Smaller anterior hippocampal subfields in the early stage of psychosis.

Hippocampal volume is smaller in schizophrenia, but it is unclear when in the illness the changes appear and whether specific regions (anterior, posterior) and subfields (CA1, CA2/3, dentate gyrus, subiculum) are affected. Here, we used a high-resolution T2-weighted sequence specialized for imaging hippocampal subfields to test the hypothesis that anterior CA1 volume is lower in early psychosis. We measured subfield volumes across hippocampal regions in a group of 90 individuals in the early stage of a non-affective psychotic disorder and 70 demographically similar healthy individuals. We observed smaller volume in the anterior CA1 and dentate gyrus subfields in the early psychosis group. Our findings support models that implicate anterior CA1 and dentate gyrus subfield deficits in the mechanism of psychosis.

Modulation of hippocampal activity in schizophrenia with levetiracetam: a randomized, double-blind, cross-over, placebo-controlled trial.

Hippocampal hyperactivity is a novel pharmacological target in the treatment of schizophrenia. We hypothesized that levetiracetam (LEV), a drug binding to the synaptic vesicle glycoprotein 2 A, normalizes hippocampal activity in persons with schizophrenia and can be measured using neuroimaging methods. Thirty healthy control participants and 30 patients with schizophrenia (28 treated with antipsychotic drugs), were randomly assigned to a double-blind, cross-over trial to receive a single administration of 500 mg oral LEV or placebo during two study visits. At each visit, we assessed hippocampal function using resting state fractional amplitude of low frequency fluctuations (fALFF), cerebral blood flow (CBF) with arterial spin labeling, and hippocampal blood-oxygen-level-dependent (BOLD) signal during a scene processing task. After placebo treatment, we found significant elevations in hippocampal fALFF in patients with schizophrenia, consistent with hippocampal hyperactivity. Additionally, hippocampal fALFF in patients with schizophrenia after LEV treatment did not significantly differ from healthy control participants receiving placebo, suggesting that LEV may normalize hippocampal hyperactivity. In contrast to our fALFF findings, we did not detect significant group differences or an effect of LEV treatment on hippocampal CBF. In the context of no significant group difference in BOLD signal, we found that hippocampal recruitment during scene processing is enhanced by LEV more significantly in schizophrenia. We conclude that pharmacological modulation of hippocampal hyperactivity in schizophrenia can be studied with some neuroimaging methods, but not others. Additional studies in different cohorts, employing alternate neuroimaging methods and study designs, are needed to establish levetiracetam as a treatment for schizophrenia.

Hippocampal Network Dysfunction in Early Psychosis: A 2-Year Longitudinal Study.

Background: Hippocampal abnormalities are among the most consistent findings in schizophrenia. Numerous studies have reported deficits in hippocampal volume, function, and connectivity in the chronic stage of illness. While hippocampal volume and function deficits are also present in the early stage of illness, there is mixed evidence of both higher and lower functional connectivity. Here, we use graph theory to test the hypothesis that hippocampal network connectivity is broadly lowered in early psychosis and progressively worsens over 2 years. Methods: We examined longitudinal resting-state functional connectivity in 140 participants (68 individuals in the early stage of psychosis, 72 demographically similar healthy control individuals). We used an anatomically driven approach to quantify hippocampal network connectivity at 2 levels: 1) a core hippocampal-medial temporal lobe cortex (MTLC) network; and 2) an extended hippocampal-cortical network. Group and time effects were tested in a linear mixed effects model. Results: Early psychosis patients showed elevated functional connectivity in the core hippocampal-MTLC network, but contrary to our hypothesis, did not show alterations within the broader hippocampal-cortical network. Hippocampal-MTLC network hyperconnectivity normalized longitudinally and predicted improvement in positive symptoms but was not associated with increasing illness duration. Conclusions: These results show abnormally elevated functional connectivity in a core hippocampal-MTLC network in early psychosis, suggesting that selectively increased hippocampal signaling within a localized cortical circuit may be a marker of the early stage of psychosis. Hippocampal-MTLC hyperconnectivity could have prognostic and therapeutic implications.

Accurate Confidence and Bayesian Interval Estimation for Non-centrality Parameters and Effect Size Indices.

