
      • Malaspina D.
      • Small S.A.
      Differential targeting of the CA1 subfield of the hippocampal formation by schizophrenia and related psychotic disorders.
      ), and likely driven by glutamatergic excess related to NMDA receptor hypofunction (
      • Schobel S.A.
      • Chaudhury N.H.
      • Khan U.A.
      • Paniagua B.
      • Styner M.A.
      • Asllani I.
      • et al.
      Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver.
      ). In the CA3 but not CA1 subfield, an increase of GluN2B-containing NMDA receptors along with other markers of synaptic plasticity in schizophrenia is reported (
      • Li W.
      • Ghose S.
      • Gleason K.
      • Begovic A.
      • Perez J.
      • Bartko J.
      • et al.
      Synaptic proteins in the hippocampus indicative of increased neuronal activity in CA3 in schizophrenia [published correction appears in Am J Psychiatry 2015; 172:488].
      ). Taken together, findings are in support of an abnormal excitation/inhibition balance related to NMDA receptor hypofunction that differentially, and possibly even progressively, adversely affects hippocampal subfields in schizophrenia.
      Here, we report a deficit in pattern separation resulting from ketamine administration. Administration of subanesthetic doses of ketamine in healthy human subjects has been shown to affect several cognitive domains including sustained attention (
      • Umbricht D.
      • Schmid L.
      • Koller R.
      • Vollenweider F.X.
      • Hell D.
      • Javitt D.C.
      Ketamine-induced deficits in auditory and visual context-dependent processing in healthy volunteers: Implications for models of cognitive deficits in schizophrenia.
      ), semantic memory (
      • Stefanovic A.
      • Brandner B.
      • Klaassen E.
      • Cregg R.
      • Nagaratnam M.
      • Bromley L.M.
      • et al.
      Acute and chronic effects of ketamine on semantic priming: Modeling schizophrenia?.
      ), verbal memory (
      • Parwani A.
      • Weiler M.A.
      • Blaxton T.A.
      • Warfel D.
      • Hardin M.
      • Frey K.
      • Lahti A.C.
      The effects of a subanesthetic dose of ketamine on verbal memory in normal volunteers.
      ), but not others such as working memory (
      • Rowland L.M.
      • Astur R.S.
      • Jung R.E.
      • Bustillo J.R.
      • Lauriello J.
      • Yeo R.A.
      Selective cognitive impairments associated with NMDA receptor blockade in humans.
      ), recall accuracy (
      • LaPorte D.J.
      • Blaxton T.A.
      • Michaelidis T.
      • Robertson D.U.
      • Weiler M.A.
      • Tamminga C.A.
      • Lahti A.C.
      Subtle effects of ketamine on memory when administered following stimulus presentation.
      ), or reaction time (
      • Passie T.
      • Karst M.
      • Wiese B.
      • Emrich H.M.
      • Schneider U.
      Effects of different subanesthetic doses of (S)-ketamine on neuropsychology, psychopathology, and state of consciousness in man.
      ). In parallel, acute ketamine administration has been shown to disrupt frontal and hippocampal contribution to encoding and retrieval of episodic memory (
      • Honey G.D.
      • Honey R.A.E.
      • O’Loughlin C.
      • Sharar S.R.
      • Kumaran D.
      • Suckling J.
      • et al.
      Ketamine disrupts frontal and hippocampal contribution to encoding and retrieval of episodic memory: An fMRI study.
      ) and affect hippocampal connectivity during memory recollection (
      • Vogt K.M.
      • Ibinson J.W.
      • Smith C.T.
      • Citro A.T.
      • Norton C.M.
      • Karim H.T.
      • et al.
      Midazolam and ketamine produce distinct neural changes in memory, pain, and fear networks during pain.
      ). Animal models suggest that intact hippocampal NMDA receptor function is necessary for learning one-trial odor-place associations, but that recall can be performed without further involvement of NMDA receptors (
      • Day M.
      • Langston R.
      • Morris R.G.M.
      Glutamate-receptor-mediated encoding and retrieval of paired-associate learning.
      ). Dentate gyrus granule cell–specific GluN1 NMDA receptor subunit knockout mice show impaired spatial, object-place association task performance, especially when places are close together and require pattern separation before storage in CA3 (
      • McHugh T.J.
      • Jones M.W.
      • Quinn J.J.
