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

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.

Neural Signatures of Memory Encoding in Schizophrenia Are Modulated by Antipsychotic Treatment.

There is no pharmacological treatment to remediate cognitive impairment in schizophrenia (SZ). It is imperative to characterize underlying pathologies of memory processing in order to effectively develop new treatments. In this longitudinal study, we combined functional magnetic resonance imaging during a memory encoding task with proton MR spectroscopy to measure hippocampal glutamate + glutamine (Glx). Seventeen SZ were scanned while unmedicated and after 6 weeks of treatment with risperidone and compared to a group of matched healthy controls (HC) scanned 6 weeks apart. Unmedicated patients showed reduced blood oxygen level dependent (BOLD) response in several regions, including the hippocampus, and greater BOLD response in regions of the default mode network (DMN) during correct memory encoding. Post hoc contrasts from significant group by time interactions indicated reduced hippocampal BOLD response at baseline with subsequent increase following treatment. Hippocampal Glx was not different between groups at baseline, but at week 6, hippocampal Glx was significantly lower in SZ compared to HC. Finally, in unmedicated SZ, higher hippocampal Glx predicted less deactivation of the BOLD response in regions of the DMN. Using 2 brain imaging modalities allowed us to concurrently investigate different mechanisms involved in memory encoding dysfunction in SZ. Hippocampal pathology during memory encoding stems from decreased hippocampal recruitment and faulty deactivation of the DMN, and hippocampal recruitment during encoding can be modulated by antipsychotic treatment. High Glx in unmedicated patients predicted less deactivation of the DMN; these results suggest a mechanism by which faulty DMN deactivation, a hallmark of pathological findings in SZ, is achieved.

A longitudinal neurite and free water imaging study in patients with a schizophrenia spectrum disorder.

Diffusion tensor imaging (DTI) studies show widespread white matter abnormalities in schizophrenia, but it is difficult to directly relate these parameters to biological processes. Neurite orientation dispersion and density imaging (NODDI) is geared toward biophysical characterization of white matter microstructure, but only few studies have leveraged this technique to study white matter alterations. We recruited 42 schizophrenia patients (30 antipsychotic-naïve and 12 currently untreated) and 42 matched controls in this prospective study. We assessed the orientation dispersion index (ODI) and extracellular free water (FW) using single-shell DTI data before and after a 6-week trial of risperidone. Longitudinal data were available for 27 patients. Voxelwise analyses showed significantly increased ODI in the posterior limb of the internal capsule in unmedicated patients (242 voxels; x = -24; y = 6; z = 6; p < 0.01; α < 0.04), but no alterations in FW. Whole brain measures did not reveal alterations in ODI but a 6.3% trend-level increase in FW in unmedicated SZ (t = -1.873; p = 0.07). Baseline ODI was negatively correlated with subsequent response to antipsychotic treatment (r = -0.38; p = 0.049). Here, we demonstrated altered fiber complexity in medication-naïve and unmedicated patients with a schizophrenia spectrum illness. Lesser whole brain fiber uniformity was predictive of poor response to treatment, suggesting this measure may be a clinically relevant biomarker. Interestingly, we found no significant changes in NODDI indices after short-term treatment with risperidone. Our data show that biophysical diffusion models have promise for the in vivo evaluation of brain microstructure in this devastating neuropsychiatric syndrome.

Micro- and Macrostructural White Matter Integrity in Never-Treated and Currently Unmedicated Patients With Schizophrenia and Effects of Short-Term Antipsychotic Treatment.