Reporting effect size index estimates with their confidence intervals (CIs) can be an excellent way to simultaneously communicate the strength and precision of the observed evidence. We recently proposed a robust effect size index (RESI) that is advantageous over common indices because it's widely applicable to different types of data. Here, we use statistical theory and simulations to develop and evaluate RESI estimators and confidence/credible intervals that rely on different covariance estimators. Our results show (1) counter to intuition, the randomness of covariates reduces coverage for Chi-squared and F CIs; (2) when the variance of the estimators is estimated, the non-central Chi-squared and F CIs using the parametric and robust RESI estimators fail to cover the true effect size at the nominal level. Using the robust estimator along with the proposed nonparametric bootstrap or Bayesian (credible) intervals provides valid inference for the RESI, even when model assumptions may be violated. This work forms a unified effect size reporting procedure, such that effect sizes with confidence/credible intervals can be easily reported in an analysis of variance (ANOVA) table format.

Anterior hippocampal dysfunction in early psychosis: a 2-year follow-up study.

BACKGROUND: Cross-sectional studies indicate that hippocampal function is abnormal across stages of psychosis. Neural theories of psychosis pathophysiology suggest that dysfunction worsens with illness stage. Here, we test the hypothesis that hippocampal function is impaired in the early stage of psychosis and declines further over the next 2 years. METHODS: We measured hippocampal function over 2 years using a scene processing task in 147 participants (76 individuals in the early stage of a non-affective psychotic disorder and 71 demographically similar healthy control individuals). Two-year follow-up was completed in 97 individuals (50 early psychosis, 47 healthy control). Voxelwise longitudinal analysis of activation in response to scenes was carried out within a hippocampal region of interest to test for group differences at baseline and a group by time interaction. RESULTS: At baseline, we observed lower anterior hippocampal activation in the early psychosis group relative to the healthy control group. Contrary to our hypothesis, hippocampal activation remained consistent and did not show the predicted decline over 2 years in the early psychosis group. Healthy controls showed a modest reduction in hippocampal activation after 2 years. CONCLUSIONS: The results of this study suggest that hippocampal dysfunction in early psychosis does not worsen over 2 years and highlight the need for longer-term longitudinal studies.

Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-analysis.

Temperament involves stable behavioral and emotional tendencies that differ between individuals, which can be first observed in infancy or early childhood and relate to behavior in many contexts and over many years.1 One of the most rigorously characterized temperament classifications relates to the tendency of individuals to avoid the unfamiliar and to withdraw from unfamiliar people, objects, and unexpected events. This temperament is referred to as behavioral inhibition or inhibited temperament (IT).2 IT is a moderately heritable trait1 that can be measured in multiple species.3 In humans, levels of IT can be quantified from the first year of life through direct behavioral observations or reports by caregivers or teachers. Similar approaches as well as self-report questionnaires on current and/or retrospective levels of IT1 can be used later in life.

Increased amplitude of hippocampal low frequency fluctuations in early psychosis: A two-year follow-up study.

Neuroimaging studies have revealed hippocampal hyperactivity in schizophrenia. In the early stage of the illness, hyperactivity is present in the anterior hippocampus and is thought to spread to other regions as the illness progresses. However, there is limited evidence for changes in basal hippocampal function following the onset of psychosis. Resting state functional MRI signal amplitude may be a proxy measure for increased metabolism and disrupted oscillatory activity, both consequences of an excitation/inhibition imbalance underlying hippocampal hyperactivity. Here, we used fractional amplitude of low frequency fluctuations (fALFF) to test the hypothesis of progressive hippocampal hyperactivity in a two-year longitudinal case-control study. We found higher fALFF in the anterior and posterior hippocampus of individuals in the early stage of non-affective psychosis at study entry. Contrary to our hypothesis of progressive hippocampal dysfunction, we found evidence for normalization of fALFF over time in psychosis. Our findings support a model in which hippocampal fALFF is a marker of psychosis vulnerability or acute illness state rather than an enduring feature of the illness.

Development of Thalamocortical Structural Connectivity in Typically Developing and Psychosis Spectrum Youths.