      • Balthasar N.
      • Coppari R.
      • Elmquist J.K.
      • et al.
      Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network.
      ). This finding was later extended by Kannangara et al. (
      • Kannangara T.S.
      • Eadie B.D.
      • Bostrom C.A.
      • Morch K.
      • Brocardo P.S.
      • Christie B.R.
      GluN2A−/− mice lack bidirectional synaptic plasticity in the dentate gyrus and perform poorly on spatial pattern separation tasks.
      ), who showed that global deletion of GluN2A, a subunit of the NMDA receptor, resulted in disrupted dentate gyrus signaling and compromised spatial pattern separation, likely related to a disturbance in synaptic plasticity. Similarly, lower GluN1, another NMDA receptor subunit, has been found to be decreased in the dentate gyrus, but not other hippocampal subregions (
      • Stan A.D.
      • Ghose S.
      • Zhao C.
      • Hulsey K.
      • Mihalakos P.
      • Yanagi M.
      • et al.
      Magnetic resonance spectroscopy and tissue protein concentrations together suggest lower glutamate signaling in dentate gyrus in schizophrenia.
      ). Consistent with this, computational models demonstrated that weak network inhibition increased errors in pattern separation (
      • Hanson J.E.
      • Madison D.V.
      Imbalanced pattern completion vs. separation in cognitive disease: Network simulations of synaptic pathologies predict a personalized therapeutics strategy.
      ), and absence of feedback inhibition resulted in an increased firing probability and decreased dentate gyrus pattern separation efficiency (
      • Faghihi F.
      • Moustafa A.A.
      A computational model of pattern separation efficiency in the dentate gyrus with implications in schizophrenia.
      ). In addition, several in vivo neuroimaging studies in healthy subjects have linked dentate gyrus activity with pattern separation (
      • Bakker A.
      • Kirwan C.B.
      • Miller M.
      • Stark C.E.L.
      Pattern separation in the human hippocampal CA3 and dentate gyrus.
      ,
      • Berron D.
      • Schütze H.
      • Maass A.
      • Cardenas-Blanco A.
      • Kuijf H.J.
      • Kumaran D.
      • Düzel E.
      Strong evidence for pattern separation in human dentate gyrus.
      ), which is congruent with preclinical studies in rodents (
      • Leutgeb J.K.
      • Leutgeb S.
      • Moser M.B.
      • Moser E.I.
      Pattern separation in the dentate gyrus and CA3 of the hippocampus.
      ,
      • McHugh T.J.
      • Jones M.W.
      • Quinn J.J.
      • Balthasar N.
      • Coppari R.
      • Elmquist J.K.
      • et al.
      Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network.
      ,
      • Kesner R.P.
      • Kirk R.A.
      • Yu Z.
      • Polansky C.
      • Musso N.D.
      Dentate gyrus supports slope recognition memory, shades of grey-context pattern separation and recognition memory, and CA3 supports pattern completion for object memory.
      ).
      It is noteworthy that we replicated findings from two prior studies examining pattern separation performance in patients with chronic schizophrenia (
      • Martinelli C.
      • Shergill S.S.
      Clarifying the role of pattern separation in schizophrenia: The role of recognition and visual discrimination deficits.
      ,
      • Das T.
      • Ivleva E.I.
      • Wagner A.D.
      • Stark C.E.L.
      • Tamminga C.A.
      Loss of pattern separation performance in schizophrenia suggests dentate gyrus dysfunction.
      ) in patients with first-episode psychosis, which suggests that dentate gyrus dysfunction may not merely be a result of disease progression. Impaired pattern separation in schizophrenia has been hypothesized to be associated with memory impairment and positive symptoms due to false memories with psychotic content (
      • Martinelli C.
      • Shergill S.S.
      Clarifying the role of pattern separation in schizophrenia: The role of recognition and visual discrimination deficits.
      ,
      • Tamminga C.A.
      Psychosis is emerging as a learning and memory disorder.
      ). We did not observe a correlation between pattern separation and RBANS scores, and neither did we find a significant correlation between positive symptom severity and pattern separation performance, which is consistent with a finding by Kim and Yassa (
      • Kim J.
      • Yassa M.A.
      Assessing recollection and familiarity of similar lures in a behavioral pattern separation task.
      ) who reported no difference in the occurrence of false recollections across experiences where pattern separation does and does not occur.
