The importance of covert memory consolidation in schizophrenia: Dysfunctional network profiles of the hippocampus and the dorsolateral prefrontal cortex.

Altered brain network profiles in schizophrenia (SCZ) during memory consolidation are typically observed during task-active periods such as encoding or retrieval. However active processes are also sub served by covert periods of memory consolidation. These periods are active in that they allow memories to be recapitulated even in the absence of overt sensorimotor processing. It is plausible that regions central to memory formation like the dlPFC and the hippocampus, exert network signatures during covert periods. Are these signatures altered in patients? The question is clinically relevant because real world learning and memory is facilitated by covert processing, and may be impaired in schizophrenia. Here, we compared network signatures of the dlPFC and the hippocampus during covert periods of a learning and memory task. Because behavioral proficiency increased non-linearly, functional connectivity of the dlPFC and hippocampus [psychophysiological interaction (PPI)] was estimated for each of the Early (linear increases in performance) and Late (asymptotic performance) covert periods. During Early periods, we observed hypo-modulation by the hippocampus but hyper-modulation by dlPFC. Conversely, during Late periods, we observed hypo-modulation by both the dlPFC and the hippocampus. We stitch these results into a conceptual model of network deficits during covert periods of memory consolidation.

Learning without contingencies: A loss of synergy between memory and reward circuits in schizophrenia.

Motivational deficits in schizophrenia may interact with foundational cognitive processes including learning and memory to induce impaired cognitive proficiency. If such a loss of synergy exists, it is likely to be underpinned by a loss of synchrony between the brains learning and reward sub-networks. Moreover, this loss should be observed even during tasks devoid of explicit reward contingencies given that such tasks are better models of real world performance than those with artificial contingencies. Here we applied undirected functional connectivity (uFC) analyses to fMRI data acquired while participants engaged in an associative learning task without contingencies or feedback. uFC was estimated and inter-group differences (between schizophrenia patients and controls, n = 54 total, n = 28 patients) were assessed within and between reward (VTA and NAcc) and learning/memory (Basal Ganglia, DPFC, Hippocampus, Parahippocampus, Occipital Lobe) sub-networks. The task paradigm itself alternated between Encoding, Consolidation, and Retrieval conditions, and uFC differences were quantified for each of the conditions. Significantly reduced uFC dominated the connectivity profiles of patients across all conditions. More pertinent to our motivations, these reductions were observed within and across classes of sub-networks (reward-related and learning/memory related). We suggest that disrupted functional connectivity between reward and learning sub-networks may drive many of the performance deficits that characterize schizophrenia. Thus, cognitive deficits in schizophrenia may in fact be underpinned by a loss of synergy between reward-sensitivity and cognitive processes.

The topology, stability, and instability of learning-induced brain network repertoires in schizophrenia.

There is a paucity of graph theoretic methods applied to task-based data in schizophrenia (SCZ). Tasks are useful for modulating brain network dynamics, and topology. Understanding how changes in task conditions impact inter-group differences in topology can elucidate unstable network characteristics in SCZ. Here, in a group of patients and healthy controls (n = 59 total, 32 SCZ), we used an associative learning task with four distinct conditions (Memory Formation, Post-Encoding Consolidation, Memory Retrieval, and Post-Retrieval Consolidation) to induce network dynamics. From the acquired fMRI time series data, betweenness centrality (BC), a metric of a node's integrative value was used to summarize network topology in each condition. Patients showed (a) differences in BC across multiple nodes and conditions; (b) decreased BC in more integrative nodes, but increased BC in less integrative nodes; (c) discordant node ranks in each of the conditions; and (d) complex patterns of stability and instability of node ranks across conditions. These analyses reveal that task conditions induce highly variegated patterns of network dys-organization in SCZ. We suggest that the dys-connection syndrome that is schizophrenia, is a contextually evoked process, and that the tools of network neuroscience should be oriented toward elucidating the limits of this dys-connection.

