Effects of neuroactive metabolites of the tryptophan pathway on working memory and cortical thickness in schizophrenia.
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ABSTRACT:
SUBMITTER: Huang J
PROVIDER: S-EPMC8016899 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:OBJECTIVE:To better understand the origins of working memory (WM) impairment in schizophrenia we investigated cortical oscillatory activity in people with schizophrenia (PSZ) while they performed a WM task requiring encoding, maintenance, and retrieval/manipulation processes of spatial information. METHODS:We examined time-frequency synchronous energy of cortical source signals that were derived from magnetoencephalography (MEG) localized to cortical regions using WM-related hemodynamic responses and individualized structural head-models. RESULTS:Compared to thirteen healthy controls (HC), twelve PSZ showed performance deficits regardless of WM-load or duration. During encoding, PSZ had early theta and delta event-related synchrony (ERS) deficits in prefrontal and visual cortices which worsened with greater memory load and predicted WM performance. During prolonged maintenance of material, PSZ showed deficient beta event-related desynchrony (ERD) in dorsolateral prefrontal, posterior parietal, and visual cortices. In retrieval, PSZ showed reduced delta/theta ERS in the anterior prefrontal and ventral visual cortices and diminished gamma ERS in the premotor and posterior parietal cortices. CONCLUSIONS:Although beta/gamma cortical neural oscillatory deficits for maintenance/retrieval are evident during WM, the abnormal prefrontal theta-frequency ERS for encoding is most predictive of poor WM in schizophrenia. SIGNIFICANCE:Time-frequency-spatial analysis identified process- and frequency-specific neural synchrony abnormalities underlying WM deficits in schizophrenia.
| S-EPMC5745038 | biostudies-literature
Project description:The data and supplementary information provided in this article relate to our research article "Task complexity and location specific changes of cortical thickness in executive and salience networks after working memory training" (Metzler-Baddeley et al., 2016) [1]. We provide cortical thickness and subcortical volume data derived from parieto-frontal cortical regions and the basal ganglia with the FreeSurfer longitudinal analyses stream (http://surfer.nmr.mgh.harvard.edu [2]) before and after Cogmed working memory training (Cogmed and Cogmed Working Memory Training, 2012) [3]. This article also provides supplementary information to the research article, i.e., within-group comparisons between baseline and outcome cortical thickness and subcortical volume measures, between-group tests of performance changes in cognitive benchmark tests (www.cambridgebrainsciences.com [4]), correlation analyses between performance changes in benchmark tests and training-related structural changes, correlation analyses between the time spent training and structural changes, a scatterplot of the relationship between cortical thickness measures derived from the occipital lobe as control region and the chronological order of the MRI sessions to assess potential scanner drift effects and a post-hoc vertex-wise whole brain analysis with FreeSurfer Qdec (https://surfer.nmr.mgh.harvard.edu/fswiki/Qdec [5]).
| S-EPMC4833123 | biostudies-literature
Project description:Working memory (WM) supports several higher-level cognitive abilities, yet we know less about factors associated with development and decline in WM compared to other cognitive processes. Here, we investigated lifespan changes in WM capacity and their structural brain correlates, using a longitudinal sample including 2358 magnetic resonance imaging (MRI) scans and WM scores from 1656 participants (4.4-86.4 years, mean follow-up interval 4.3 years). 8764 participants (9.0-10.9 years) with MRI, WM scores and genetic information from the Adolescent Brain Cognitive Development study were used for follow-up analyses. Results showed that both the information manipulation component and the storage component of WM improved during childhood and adolescence, but the age-decline could be fully explained by reductions in passive storage capacity alone. Greater WM function in development was related to apparent thinner cortex in both samples, also when general cognitive function was accounted for. The same WM-apparent thickness relationship was found for young adults. The WM-thickness relationships could not be explained by SNP-based co-heritability or by socioeconomic status. A larger sample with genetic information may be necessary to disentangle the true gene-environment effects. In conclusion, WM capacity changes greatly through life and has anatomically extended rather than function-specific structural cortical correlates.
| S-EPMC8371229 | biostudies-literature
Project description:Working memory studies in schizophrenia (SZ), using functional magnetic resonance imaging (fMRI) and univariate analyses, have led to observations of hypo- or hyperactivation of discrete cortical regions and subsequent interpretations (e.g. neural inefficiencies). We employed a data-driven, multivariate analysis to identify the patterns of brain-behavior relationships in SZ during working memory.fMRI scans were collected from 13 SZ and 18 healthy control (HC) participants performing a modified Sternberg item recognition paradigm with three memory loads. We applied partial least squares analysis (PLS) to assess brain activation during the task both alone and with behavioral measures (accuracy and response time, RT) as covariates.While the HC primary pattern was not affected by increasing load demands, SZ participants showed an exaggerated change in the Blood Oxygenation Level Dependent (BOLD) signal from the low to moderate memory load conditions and subsequent decrease in the greatest memory load, in frontal, motor, parietal and subcortical areas. With behavioral covariates, the separate groups identified distinct brain-behavior relationships and circuits. Increased activation of the middle temporal gyrus was associated with greater accuracy and faster RT only in SZ.The inverted U-shaped curves in the SZ BOLD signal in the same areas that show flat activation in the HC data indicate widespread neural inefficiency in working memory in SZ. While both groups performed the task with similar levels of accuracy, participants with schizophrenia show a compensatory network of different sub-regions of the prefrontal cortex, parietal lobule, and the temporal gyri in this working memory task.