      Results of our experiments need to be interpreted in the context of several strengths and limitations. Patients with first-episode psychosis and healthy volunteers in the first experiment were carefully matched on several key variables including age, gender, and parental socioeconomic status; demographics were comparable to those of healthy volunteers in the second experiment. We implemented a widely used task paradigm, calculated bias-corrected outcome measures, and included a practice run to mitigate training effects. However, we did not parametrically alter the degree of inference of stimuli in the task, precluding us to make conclusions on the sensitivity of the task to detect changes in pattern separation (
      • Liu K.Y.
      • Gould R.L.
      • Coulson M.C.
      • Ward E.V.
      • Howard R.J.
      Tests of pattern separation and pattern completion in humans-A systematic review.
      ). We also did not formally test visual discrimination, which has been shown to be associated with poor performance on a pattern separation task in patients with schizophrenia (
      • Martinelli C.
      • Shergill S.S.
      Clarifying the role of pattern separation in schizophrenia: The role of recognition and visual discrimination deficits.
      ); it is therefore not possible to definitively attribute our findings to deficits in pattern separation as opposed to visual discrimination deficits. The increased tendency of identifying target and lure items as new in patients with first-episode psychosis suggests failure to recognize previously seen items. As recommended by Martinelli and Shergill (
      • Martinelli C.
      • Shergill S.S.
      Clarifying the role of pattern separation in schizophrenia: The role of recognition and visual discrimination deficits.
      ), future studies should include appropriate measures of recognition and visual discrimination performance to aid in interpretation of findings. Patients with first-episode psychosis were treated with antipsychotic medication, which could have confounded outcomes. It will be important to include unmedicated patients in future studies to disentangle medication effects from intrinsic characteristics of the illness. We did not use a placebo control or a crossover design in our ketamine experiment, which renders it possible that observed changes in task performance are not entirely attributable to drug effects. Future studies should include a placebo-controlled experimental design to be able to make more definitive conclusions. It should also be noted that due to the systemic administration of ketamine, it is possible that other areas of the brain that are involved in pattern separation (
      • Rolls E.T.
      Pattern separation, completion, and categorisation in the hippocampus and neocortex.
      ,
      • Pidgeon L.M.
      • Morcom A.M.
      Cortical pattern separation and item-specific memory encoding.
      ) are affected by the drug and may contribute to the behavioral alterations observed with ketamine administration. Furthermore, ketamine has a complex pharmacological profile, and to our knowledge, there is no experimental data published that definitively demonstrate that the overall action of ketamine is inhibitory in the dentate gyrus. Finally, data from the behavioral task we used allow us to indirectly make inferences on hippocampal subfield function, but we did not have neuroimaging or molecular data that provide direct evidence of dentate gyrus pathology or NMDA receptor hypofunction in this patient population.
      In summary, we present empirical evidence supporting a proposed mechanistic link between dentate gyrus dysfunction and NMDA receptor hypofunction, a key concept in this complex neuropsychiatric syndrome. Collectively, our findings add to the effort of bridging fundamental gaps in our understanding of neuropathological mechanisms of the illness and have potential clinical relevance. To date, no treatments for cognitive or negative symptoms are available. Targeting dentate gyrus dysfunction by modulating NMDA receptors may help alleviate symptom burden across symptom domains. A major challenge in this regard is that only systemic NMDA-sensitive drugs are available, which fail to take into account that glutamatergic alterations may differ between subfields. In addition, high-resolution neuroimaging needs to confirm a direct conjunction between NMDA receptor hypofunction and dentate gyrus–specific functional task activation deficits, and longitudinal studies need to establish utility and robustness of pattern separation as a simple and inexpensive marker of NMDA receptor hypofunction in schizophrenia.

      Acknowledgments and Disclosures

      This study was funded by the National Institute of Mental Health (Grant No. R01MH102951 [to ACL]), the National Institute of Mental Health (Grant No. K23MH106683 [to NVK]), the University of Alabama at Birmingham Civitan International Research Center (to NVK), and UAB Center for Clinical and Translational Science (to NVK).
      NVK served as consultant for Neurocrine Biosciences, Inc. All other authors report no biomedical financial interests or potential conflicts of interest.

      References

        • Johnston S.T.
        • Shtrahman M.
        • Parylak S.