Basal glutamate in the hippocampus and the dorsolateral prefrontal cortex in schizophrenia: Relationships to cognitive proficiency investigated with structural equation modelling.

OBJECTIVES: Schizophrenia is characterised by deficits across multiple cognitive domains and altered glutamate related neuroplasticity. The purpose was to investigate whether glutamate deficits are related to cognition in schizophrenia, and whether glutamate-cognition relationships are different between schizophrenia and controls. METHODS: Magnetic resonance spectroscopy (MRS) at 3 Tesla was acquired from the dorsolateral prefrontal cortex (dlPFC) and hippocampus in 44 schizophrenia participants and 39 controls during passive viewing visual task. Cognitive performance (working memory, episodic memory, and processing speed) was assessed on a separate session. Group differences in neurochemistry and mediation/moderation effects using structural equation modelling (SEM) were investigated. RESULTS: Schizophrenia participants showed lower hippocampal glutamate (p = .0044) and myo-Inositol (p = .023) levels, and non-significant dlPFC levels. Schizophrenia participants also demonstrated poorer cognitive performance (p < .0032). SEM-analyses demonstrated no mediation or moderation effects, however, an opposing dlPFC glutamate-processing speed association between groups was observed. CONCLUSIONS: Hippocampal glutamate deficits in schizophrenia participants are consistent with evidence of reduced neuropil density. Moreover, SEM analyses indicated that hippocampal glutamate deficits in schizophrenia participants as measured during a passive state were not driven by poorer cognitive ability. We suggest that functional MRS may provide a better framework for investigating glutamate-cognition relationships in schizophrenia.

Disordered directional brain network interactions during learning dynamics in schizophrenia revealed by multivariate autoregressive models.

Directional network interactions underpin normative brain function in key domains including associative learning. Schizophrenia (SCZ) is characterized by altered learning dynamics, yet dysfunctional directional functional connectivity (dFC) evoked during learning is rarely assessed. Here, nonlinear learning dynamics were induced using a paradigm alternating between conditions (Encoding and Retrieval). Evoked fMRI time series data were modeled using multivariate autoregressive (MVAR) models, to discover dysfunctional direction interactions between brain network constituents during learning stages (Early vs. Late), and conditions. A functionally derived subnetwork of coactivated (healthy controls [HC] ∩ SCZ] nodes was identified. MVAR models quantified directional interactions between pairs of nodes, and coefficients were evaluated for intergroup differences (HC ≠ SCZ). In exploratory analyses, we quantified statistical effects of neuroleptic dosage on performance and MVAR measures. During Early Encoding, SCZ showed reduced dFC within a frontal-hippocampal-fusiform network, though during Late Encoding reduced dFC was associated with pathways toward the dorsolateral prefrontal cortex (dlPFC). During Early Retrieval, SCZ showed increased dFC in pathways to and from the dorsal anterior cingulate cortex, though during Late Retrieval, patients showed increased dFC in pathways toward the dlPFC, but decreased dFC in pathways from the dlPFC. These discoveries constitute novel extensions of our understanding of task-evoked dysconnection in schizophrenia and motivate understanding of the directional aspect of the dysconnection in schizophrenia. Disordered directionality should be investigated using computational psychiatric approaches that complement the MVAR method used in our work.

Distinct differences in striatal dysmorphology between attention deficit hyperactivity disorder boys with and without a comorbid reading disability.