BACKGROUND: Schizophrenia is associated with progressive white matter changes, but it is unclear whether antipsychotic medications contribute to these. Our objective was to characterize effects of short-term treatment with risperidone on white matter diffusion indices. METHODS: We recruited 42 patients with schizophrenia (30 never treated and 12 currently untreated) and 42 matched healthy control subjects in this prospective case-control neuroimaging study. Patients received a 6-week trial of risperidone. Using diffusion tensor imaging, we assessed microstructural (fractional anisotropy, mean diffusivity, and radial diffusivity) and macrostructural (radial fiber trophy) white matter integrity deficits in unmedicated patients compared with control subjects and change in white matter integrity in patients before and after antipsychotic treatment (mean risperidone dose at end point was 3.73 ± 1.72 mg). RESULTS: At baseline, fractional anisotropy was decreased in the left medial temporal white matter (cluster extent: 123 voxels; Montreal Neurological Institute peak coordinates: x = -51, y = -44, z = -7; α < .05), and mean diffusivity was increased in the fusiform/lingual gyrus white matter extending to the hippocampal part of the cingulum (cluster extent: 185 voxels; peak coordinates: x = -27, y = -49, z = 2; α < .04) in patients compared with control subjects. Radial diffusivity and macrostructure were not abnormal. None of the diffusion indices showed a significant change after 6 weeks of treatment with both voxelwise and whole-brain white matter analyses. CONCLUSIONS: We demonstrate microstructural white matter integrity abnormalities in the absence of macrostructural impairment in unmedicated patients with primarily early-stage schizophrenia. In our data, we found no significant white matter changes after short-term treatment with risperidone.

RETRACTED: Mnemonic Discrimination Deficits in First-Episode Psychosis and a Ketamine Model Suggests Dentate Gyrus Pathology Linked to N-Methyl-D-Aspartate Receptor Hypofunction.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). Retraction notice to: "Mnemonic Discrimination Deficits in First-Episode Psychosis and a Ketamine Model Suggests Dentate Gyrus Pathology Linked to N-Methyl-D-Aspartate Receptor Hypofunction" by Nina Vanessa Kraguljac, Matthew Carle, Michael A. Frölich, Steve Tran, Michael A. Yassa, David Matthew White, Abhishek Reddy, and Adrienne Carol Lahti (Biol Psychiatry Cogn Neurosci Neuroimaging 2018; 3:231-238); https://doi.org/10.1016/j.bpsc.2017.02.005. This article has been retracted at the request of Cameron S. Carter, M.D., Editor of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, with agreement from all authors. The authors discovered an error in the calculation of the response bias­corrected pattern recognition score in this article, which has significantly changed the results for experiment 1. Specifically, the authors discovered that the response bias corrected pattern recognition score was erroneously computed as P('old'|target) minus P('old'|lure) rather than P('old'|target) minus P('old'|foil). After re-running statistical analyses with the correct values, the authors found a significant difference in the response bias­corrected pattern recognition score in healthy volunteers (HV) compared with first-episode psychosis (FEP) patients (HV: 84.13 ± 10.96; FEP: 63.70 ± 21.83; t = 4.01; p < .01) in experiment 1. This finding is not consistent with the original report, where the authors reported no group differences in bias-corrected pattern recognition scores (originally reported values: t = 0.93, p = .36). The authors again found no significant correlations between pattern completion scores and BPRS total, positive, or negative symptom scores or RBANS scores, consistent with the original report. In experiment 2, bias-corrected pattern recognition scores did not differ between the saline and ketamine conditions (saline: 78.29 ± 28.04; ketamine: 73.59 ± 18.94; t = 0.81; p = 0.43), which is consistent with the original report (originally reported values: t = −0.69, p = .50). Contrary to the original report, task performance during the saline and ketamine infusions was no longer correlated at trend level for pattern recognition. Repeat analyses showed no correlations between pattern recognition scores during the ketamine challenge and BPRS total, positive, and negative symptom scores, or ketamine plasma levels at either time point, consistent with the original report. The authors have verified that bias-corrected pattern separation scores were calculated correctly for both experiments in the initial report. This error affects the abstract, the results, Figure 1, and discussion of the manuscript. The authors voluntarily informed the Journal of this honest error upon its discovery. Because of the extent and nature of the changes to the paper, the editors and authors concluded that, to ensure maximum clarity and transparency, the only course of action was to retract this version of the paper. The authors are revising the paper, which the Journal will re-review and consider further for publication.

Change in brain network topology as a function of treatment response in schizophrenia: a longitudinal resting-state fMRI study using graph theory.