        • Gonçalves J.T.
        • Gage F.H.
        Paradox of pattern separation and adult neurogenesis: A dual role for new neurons balancing memory resolution and robustness.
        Neurobiol Learn Mem. 2016; 129: 60-68
        • Leutgeb J.K.
        • Leutgeb S.
        • Moser M.B.
        • Moser E.I.
        Pattern separation in the dentate gyrus and CA3 of the hippocampus.
        Science. 2007; 315: 961-966
        • Leutgeb S.
        • Leutgeb J.K.
        Pattern separation, pattern completion, and new neuronal codes within a continuous CA3 map.
        Learn Mem. 2007; 14: 745-757
        • Rolls E.T.
        Pattern separation, completion, and categorisation in the hippocampus and neocortex.
        Neurobiol Learn Mem. 2016; 129: 4-28
        • Treves A.
        • Rolls E.T.
        Computational constraints suggest the need for two distinct input systems to the hippocampal CA3 network.
        Hippocampus. 1992; 2: 189-199
        • Rolls E.T.
        The mechanisms for pattern completion and pattern separation in the hippocampus.
        Front Syst Neurosci. 2013; 7: 74
        • Neunuebel J.P.
        • Knierim J.J.
        CA3 retrieves coherent representations from degraded input: Direct evidence for CA3 pattern completion and dentate gyrus pattern separation.
        Neuron. 2014; 81: 416-427
        • Bakker A.
        • Kirwan C.B.
        • Miller M.
        • Stark C.E.L.
        Pattern separation in the human hippocampal CA3 and dentate gyrus.
        Science. 2008; 319: 1640-1642
        • Lacy J.W.
        • Yassa M.A.
        • Stark S.M.
        • Muftuler L.T.
        • Stark C.E.L.
        Distinct pattern separation related transfer functions in human CA3/dentate and CA1 revealed using high-resolution fMRI and variable mnemonic similarity.
        Learn Mem. 2010; 18: 15-18
        • English D.F.
        • Peyrache A.
        • Stark E.
        • Roux L.
        • Vallentin D.
        • Long M.A.
        • Buzsáki G.
        Excitation and inhibition compete to control spiking during hippocampal ripples: Intracellular study in behaving mice.
        J Neurosci. 2014; 34: 16509-16517
        • Nitz D.
        • McNaughton B.
        Differential modulation of CA1 and dentate gyrus interneurons during exploration of novel environments.
        J Neurophysiol. 2004; 91: 863-872
        • McHugh T.J.
        • Jones M.W.
        • Quinn J.J.
        • Balthasar N.
        • Coppari R.
        • Elmquist J.K.
        • et al.
        Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network.
        Science. 2007; 317: 94-99
        • Olney J.W.
        • Farber N.B.
        Glutamate receptor dysfunction and schizophrenia.
        Arch Gen Psychiatry. 1995; 52: 998-1007
        • Coyle J.T.
        • Tsai G.
        NMDA receptor function, neuroplasticity, and the pathophysiology of schizophrenia.
        Int Rev Neurobiol. 2004; 59: 491-515
        • Heckers S.
        • Konradi C.
        GABAergic mechanisms of hippocampal hyperactivity in schizophrenia.
        Schizophr Res. 2015; 167: 4-11
        • Reid M.A.
        • White D.M.
        • Kraguljac N.V.
        • Lahti A.C.
        A combined diffusion tensor imaging and magnetic resonance spectroscopy study of patients with schizophrenia.
        Schizophr Res. 2016; 170: 341-350
        • Hutcheson N.L.
        • Reid M.A.
        • White D.M.
        • Kraguljac N.V.
        • Avsar K.B.
        • Bolding M.S.
        • et al.
        Multimodal analysis of the hippocampus in schizophrenia using proton magnetic resonance spectroscopy and functional magnetic resonance imaging.
        Schizophr Res. 2012; 140: 136-142
        • Hutcheson N.L.
        • Sreenivasan K.R.
        • Deshpande G.
        • Reid M.A.
        • Hadley J.
        • White D.M.
        • et al.
        Effective connectivity during episodic memory retrieval in schizophrenia participants before and after antipsychotic medication.
        Hum Brain Mapp. 2015; 36: 1442-1457
        • Kraguljac N.V.
        • Reid M.A.
        • White D.M.
        • den Hollander J.