There is evidence of greater cognitive deficits in attention deficit hyperactivity disorder with a comorbid reading disability (ADHD/+RD) compared to ADHD alone (ADHD/-RD). Additionally, the striatum has been consistently implicated in ADHD. However, the extent of morphological alterations in the striatum of ADHD/+RD is poorly understood, which is the main purpose of this study. Based on structural MRI images, the surface deformation of the caudate and putamen was assessed in 59 boys matching in age and IQ [19 ADHD/-RD, 15 ADHD/+RD and 25 typically developing controls (TDC)]. A vertex based analysis with multiple comparison correction was conducted to compare ADHD/-RD and ADHD/+RD to TDC. Compared to TDC, ADHD/+RD showed multiple bilateral significant clusters of surface compression. In contrast, ADHD/-RD showed fewer significant clusters of surface compression and restricted to the left side. Regarding the putamen, only ADHD/-RD showed significant clusters of surface compression. Results demonstrate for the first time a greater extent of morphological alterations in the caudate of ADHD/+RD than ADHD/-RD compared to TDC, which may suggest greater implicated cortical areas projecting to the caudate that are associated with the greater neuropsychological impairments observed in ADHD/+RD.

Disordered corticolimbic interactions during affective processing in children and adolescents at risk for schizophrenia revealed by functional magnetic resonance imaging and dynamic causal modeling.

CONTEXT: Disordered functional architecture of brain networks may contribute to the well-documented increased risk for psychiatric disorders in offspring of patients with schizophrenia. OBJECTIVE: To investigate aberrant interactions between regions associated with affective processing in children and adolescent offspring of patients with schizophrenia (HR-SCZ group) and healthy control subjects using dynamic causal modeling of functional magnetic resonance imaging data. DESIGN: Subjects participated in a continuous affective processing task during which positive, negative, and neutral valenced faces were presented. Interactions between regions in the brain's face- and emotion-processing network were modeled using dynamic causal modeling. Multiple competing models were evaluated by a combinatorial approach and distinguished at the second level using Bayesian model selection before parameter inference. SETTING: Participants were recruited from the community. PARTICIPANTS: Twenty-four controls with no family history of psychosis (to the second degree) and 19 children and adolescent offspring of a parent with schizophrenia (age range, 8 to 20 years). RESULTS: Bayesian model selection revealed a winning model, the architecture of which revealed bidirectional frontolimbic connections that were modulated by valence. Analyses of parameter estimates revealed that HR-SCZ group members were characterized by (1) decreased driving inputs to the visual cortex; (2) decreased intrinsic coupling, most robustly between frontolimbic regions; and (3) increased modulatory inhibition by negative valence of frontolimbic connections (all P < .01, Bonferroni corrected). CONCLUSIONS: These results are the first demonstration of network analyses techniques for functional magnetic resonance imaging data in children and adolescents at risk for schizophrenia. Dysfunctional interactions within the emotional processing network provide evidence of latent vulnerabilities that may confer risk for disordered adolescent development and eventually the emergence of the manifest disorder.

The neural correlates of performance in adolescents at risk for schizophrenia: inefficiently increased cortico-striatal responses measured with fMRI.

BACKGROUND: fMRI studies indicate that schizophrenia patients and their adult relatives require greater prefrontal activation to maintain performance at levels equal to controls, but studies have not established if this pattern of inefficiency is observed in child and adolescent offspring of schizophrenia patients (SCZ-Off). METHODS: Using a task with visual working memory demands, we investigated activation in cortico-striatal networks and dorsal prefrontal modulation of regions underlying visual working memory in a group of SCZ-Off (n = 19) and controls with no family history of psychosis (n = 25 subjects) using an event-related design. Trials were divided based on memory performance (correct vs. incorrect) to specifically identify the neural correlates of correct working memory performance. RESULTS: Whereas groups did not differ in terms of behavioral accuracy, SCZ-Off demonstrated significantly increased fMRI-measured activation in dorsal prefrontal cortex and the caudate nucleus during correct, relative to incorrect memory performance. Whereas activation in SCZ-Off was high and independent of performance in each region, in controls the fMRI response was related to behavioral proficiency in the caudate. Further, exploratory analyses indicated that this inefficiency in the dorsal prefrontal cortex response increased with age in SCZ-Off (but in no other regions or group). Finally, these differences were not based in differences in dorsal prefrontal modulation of other regions during successful performance. DISCUSSION: These results are consistent with observed patterns in adult patients and first-degree relatives. Inefficient fronto-striatal responses during working memory may characterize the schizophrenia diathesis and may reflect the effects of the illness and vulnerability for the illness.