A number of neuroimaging studies have provided evidence in support of the hypothesis that faulty interactions between spatially disparate brain regions underlie the pathophysiology of schizophrenia, but it remains unclear to what degree antipsychotic medications affect these. We hypothesized that the balance between functional integration and segregation of brain networks is impaired in unmedicated patients with schizophrenia, but that it can be partially restored by antipsychotic medications. We included 32 unmedicated patients with schizophrenia (SZ) and 32 matched healthy controls (HC) in this study. We obtained resting-state scans while unmedicated, and again after 6 weeks of treatment with risperidone to assess functional integration and functional segregation of brain networks using graph theoretical measures. Compared with HC, unmedicated SZ showed reduced global efficiency and increased clustering coefficients. This pattern of aberrant functional network integration and segregation was modulated with antipsychotic medications, but only in those who responded to treatment. Our work lends support to the concept of schizophrenia as a dysconnectivity syndrome, and suggests that faulty brain network topology in schizophrenia is modulated by antipsychotic medication as a function of treatment response.

Aberrant Hippocampal Connectivity in Unmedicated Patients With Schizophrenia and Effects of Antipsychotic Medication: A Longitudinal Resting State Functional MRI Study.

To better characterize hippocampal pathophysiology in schizophrenia, we conducted a longitudinal study evaluating hippocampal functional connectivity during resting state, using seeds prescribed in its anterior and posterior regions. We enrolled 34 unmedicated patients with schizophrenia or schizoaffective disorder (SZ) and 34 matched healthy controls. SZ were scanned while off medication, then were treated with risperidone for 6 weeks and re-scanned (n = 22). Group differences in connectivity, as well as changes in connectivity over time, were assessed on the group's participant level functional connectivity maps. We found significant dysconnectivity with anterior and posterior hippocampal seeds in unmedicated SZ. Baseline connectivity between the hippocampus and anterior cingulate cortex, caudate nucleus, auditory cortex and calcarine sulcus in SZ predicted subsequent response to antipsychotic medications. These same regions demonstrated changes over the 6-week treatment trial that were correlated with symptomatic improvement. Our findings implicate several neural networks relevant to clinical improvement with antipsychotic medications.

Abnormalities in large scale functional networks in unmedicated patients with schizophrenia and effects of risperidone.

OBJECTIVE: To describe abnormalities in large scale functional networks in unmedicated patients with schizophrenia and to examine effects of risperidone on networks. MATERIAL AND METHODS: 34 unmedicated patients with schizophrenia and 34 matched healthy controls were enrolled in this longitudinal study. We collected resting state functional MRI data with a 3T scanner at baseline and six weeks after they were started on risperidone. In addition, a group of 19 healthy controls were scanned twice six weeks apart. Four large scale networks, the dorsal attention network, executive control network, salience network, and default mode network were identified with seed based functional connectivity analyses. Group differences in connectivity, as well as changes in connectivity over time, were assessed on the group's participant level functional connectivity maps. RESULTS: In unmedicated patients with schizophrenia we found resting state connectivity to be increased in the dorsal attention network, executive control network, and salience network relative to control participants, but not the default mode network. Dysconnectivity was attenuated after six weeks of treatment only in the dorsal attention network. Baseline connectivity in this network was also related to clinical response at six weeks of treatment with risperidone. CONCLUSIONS: Our results demonstrate abnormalities in large scale functional networks in patients with schizophrenia that are modulated by risperidone only to a certain extent, underscoring the dire need for development of novel antipsychotic medications that have the ability to alleviate symptoms through attenuation of dysconnectivity.

Hippocampal-parietal dysconnectivity and glutamate abnormalities in unmedicated patients with schizophrenia.

Abnormalities in resting state connectivity in schizophrenia (SZ) are now well established, but the biological substrates of these functional alterations remain to be elucidated. We performed a combined functional magnetic resonance imaging and magnetic resonance spectroscopy study in 22 unmedicated patients with SZ and 22 matched healthy controls (HCs) to evaluate resting state functional connectivity of the hippocampus and Glx/Cr (a combined glutamate + glutamine peak normalized to creatine) in the hippocampus and investigate functional and neurometabolic abnormalities and examine the relationship between these. Functional connectivity between the left hippocampus and bilateral precuneus was significantly decreased in unmedicated patients with SZ when compared to HCs [t(4.22), cluster extent (kE) = 751, PFDRcorr = 0.001, Montreal Neurological Institute coordinates: x = -4, y = -56, z = 44]. Glx/Cr in the hippocampus was significantly elevated in SZ (HC: mean = 0.60+/-0.10 SZ: 0.67+/-0.10; F = 5.742; P = 0.02), but was not correlated with functional connectivity deficits (P > 0.05). In this study, we found hippocampal resting state functional connectivity deficits to the precuneus in unmedicated patients with SZ and an increase of Glx/Cr in the hippocampus, but did not observe a direct relationship between these abnormalities. However, our findings do not exclude the possibility of a shared underlying pathology, which warrants further investigation.