        • Lahti A.C.
        Regional decoupling of N-acetyl-aspartate and glutamate in schizophrenia.
        Neuropsychopharmacology. 2012; 37: 2635-2642
        • Kraguljac N.V.
        • Reid M.
        • White D.
        • Jones R.
        • den Hollander J.
        • Lowman D.
        • Lahti A.C.
        Neurometabolites in schizophrenia and bipolar disorder—A systematic review and meta-analysis.
        Psychiatry Res. 2012; 203: 111-125
        • Kraguljac N.V.
        • White D.M.
        • Reid M.A.
        • Lahti A.C.
        Increased hippocampal glutamate and volumetric deficits in unmedicated patients with schizophrenia.
        JAMA Psychiatry. 2013; 70: 1294-1302
        • Kraguljac N.V.
        • White D.M.
        • Hadley J.
        • Reid M.A.
        • Lahti A.C.
        Hippocampal-parietal dysconnectivity and glutamate abnormalities in unmedicated patients with schizophrenia.
        Hippocampus. 2014; 24: 1524-1532
        • Kraguljac N.V.
        • White D.M.
        • Hadley N.
        • Hadley J.A.
        • Ver Hoef L.
        • Davis E.
        • Lahti A.C.
        Aberrant hippocampal connectivity in unmedicated patients with schizophrenia and effects of antipsychotic medication: A longitudinal resting state functional MRI study.
        Schizophr Bull. 2016; 42: 1046-1055
        • Kraguljac N.V.
        • Frölich M.A.
        • Tran S.
        • White D.M.
        • Nichols N.
        • Barton-McArdle A.
        • et al.
        Ketamine modulates hippocampal neurochemistry and functional connectivity: A combined magnetic resonance spectroscopy and resting-state fMRI study in healthy volunteers.
        Mol Psychiatry. 2017; 22: 562-569
        • Sapkota K.
        • Mao Z.
        • Synowicki P.
        • Lieber D.
        • Liu M.
        • Ikezu T.
        • et al.
        GluN2D N-methyl-d-aspartate receptor subunit contribution to the stimulation of brain activity and gamma oscillations by ketamine: Implications for schizophrenia.
        J Pharmacol Exp Ther. 2016; 356: 702-711
        • Yamamoto T.
        • Nakayama T.
        • Yamaguchi J.
        • Matsuzawa M.
        • Mishina M.
        • Ikeda K.
        • Yamamoto H.
        Role of the NMDA receptor GluN2D subunit in the expression of ketamine-induced behavioral sensitization and region-specific activation of neuronal nitric oxide synthase.
        Neurosci Lett. 2016; 610: 48-53
        • von Engelhardt J.
        • Bocklisch C.
        • Tönges L.
        • Herb A.
        • Mishina M.
        • Monyer H.
        GluN2D-containing NMDA receptors-mediate synaptic currents in hippocampal interneurons and pyramidal cells in juvenile mice.
        Front Cell Neurosci. 2015; 9: 95
        • Canadian Agency for Drugs and Technologies in Health
        Intravenous Ketamine for the Treatment of Mental Health Disorders: A Review of Clinical Effectiveness and Guidelines.
        Canadian Agency for Drugs and Technologies in Health, Ottawa2014
        • Lahti A.C.
        • Weiler M.A.
        • Tamara Michaelidis B.A.
        • Parwani A.
        • Tamminga C.A.
        Effects of ketamine in normal and schizophrenic volunteers.
        Neuropsychopharmacology. 2001; 25: 455-467
        • Lahti A.C.
        • Koffel B.
        • LaPorte D.
        • Tamminga C.A.
        Subanesthetic doses of ketamine stimulate psychosis in schizophrenia.
        Neuropsychopharmacology. 1995; 13: 9-19
        • Lahti A.C.
        • Holcomb H.H.
        Schizophrenia, VIII: Pharmacologic models.
        Am J Psychiatry. 2003; 160: 2091
        • Anticevic A.
        • Corlett P.R.
        • Cole M.W.
        • Savic A.
        • Gancsos M.
        • Tang Y.
        • et al.
        N-methyl-D-aspartate receptor antagonist effects on prefrontal cortical connectivity better model early than chronic schizophrenia [published correction appears in Biol Psychiatry 2016; 79:620–621].