Fronto-parietal hypo-activation during working memory independent of structural abnormalities: conjoint fMRI and sMRI analyses in adolescent offspring of schizophrenia patients.

Adolescent offspring of schizophrenia patients (HR-S) are an important group in whom to study impaired brain function and structure, particularly of the frontal cortices. Studies of working memory have suggested behavioral deficits and fMRI-measured hypoactivity in fronto-parietal regions in these subjects. Independent structural MRI (sMRI) studies have suggested exaggerated frontal gray matter decline. Therefore the emergent view is that fronto-parietal deficits in function and structure characterize HR-S. However, it is unknown if fronto-parietal sub-regions in which fMRI-measured hypo-activity might be observed are precisely those regions of the cortex in which gray matter deficits are also observed. To investigate this question we conducted conjoint analyses of fronto-parietal function and structure in HR-S (n=19) and controls (n=24) with no family history of psychoses using fMRI data during a continuous working memory task (2 back), and sMRI collected in the same session. HR-S demonstrated significantly reduced BOLD activation in left dorso-lateral prefrontal cortex (BA 9/46) and bilateral parietal cortex (BA 7/40). Sub-regions of interest were created from the significant fronto-parietal functional clusters. Analyses of gray matter volume from volume-modulated gray matter segments in these clusters did not reveal significant gray matter differences between groups. The results suggest that functional impairments in adolescent HR-S can be independent of impairments in structure, suggesting that the relationship between impaired function and structure is complex. Further studies will be needed to more closely assess whether impairments in function and structure provide independent or interacting pathways of vulnerability in this population.

Working memory and attention deficits in adolescent offspring of schizophrenia or bipolar patients: comparing vulnerability markers.

BACKGROUND: Working memory deficits abound in schizophrenia and attention deficits have been documented in schizophrenia and bipolar disorder. Adolescent offspring of patients may inherit vulnerabilities in brain circuits that subserve these cognitive domains. Here we assess impairments in offspring of schizophrenia (SCZ-Offspring) or bipolar (BP-Offspring) patients compared to controls (HC) with no family history of mood or psychotic disorders to the second degree. METHODS: Three groups (n=100 subjects; range: 10-20 yrs) of HC, SCZ-Offspring and BP-Offspring gave informed consent. Working memory was assessed using a delayed spatial memory paradigm with two levels of delay (2s & 12s); sustained attention processing was assessed using the Continuous Performance Task-Identical Pairs version. RESULTS: SCZ-Offspring (but not BP-Offspring) showed impairments in working memory (relative to HC) at the longer memory delay indicating a unique deficit. Both groups showed reduced sensitivity during attention but only BP-Offspring significantly differed from controls. CONCLUSIONS: These results suggest unique (working memory/dorsal frontal cortex) and potentially overlapping (attention/fronto-striatal cortex) vulnerability pathways in adolescent offspring of patients with schizophrenia and bipolar disorder. Working memory and attention assessments in these offspring may assist in the clinical characterization of the adolescents vulnerable to SCZ or BP.

Hypo-activation in the executive core of the sustained attention network in adolescent offspring of schizophrenia patients mediated by premorbid functional deficits.