BACKGROUND: Thalamocortical white matter connectivity is disrupted in psychosis and is hypothesized to play a role in its etiology and associated cognitive impairment. Attenuated cognitive symptoms often begin in adolescence, during a critical phase of white matter and cognitive development. However, little is known about the development of thalamocortical white matter connectivity and its association with cognition. METHODS: This study characterized effects of age, sex, psychosis symptomatology, and cognition in thalamocortical networks in a large sample of youths (N = 1144, ages 8-22 years, 46% male) from the Philadelphia Neurodevelopmental Cohort, which included 316 typically developing youths, 330 youths on the psychosis spectrum, and 498 youths with other psychopathology. Probabilistic tractography was used to quantify percent total connectivity between the thalamus and six cortical regions and assess microstructural properties (i.e., fractional anisotropy) of thalamocortical white matter tracts. RESULTS: Overall, percent total connectivity of the thalamus was weakly associated with age and was not associated with psychopathology or cognition. In contrast, fractional anisotropy of all thalamocortical tracts increased significantly with age, was generally higher in males than females, and was lowest in youths on the psychosis spectrum. Fractional anisotropy of tracts linking the thalamus to prefrontal and posterior parietal cortices was related to better cognitive function across subjects. CONCLUSIONS: By characterizing the pattern of typical development and alterations in those at risk for psychotic disorders, this study provides a foundation for further conceptualization of thalamocortical white matter microstructure as a marker of neurodevelopment supporting cognition and an important risk marker for psychosis.

Stable habituation deficits in the early stage of psychosis: a 2-year follow-up study.

Neural habituation, the decrease in brain response to repeated stimuli, is a fundamental, highly conserved mechanism that acts as an essential filter for our complex sensory environment. Convergent evidence indicates neural habituation is disrupted in both early and chronic stages of schizophrenia, with deficits co-occurring in brain regions that show inhibitory dysfunction. As inhibitory deficits have been proposed to contribute to the onset and progression of illness, habituation may be an important treatment target. However, a crucial first step is clarifying whether habituation deficits progress with illness. In the present study, we measured neural habituation in 138 participants (70 early psychosis patients (<2 years of illness), 68 healthy controls), with 108 participants assessed longitudinally at both baseline and 2-year follow-up. At follow-up, all early psychosis patients met criteria for a schizophrenia spectrum disorder (i.e., schizophreniform disorder, schizophrenia, schizoaffective disorder). Habituation slopes (i.e., rate of fMRI signal change) to repeated images were computed for the anterior hippocampus, occipital cortex, and the fusiform face area. Habituation slopes were entered into a linear mixed model to test for effects of group and time by region. We found that early psychosis patients showed habituation deficits relative to healthy control participants across brain regions, and that these deficits were maintained, but did not worsen, over two years. These results suggest a stable period of habituation deficits in the early stage of schizophrenia.

Relational Memory in the Early Stage of Psychosis: A 2-Year Follow-up Study.

BACKGROUND: Relational memory, the ability to bind information into complex memories, is moderately impaired in early psychosis and severely impaired in chronic schizophrenia, suggesting relational memory may worsen throughout the course of illness. METHODS: We examined relational memory in 66 early psychosis patients and 64 healthy control subjects, with 59 patients and 52 control subjects assessed longitudinally at baseline and 2-year follow-up. Relational memory was assessed with 2 complementary tasks, to test how individuals learn relationships between items (face-scene binding task) and make inferences about trained relationships (associative inference task). RESULTS: The early psychosis group showed impaired relational memory in both tasks relative to the healthy control group. The ability to learn relationships between items remained impaired in early psychosis patients, while the ability to make inferences about trained relationships improved, although never reaching the level of healthy control performance. Early psychosis patients who did not progress to schizophrenia at follow-up had better relational memory than patients who did. CONCLUSIONS: Relational memory impairments, some of which improve and are less severe in patients who do not progress to schizophrenia, are a target for intervention in early psychosis.

Relational memory in the early stage of psychotic bipolar disorder.