        Biol Psychiatry. 2015; 77: 569-580
        • Mathew I.
        • Gardin T.M.
        • Tandon N.
        • Eack S.
        • Francis A.N.
        • Seidman L.J.
        • et al.
        Medial temporal lobe structures and hippocampal subfields in psychotic disorders: Findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study.
        JAMA Psychiatry. 2014; 71: 769-777
        • Haukvik U.K.
        • Westlye L.T.
        • Mørch-Johnsen L.
        • Jørgensen K.N.
        • Lange E.H.
        • Dale A.M.
        • et al.
        In vivo hippocampal subfield volumes in schizophrenia and bipolar disorder.
        Biol Psychiatry. 2015; 77: 581-588
        • Kawano M.
        • Sawada K.
        • Shimodera S.
        • Ogawa Y.
        • Kariya S.
        • Lang D.J.
        • et al.
        Hippocampal subfield volumes in first episode and chronic schizophrenia.
        PLoS One. 2015; 10e0117785
        • Ho N.F.
        • Iglesias J.E.
        • Sum M.Y.
        • Kuswanto C.N.
        • Sitoh Y.Y.
        • De Souza J.
        • et al.
        Progression from selective to general involvement of hippocampal subfields in schizophrenia.
        Mol Psychiatry. 2017; 22: 142-152
        • Martinelli C.
        • Shergill S.S.
        Clarifying the role of pattern separation in schizophrenia: The role of recognition and visual discrimination deficits.
        Schizophr Res. 2015; 166: 328-333
        • Das T.
        • Ivleva E.I.
        • Wagner A.D.
        • Stark C.E.L.
        • Tamminga C.A.
        Loss of pattern separation performance in schizophrenia suggests dentate gyrus dysfunction.
        Schizophr Res. 2014; 159: 193-197
        • Tamminga C.A.
        Psychosis is emerging as a learning and memory disorder.
        Neuropsychopharmacology. 2013; 38: 247
        • Carpenter Jr., W.T.
        • Gold J.M.
        • Lahti A.C.
        • Queern C.A.
        • Conley R.R.
        • Bartko J.J.
        • et al.
        Decisional capacity for informed consent in schizophrenia research.
        Arch Gen Psychiatry. 2000; 57: 533-538
        • Stark S.M.
        • Yassa M.A.
        • Lacy J.W.
        • Stark C.E.L.
        A task to assess behavioral pattern separation (BPS) in humans: Data from healthy aging and mild cognitive impairment.
        Neuropsychologia. 2013; 51: 2442-2449
        • Nurnberger Jr., J.I.
        • Blehar M.C.
        • Kaufmann C.A.
        • York-Cooler C.
        • Simpson S.G.
        • Harkavy-Friedman J.
        • et al.
        Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative.
        Arch Gen Psychiatry. 1994; 51 (discussion 863–864): 849-859
        • Yassa M.A.
        • Lacy J.W.
        • Stark S.M.
        • Albert M.S.
        • Gallagher M.
        • Stark C.E.L.
        Pattern separation deficits associated with increased hippocampal CA3 and dentate gyrus activity in nondemented older adults.
        Hippocampus. 2011; 21: 968-979
        • Adriano F.
        • Caltagirone C.
        • Spalletta G.
        Hippocampal volume reduction in first-episode and chronic schizophrenia: A review and meta-analysis.
        Neuroscientist. 2012; 18: 180-200
        • Kühn S.
        • Musso F.
        • Mobascher A.
        • Warbrick T.
        • Winterer G.
        • Gallinat J.
        Hippocampal subfields predict positive symptoms in schizophrenia: First evidence from brain morphometry.
        Transl Psychiatry. 2012; 2: e127
        • Kirov I.I.
        • Hardy C.J.
        • Matsuda K.
        • Messinger J.
        • Cankurtaran C.Z.
        • Warren M.
        • et al.
        In vivo 7 Tesla imaging of the dentate granule cell layer in schizophrenia.
        Schizophr Res. 2013; 147: 362-367
        • Narr K.L.
        • Thompson P.M.
        • Szeszko P.
        • Robinson D.
        • Jang S.
        • Woods R.P.
        • et al.
        Regional specificity of hippocampal volume reductions in first-episode schizophrenia.
        Neuroimage. 2004; 21: 1563-1575
        • Zierhut K.C.
        • Graßmann R.