Adolescent offspring of schizophrenia patients (SCZ-Off) are vulnerable to psychiatric disorders. Assessing relationships between clinical and biological measures (such as functional magnetic resonance imaging, fMRI) may elucidate pathways of vulnerability in this group. Here we assessed the relationship between clinically assessed premorbid function, and cortico-striatal activity during sustained attention in controls (HC: with no family history of psychosis) and SCZ-Off. Subjects (n=39) were assessed using the Structured Interview for Prodromal Syndromes and the Scale of Prodromal Symptoms. Based on the Global Assessment of Functioning (GAF) score, SCZ-Off were cleaved into "high" or "low" clinically functioning sub-groups (SCZ-Off(HF), SCZ-Off(LF) respectively). During fMRI, subjects participated in a modified continuous performance task (CPT-IP). fMRI was conducted on a Bruker MedSpec 4T system (345 EPI scans; TR=2s; 24 slices; 3.8×3.8×4mm). Results show SCZ-Off(LF) evinced less activation than both HC and SCZ-Off(HF) in the executive core of the brain's attentional system (anterior cingulate, dorsal prefrontal cortex and caudate), but not visuo-spatial regions such as primary visual or superior parietal cortex. Differences were independent of behavioral performance, and reduction in activity was related to GAF score in a dose-dependent manner. Assessing the relationship between clinical measures and brain activity in domains such as attention provides a window into mechanisms of vulnerability in the developing adolescent brain.

Inefficiently increased anterior cingulate modulation of cortical systems during working memory in young offspring of schizophrenia patients.

BACKGROUND: Children and adolescent offspring of schizophrenia patients are at increased risk for schizophrenia and are also characterized by impairments in brain structure and function. To date, few studies have investigated whether functional interactions between brain regions are intact or altered. Using an established verbal working memory paradigm with variable levels of memory load, we investigated the modulatory effect of activity in cognitive control regions of the brain (specifically the dorsal anterior cingulate cortex) on activity in core working memory regions, in particular the dorsal prefrontal cortex and the parietal lobe. METHODS: Forty four subjects participated. An n-back task with two levels of working memory load (1- and 2-back) was employed during fMRI (4 T Bruker MedSpec system). Data were processed with SPM5 and the modulatory effects of the anterior cingulate were investigated using psycho-physiological interaction (PPI). RESULTS: In spite of only subtle activation differences, and no significant differences in performance accuracy, a significant group x memory load interaction in the parietal lobe, indicated aberrantly increased modulatory inputs to this region under conditions of high working memory load in schizophrenia offspring. DISCUSSION: Increased modulatory inputs from a central control region like the anterior cingulate presumably reflect relative inefficiency in intra-cortical interactions in the vulnerable brain. This inefficiency may reflect a developmentally mediated impairment in functional brain interactions in this important vulnerable population. It is highly plausible that the resultant effect of these altered interactions is an increased vulnerability to impaired brain development, and therefore to psychiatric disorders including schizophrenia.

Reduced intra-amygdala activity to positively valenced faces in adolescent schizophrenia offspring.

Studies suggest that the affective response is impaired in both schizophrenia and adolescent offspring of schizophrenia patients. Adolescent offspring of patients are developmentally vulnerable to impairments in several domains, including affective responding, yet the bases of these impairments and their relation to neuronal responses within the limbic system are poorly understood. The amygdala is the central region devoted to the processing of emotional valence and its sub-nuclei including the baso-lateral and centro-medial are organized in a relative hierarchy of affective processing. Outputs from the centro-medial nucleus converge on regions involved in the autonomous regulation of behavior, and outputs from the baso-lateral nucleus modulate the response of reward processing regions. Here using fMRI we assessed the intra-amygdala response to positive, negative, and neutral valenced faces in a group of controls (with no family history of psychosis) and offspring of schizophrenia parents (n=44 subjects in total). Subjects performed an affective continuous performance task during which they continually appraised whether the affect signaled by a face on a given trial was the same or different from the previous trial (regardless of facial identity). Relative to controls, offspring showed reduced activity in the left centro-medial nucleus to positively (but not negatively or neutral) valenced faces. These results were independent of behavioral/cognitive performance (equal across groups) suggesting that an impaired affective substrate in the intra-amygdala response may lie at the core of deficits of social behavior that have been documented in this population.