Delay discounting and task performance consistency in patients with schizophrenia.

To study impaired goal-oriented behavior in schizophrenia (SZ), we used a delay discounting task, which consists of a series of choices between receiving a small immediate or larger delayed reward. Few studies of delay discounting have evaluated response consistency (R(2)), which is especially relevant in SZ because of documented inconsistency in task performance. We calculated the rate of discounting (k) and R(2) in SZ (n=35) and healthy controls (HC; n=21). Using a criterion value of R(2)>0.60 to define consistent performance allowed us to compare discounting in consistent SZ and HC, as well as in inconsistent SZ. Groups did not differ significantly in smoking. Compared to HC, consistent SZ showed greater delay discounting. Both groups exhibited similar patterns of decreasing immediate choices across trial categories, although the decrease was less for SZ. Separate analyses on smokers and non-smokers showed that this group difference was carried by the non-smokers. Inconsistent SZ discounted more than HC and consistent SZ, but their aberrant pattern of choices casts doubt on the validity of their calculated k values.

An fMRI investigation of delay discounting in patients with schizophrenia.

Schizophrenia (SZ) is associated with a reduced ability to set meaningful goals to reach desired outcomes. The delay-discounting (DD) task, in which one chooses between sooner smaller and later larger rewards, has proven useful in revealing executive function and reward deficits in various clinical groups. We used fMRI in patients with SZ and healthy controls (HC) to compare brain activation during performance of a DD task. Prior to the neuroimaging session, we obtained each participant's rate of DD, k, on a DD task and used it to select a version of the DD task for each participant's fMRI session. Because of the importance of comparing fMRI results from groups matched on performance, we used a criterion value of R (2) > 0.60 for response consistency on the DD task to analyze fMRI activation to DD task versus control trials from consistent SZ (n = 14) and consistent HC (n = 14). We also compared activation between the groups on contrasts related to trial difficulty. Finally, we contrasted the inconsistent SZ (n = 9) with the consistent HC and consistent SZ; these results should be interpreted with caution because of inconsistent SZ's aberrant performance on the task. Compared with consistent HC, consistent SZ showed reduced activation to DD task versus control trials in executive function and reward areas. In contrast, consistent SZ showed more activation in the precuneus and posterior cingulate, regions of the default mode network (DMN) that are typically deactivated during tasks, and in the insula, a region linked to emotional processing. Furthermore, consistent SZ had abnormal activation of lateral and medial frontal regions in relation to trial difficulty. These results point to disruption of several neural networks during decision making, including the executive, reward, default mode, and emotional networks, and suggest processes that are impaired during decision making in schizophrenia.

Aberrant visual circuitry associated with normal spatial match-to-sample accuracy in schizophrenia.

A goal of this study was to evaluate the function of the anterior cingulate cortex (ACC) and of the dorsolateral prefrontal cortex (DLPFC) in medicated patients with schizophrenia (SZ), a small group of first-degree relatives, and healthy controls using a visual delayed match-to-sample task in conjunction with functional magnetic resonance imaging (fMRI). To mitigate performance differences between SZ and healthy controls, we used a novel task that allows for individualized adjustment of task difficulty to match ability level. We also trained participants on the task prior to scanning. Using an event-related design, we modeled three components of the match-to-sample trial: visual encoding, delay, and discrimination. We did not find significant differences in ACC/medial frontal cortex activation between the groups. However, compared to healthy controls, SZ showed decreased activation in visual processing areas during the encoding and discrimination phases of the task and in the ventrolateral prefrontal cortex during the delay. These findings emphasize the tendency of schizophrenia subjects to solve perceptual memory problems by engaging diverse regions.