        • Kaufmann J.
        • Steiner J.
        • Bogerts B.
        • Schiltz K.
        Hippocampal CA1 deformity is related to symptom severity and antipsychotic dosage in schizophrenia.
        Brain. 2013; 136: 804-814
        • Ho B.C.
        • Alicata D.
        • Ward J.
        • Moser D.J.
        • O’Leary D.S.
        • Arndt S.
        • Andreasen N.C.
        Untreated initial psychosis: Relation to cognitive deficits and brain morphology in first-episode schizophrenia.
        Am J Psychiatry. 2003; 160: 142-148
        • Walker M.A.
        • Highley J.R.
        • Esiri M.M.
        • McDonald B.
        • Roberts H.C.
        • Evans S.P.
        • Crow T.J.
        Estimated neuronal populations and volumes of the hippocampus and its subfields in schizophrenia.
        Am J Psychiatry. 2002; 159: 821-828
        • Schmitt A.
        • Steyskal C.
        • Bernstein H.G.
        • Schneider-Axmann T.
        • Parlapani E.
        • Schaeffer E.L.
        • et al.
        Stereologic investigation of the posterior part of the hippocampus in schizophrenia.
        Acta Neuropathol. 2009; 117: 395-407
        • Konradi C.
        • Yang C.K.
        • Zimmerman E.I.
        • Lohmann K.M.
        • Gresch P.
        • Pantazopoulos H.
        • et al.
        Hippocampal interneurons are abnormal in schizophrenia.
        Schizophr Res. 2011; 131: 165-173
        • Reif A.
        • Fritzen S.
        • Finger M.
        • Strobel A.
        • Lauer M.
        • Schmitt A.
        • Lesch K.P.
        Neural stem cell proliferation is decreased in schizophrenia, but not in depression.
        Mol Psychiatry. 2006; 11: 514-522
        • Steiner J.
        • Brisch R.
        • Schiltz K.
        • Dobrowolny H.
        • Mawrin C.
        • Krzyżanowska M.
        • et al.
        GABAergic system impairment in the hippocampus and superior temporal gyrus of patients with paranoid schizophrenia: A post-mortem study.
        Schizophr Res. 2016; 177: 10-17
        • Schobel S.A.
        • Lewandowski N.M.
        • Corcoran C.M.
        • Moore H.
        • Brown T.
        • Malaspina D.
        • Small S.A.
        Differential targeting of the CA1 subfield of the hippocampal formation by schizophrenia and related psychotic disorders.
        Arch Gen Psychiatry. 2009; 66: 938-946
        • Talati P.
        • Rane S.
        • Kose S.
        • Blackford J.U.
        • Gore J.
        • Donahue M.J.
        • Heckers S.
        Increased hippocampal CA1 cerebral blood volume in schizophrenia.
        Neuroimage Clin. 2014; 5: 359-364
        • Schobel S.A.
        • Chaudhury N.H.
        • Khan U.A.
        • Paniagua B.
        • Styner M.A.
        • Asllani I.
        • et al.
        Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver.
        Neuron. 2013; 78: 81-93
        • Li W.
        • Ghose S.
        • Gleason K.
        • Begovic A.
        • Perez J.
        • Bartko J.
        • et al.
        Synaptic proteins in the hippocampus indicative of increased neuronal activity in CA3 in schizophrenia [published correction appears in Am J Psychiatry 2015; 172:488].
        Am J Psychiatry. 2015; 172: 373-382
        • Umbricht D.
        • Schmid L.
        • Koller R.
        • Vollenweider F.X.
        • Hell D.
        • Javitt D.C.
        Ketamine-induced deficits in auditory and visual context-dependent processing in healthy volunteers: Implications for models of cognitive deficits in schizophrenia.
        Arch Gen Psychiatry. 2000; 57: 1139-1147
        • Stefanovic A.
        • Brandner B.
        • Klaassen E.
        • Cregg R.
        • Nagaratnam M.
        • Bromley L.M.
        • et al.
        Acute and chronic effects of ketamine on semantic priming: Modeling schizophrenia?.
        J Clin Psychopharmacol. 2009; 29: 124-133
        • Parwani A.
        • Weiler M.A.
        • Blaxton T.A.
        • Warfel D.
        • Hardin M.
        • Frey K.
        • Lahti A.C.