Relational memory is impaired in psychotic disorders. In non-affective psychotic disorders, relational memory deficits are present in the early stage of illness and become more pronounced in the chronic stage. Previous studies have demonstrated cognitive deficits in early-stage psychotic bipolar disorder, but it is unclear whether relational memory is impaired. We examined relational memory using a face-scene binding task in early-stage psychotic bipolar disorder patients (n = 33) and compared their performance with healthy control (n = 40) and early-stage non-affective psychosis participants (n = 40). During training, participants learned to associate faces with background scenes. During testing, participants viewed a scene overlaid by three faces and were asked to recall the matching face. Relational memory was assessed indirectly using eye movements and explicitly using forced-choice recognition. Preferential viewing of the matching face, as captured by overall proportion of viewing and viewing across time, was significantly lower in psychotic bipolar disorder than in the healthy control group. However, preferential viewing of the matching face in psychotic bipolar disorder was significantly better than in non-affective psychosis. These findings provide novel evidence that relational memory in patients with early-stage psychotic bipolar disorder is intermediate between healthy control and early-stage non-affective psychosis subjects.

Habituation during encoding: A new approach to the evaluation of memory deficits in schizophrenia.

BACKGROUND: Memory is significantly impaired in schizophrenia. However, memory measures are often complex and confounded by additional impairments such as motivation and task comprehension, which can affect behavioral performance and obscure neural function during memory tasks. Neural signatures of memory encoding that are robust to potential confounds may shed additional light on neural deficits contributing to memory impairment in schizophrenia. METHODS: Here, we investigate a potential neural signature of memory-habituation-and its relationship with healthy and impaired memory function. To limit potential confounds, we used a passive depth of encoding memory task designed to elicit neural responses associated with memory encoding while limiting other cognitive demands. To determine whether habituation during encoding was predictive of intact memory processing, we first compared neural habituation over repeated encoding exposures with subsequent explicit memory in healthy individuals. We then tested whether a similar relationship existed in patients with schizophrenia. RESULTS: Explicit memory performance was impaired in patients with schizophrenia relative to healthy control subjects. In healthy participants, more habituation over repeated exposures during encoding was associated with greater repetition-related increases in accuracy during testing. However, in patients with schizophrenia, better performance was associated with less habituation, or a more sustained neural response during encoding. CONCLUSIONS: These results suggest that sustained neural activity is required for normal repetition-related improvements in memory performance in schizophrenia, in line with a neural inefficiency model. Habituation may serve as a valuable index of neural processes that underlie behavioral memory performance.

Visual exploration differences during relational memory encoding in early psychosis.

Relational memory, or the ability to form contextual associations among items encountered closely in time, is impaired in schizophrenia. The ability to bind items into a relational memory is dependent on the hippocampus, a region that is abnormal in schizophrenia. However, the hippocampus is also involved in exploratory behavior, leaving open the question whether relational memory deficits in schizophrenia are due to failure of relational binding or diminished visual exploration of individual items during encoding. We studied visual exploration patterns during the encoding of face-scene pairs in 66 healthy control subjects and 69 early psychosis patients, to test the hypothesis that differences in visual exploration during the encoding phase can explain task accuracy differences between the two groups. Psychosis patients had lower explicit test accuracy and were less likely to transition from mouth to eyes during encoding. The visual exploration pattern differences between groups did not mediate the relationship between group and explicit test accuracy. We conclude that early psychosis patients have an abnormal pattern of binding items together during encoding that warrants further research.

BNST-insula structural connectivity in humans.

The bed nucleus of the stria terminalis (BNST) is emerging as a critical region in multiple psychiatric disorders including anxiety, PTSD, and alcohol and substance use disorders. In conjunction with growing knowledge of the BNST, an increasing number of studies examine connections of the BNST and how those connections impact BNST function. The importance of this BNST network is highlighted by rodent studies demonstrating that projections from other brain regions regulate BNST activity and influence BNST-related behavior. While many animal and human studies replicate the components of the BNST network, to date, structural connections between the BNST and insula have only been described in rodents and have yet to be shown in humans. In this study, we used probabilistic tractography to examine BNST-insula structural connectivity in humans. We used two methods of dividing the insula: 1) anterior and posterior insula, to be consistent with much of the existing insula literature; and 2) eight subregions that represent informative cytoarchitectural divisions. We found evidence of a BNST-insula structural connection in humans, with the strongest BNST connectivity localized to the anteroventral insula, a region of agranular cortex. BNST-insula connectivity differed by hemisphere and was moderated by sex. These results translate rodent findings to humans and lay an important foundation for future studies examining the role of BNST-insula pathways in psychiatric disorders.