        The effects of a subanesthetic dose of ketamine on verbal memory in normal volunteers.
        Psychopharmacology (Berl). 2005; 183: 265-274
        • Rowland L.M.
        • Astur R.S.
        • Jung R.E.
        • Bustillo J.R.
        • Lauriello J.
        • Yeo R.A.
        Selective cognitive impairments associated with NMDA receptor blockade in humans.
        Neuropsychopharmacology. 2005; 30: 633-639
        • LaPorte D.J.
        • Blaxton T.A.
        • Michaelidis T.
        • Robertson D.U.
        • Weiler M.A.
        • Tamminga C.A.
        • Lahti A.C.
        Subtle effects of ketamine on memory when administered following stimulus presentation.
        Psychopharmacology (Berl). 2005; 180: 385-390
        • Passie T.
        • Karst M.
        • Wiese B.
        • Emrich H.M.
        • Schneider U.
        Effects of different subanesthetic doses of (S)-ketamine on neuropsychology, psychopathology, and state of consciousness in man.
        Neuropsychobiology. 2005; 51: 226-233
        • Honey G.D.
        • Honey R.A.E.
        • O’Loughlin C.
        • Sharar S.R.
        • Kumaran D.
        • Suckling J.
        • et al.
        Ketamine disrupts frontal and hippocampal contribution to encoding and retrieval of episodic memory: An fMRI study.
        Cereb Cortex. 2005; 15: 749-759
        • Vogt K.M.
        • Ibinson J.W.
        • Smith C.T.
        • Citro A.T.
        • Norton C.M.
        • Karim H.T.
        • et al.
        Midazolam and ketamine produce distinct neural changes in memory, pain, and fear networks during pain.
        Anesthesiology. 2021; 135: 69-82
        • Day M.
        • Langston R.
        • Morris R.G.M.
        Glutamate-receptor-mediated encoding and retrieval of paired-associate learning.
        Nature. 2003; 424: 205-209
        • Kannangara T.S.
        • Eadie B.D.
        • Bostrom C.A.
        • Morch K.
        • Brocardo P.S.
        • Christie B.R.
        GluN2A−/− mice lack bidirectional synaptic plasticity in the dentate gyrus and perform poorly on spatial pattern separation tasks.
        Cereb Cortex. 2015; 25: 2102-2113
        • Stan A.D.
        • Ghose S.
        • Zhao C.
        • Hulsey K.
        • Mihalakos P.
        • Yanagi M.
        • et al.
        Magnetic resonance spectroscopy and tissue protein concentrations together suggest lower glutamate signaling in dentate gyrus in schizophrenia.
        Mol Psychiatry. 2015; 20: 433-439
        • Hanson J.E.
        • Madison D.V.
        Imbalanced pattern completion vs. separation in cognitive disease: Network simulations of synaptic pathologies predict a personalized therapeutics strategy.
        BMC Neurosci. 2010; 11: 96
        • Faghihi F.
        • Moustafa A.A.
        A computational model of pattern separation efficiency in the dentate gyrus with implications in schizophrenia.
        Front Syst Neurosci. 2015; 9: 42
        • Berron D.
        • Schütze H.
        • Maass A.
        • Cardenas-Blanco A.
        • Kuijf H.J.
        • Kumaran D.
        • Düzel E.
        Strong evidence for pattern separation in human dentate gyrus.
        J Neurosci. 2016; 36: 7569-7579
        • Kesner R.P.
        • Kirk R.A.
        • Yu Z.
        • Polansky C.
        • Musso N.D.
        Dentate gyrus supports slope recognition memory, shades of grey-context pattern separation and recognition memory, and CA3 supports pattern completion for object memory.
        Neurobiol Learn Mem. 2016; 129: 29-37
        • Kim J.
        • Yassa M.A.
        Assessing recollection and familiarity of similar lures in a behavioral pattern separation task.
        Hippocampus. 2013; 23: 287-294
        • Liu K.Y.
        • Gould R.L.
        • Coulson M.C.
        • Ward E.V.
        • Howard R.J.
        Tests of pattern separation and pattern completion in humans-A systematic review.
        Hippocampus. 2016; 26: 705-717
        • Pidgeon L.M.
        • Morcom A.M.
        Cortical pattern separation and item-specific memory encoding.
        Neuropsychologia. 2016; 85: 256-271