The 2019 Schizophrenia International Research Society Conference, 10-14 April, Orlando, Florida: A summary of topics and trends.

The Schizophrenia International Research Society (SIRS) recently held its first North American congress, which took place in Orlando, Florida from 10-14 April 2019. The overall theme of this year's congress was United in Progress - with the aim of cultivating a collaborative effort towards advancing the field of schizophrenia research. Student travel awardees provided reports of the oral sessions and concurrent symposia that took place during the congress. A collection of these reports is summarized and presented below and highlights the main themes and topics that emerged during the congress. In summary, the congress covered a broad range of topics relevant to the field of psychiatry today.

Impaired relational memory in the early stage of psychosis.

BACKGROUND: Humans constantly take in vast amounts of information, which must be filtered, flexibly manipulated, and integrated into cohesive relational memories in order to choose relevant behaviors. Relational memory is impaired in chronic schizophrenia, which has been linked to hippocampal dysfunction. It is unclear whether relational memory is impaired in the early stage of psychosis. METHODS: We studied eye movements during a face-scene pairs task as an indirect measure of relational memory in 89 patients in the early stage of psychosis and 84 healthy control participants. During testing, scenes were overlaid with three equally-familiar faces and participants were asked to recall the matching (i.e. previously-paired) face. During Match trials, one face had been previously paired with the scene. During Non-Match trials, no faces matched the scene. Forced-choice explicit recognition was recorded as a direct measure of relational memory. RESULTS: Healthy control subjects rapidly (within 250-500 ms) showed preferential viewing of the matching face during Match trials. In contrast, preferential viewing was delayed in patients in the early stage of psychosis. Explicit recognition of the matching face was also impaired in the patient group. CONCLUSIONS: This study provides novel evidence for a relational memory deficit in the early stage of psychosis. Patients showed deficits in both explicit recognition as well as abnormal eye-movement patterns during memory recall. Eye movements provide a promising avenue for the study of relational memory in psychosis, as they allow for the assessment of rapid, nonverbal memory processes.

Disrupted Habituation in the Early Stage of Psychosis.

BACKGROUND: Learning and memory are impaired in schizophrenia. Some theories have proposed that one form of memory, habituation, is particularly impaired. Preliminary evidence suggests that memory impairment is associated with failed hippocampal habituation in patients with chronic schizophrenia. We studied how abnormal habituation of the hippocampus is related to relational memory deficits in the early stage of psychosis. METHODS: We measured hippocampal activity in 62 patients with early psychosis and 70 healthy individuals using functional magnetic resonance imaging. Habituation was defined as the slope of functional magnetic resonance imaging signal change to repeated presentations of faces and objects. Relational memory ability was measured as the slope of preferential viewing during a face-scene pair eye movement task outside the scanner. RESULTS: Patients with early psychosis showed impaired relational memory (p < .001) and less hippocampal habituation to objects (p = .01) than healthy control subjects. In the healthy control group, better relational memory was associated with faster anterior hippocampal habituation (faces, r = -.28, p = .03). In contrast, patients with early psychosis showed no brain-behavior relationship (r = .12, p = .40). CONCLUSIONS: We found evidence for disrupted hippocampal habituation in the early stage of psychosis along with an altered association between hippocampal habituation and relational memory ability. These results suggest that neural habituation may provide a novel target for early cognitive interventions in psychosis.

Social anxiety is associated with BNST response to unpredictability.

BACKGROUND: Anxiety disorders are highly prevalent and cause substantial suffering and impairment. Whereas the amygdala has well-established contributions to anxiety, evidence from rodent and nonhuman primate models suggests that the bed nucleus of the stria terminalis (BNST) may play a critical, and possibly distinct, role in human anxiety disorders. The BNST mediates hypervigilance and anticipatory anxiety in response to an unpredictable or ambiguous threat, core symptoms of social anxiety, yet little is known about the BNST's role in social anxiety. METHODS: Functional magnetic resonance imaging was used to measure neural responses during a cued anticipation task with an unpredictable, predictable threat, and predictable neutral cues followed by threat or neutral images. Social anxiety was examined using a dimensional approach (N = 44 adults). RESULTS: For unpredictable cues, higher social anxiety was associated with lower BNST-amygdala connectivity. For unpredictable images, higher social anxiety was associated with greater connectivity between the BNST and both the ventromedial prefrontal cortex and the posterior cingulate cortex and lower connectivity between the BNST and postcentral gyrus. Social anxiety moderated the BNST-amygdala dissociation for unpredictable images; higher social anxiety was associated with BNST > amygdala response to unpredictable threat relative to unpredictable neutral images. CONCLUSIONS: Social anxiety was associated with alterations in BNST responses to unpredictability, particularly in the BNST's interactions with other brain regions, including the amygdala and prefrontal cortex. To our knowledge, these findings provide the first evidence for the BNST's role in social anxiety, which may be a potential new target for prevention and intervention.

Impaired associative inference in the early stage of psychosis.

Relational memory is impaired in chronic schizophrenia. It is unclear if similar deficits are already present in the early stage of psychosis. We used the Associative Inference Paradigm to test relational memory ability in the early stage of a non-affective psychotic disorder. Eighty-two early stage psychosis patients and 67 healthy control subjects were trained on 3 sets of 30 paired associates: H-F1 (house paired with face), H-F2 (same house paired with new face), F3-F4 (two new faces). Subjects who reached 80% recall accuracy of the paired associates during training were then tested for their ability to recall the previously seen pairs and solve a novel, inferential pairing F1-F2 (faces linked through association to same house). Sixty early psychosis patients (73%) and 67 healthy control subjects (100%) successfully reached the accuracy threshold (80%) during training and were included in the analysis of relational memory. The early stage psychosis patients showed less of an associative inference effect than the healthy controls (pair type by group interaction: F (1,125) = 5.04, p < 0.05). However, the majority of early psychosis patients (52%) displayed intact inferential memory, compared to our prior study which revealed just 16% of chronic schizophrenia patients had intact inferential memory. Patients in the early stage of psychosis show a relational memory deficit, although less pronounced than in chronic schizophrenia. Longitudinal studies are needed to examine the progression of relational memory deficits in schizophrenia and its associations with clinical, functional, and biological measures.

Hippocampal Network Modularity Is Associated With Relational Memory Dysfunction in Schizophrenia.

BACKGROUND: Functional dysconnectivity has been proposed as a major pathophysiological mechanism for cognitive dysfunction in schizophrenia. The hippocampus is a focal point of dysconnectivity in schizophrenia, with decreased hippocampal functional connectivity contributing to the marked memory deficits observed in patients. Normal memory function relies on the interaction of complex corticohippocampal networks. However, only recent technological advances have enabled the large-scale exploration of functional networks with accuracy and precision. METHODS: We investigated the modularity of hippocampal resting-state functional networks in a sample of 45 patients with schizophrenia spectrum disorders and 38 healthy control subjects. Modularity was calculated for two distinct functional networks: a core hippocampal-medial temporal lobe cortex network and an extended hippocampal-cortical network. As hippocampal function differs along its longitudinal axis, follow-up analyses examined anterior and posterior networks separately. To explore effects of resting network function on behavior, we tested associations between modularity and relational memory ability. Age, sex, handedness, and parental education were similar between groups. RESULTS: Network modularity was lower in schizophrenia patients, especially in the posterior hippocampal network. Schizophrenia patients also showed markedly lower relational memory ability compared with control subjects. We found a distinct brain-behavior relationship in schizophrenia that differed from control subjects by network and anterior/posterior division-while relational memory in control subjects was associated with anterior hippocampal-cortical modularity, schizophrenia patients showed an association with posterior hippocampal-medial temporal lobe cortex network modularity. CONCLUSIONS: Our findings support a model of abnormal resting-state corticohippocampal network coherence in schizophrenia, which may contribute to relational memory deficits.