| S-EPMC2821986 | biostudies-literature
Project description:Reward processing and cognition are disrupted in schizophrenia (SCZ), yet how these processes interface is unknown. In SCZ, deficits in reward representation may affect motivated, goal-directed behaviors. To test this, we examined the effects of monetary reward on spatial working memory (WM) performance in patients with SCZ. To capture complimentary effects, we tested biophysically grounded computational models of neuropharmacologic manipulations onto a canonical fronto-parietal association cortical microcircuit capable of WM computations. Patients with SCZ (n = 33) and healthy control subjects (HCS; n = 32) performed a spatial WM task with 2 reward manipulations: reward cues presented prior to each trial, or contextually prior to a block of trials. WM performance was compared with cortical circuit models of WM subjected to feed-forward glutamatergic excitation, feed-forward GABAergic inhibition, or recurrent modulation strengthening local connections. Results demonstrated that both groups improved WM performance to reward cues presented prior to each trial (HCS d = -0.62; SCZ d = -1.0), with percent improvement correlating with baseline WM performance (r = .472, p < .001). However, rewards presented contextually before a block of trials did not improve WM performance in patients with SCZ (d = 0.01). Modeling simulations achieved improved WM precision through strengthened local connections via neuromodulation, or feed-forward inhibition. Taken together, this work demonstrates that patients with SCZ can improve WM performance to short-term, but not longer-term rewards-thus, motivated behaviors may be limited by strength of reward representation. A potential mechanism for transiently improved WM performance may be strengthening of local fronto-parietal microcircuit connections via neuromodulation or feed-forward inhibitory drive. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
| S-EPMC6197071 | biostudies-literature
Project description:BackgroundVisuospatial working memory (vsWM), which is commonly impaired in schizophrenia, involves information processing across the primary visual cortex, association visual cortex, posterior parietal cortex, and dorsolateral prefrontal cortex (DLPFC). Within these regions, vsWM requires inhibition from parvalbumin-expressing basket cells (PVBCs). Here, we analyzed indices of PVBC axon terminals across regions of the vsWM network in schizophrenia.MethodsFor 20 matched pairs of subjects with schizophrenia and unaffected comparison subjects, tissue sections from the primary visual cortex, association visual cortex, posterior parietal cortex, and DLPFC were immunolabeled for PV, the 65- and 67-kDa isoforms of glutamic acid decarboxylase (GAD65 and GAD67) that synthesize GABA (gamma-aminobutyric acid), and the vesicular GABA transporter. The density of PVBC terminals and of protein levels per terminal was quantified in layer 3 of each cortical region using fluorescence confocal microscopy.ResultsIn comparison subjects, all measures, except for GAD65 levels, exhibited a caudal-to-rostral decline across the vsWM network. In subjects with schizophrenia, the density of detectable PVBC terminals was significantly lower in all regions except the DLPFC, whereas PVBC terminal levels of PV, GAD67, and GAD65 proteins were lower in all regions. A composite measure of inhibitory strength was lower in subjects with schizophrenia, although the magnitude of the diagnosis effect was greater in the primary visual, association visual, and posterior parietal cortices than in the DLPFC.ConclusionsIn schizophrenia, alterations in PVBC terminals across the vsWM network suggest the presence of a shared substrate for cortical dysfunction during vsWM tasks. However, regional differences in the magnitude of the disease effect on an index of PVBC inhibitory strength suggest region-specific alterations in information processing during vsWM tasks.
| S-EPMC8243491 | biostudies-literature
Project description:Schizophrenia is a severe psychiatric illness with widespread impairments of cognitive functioning; however, a certain percentage of subjects are known to perform in the normal range on neuropsychological measures. While the cognitive profiles of these individuals have been examined, there has been relatively little attention to the neuroanatomical characteristics of this important subgroup. The aims of this study were to statistically identify schizophrenia subjects with relatively normal cognition, examine their neuroanatomical characteristics relative to their more impaired counterparts using cortical thickness mapping, and to investigate relationships between these characteristics and demographic variables to better understand the nature of cognitive heterogeneity in schizophrenia. Clinical, neuropsychological, and MRI data were collected from schizophrenia (n = 79) and healthy subjects (n = 65). A series of clustering algorithms on neuropsychological scores was examined, and a 2-cluster solution that separated subjects into neuropsychologically near-normal (NPNN) and neuropsychologically impaired (NPI) groups was determined most appropriate. Surface-based cortical thickness mapping was utilized to examine differences in thinning among schizophrenia subtypes compared with the healthy participants. A widespread cortical thinning pattern characteristic of schizophrenia emerged in the NPI group, while NPNN subjects demonstrated very limited thinning relative to healthy comparison subjects. Analysis of illness duration indicated minimal effects on subtype classification and cortical thickness results. Findings suggest a strong link between cognitive impairment and cortical thinning in schizophrenia, where subjects with near-normal cognitive abilities also demonstrate near-normal cortical thickness patterns. While generally supportive of distinct etiological processes for cognitive subtypes, results provide direction for further examination of additional neuroanatomical differences.
| S-EPMC3225719 | biostudies-other
Project description:Schizophrenia is associated with severe cognitive deficits, including impaired working memory (WM). A neural mechanism that may contribute to WM impairment is the disruption in excitation-inhibition (E/I) balance in cortical microcircuits. It remains unknown, however, how these alterations map onto quantifiable behavioral deficits in patients. Based on predictions from a validated microcircuit model of spatial WM, we hypothesized two key behavioral consequences: i) increased variability of WM traces over time, reducing performance precision; and ii) decreased ability to filter out distractors that overlap with WM representations. To test model predictions, we studied N=27 schizophrenia patients and N=28 matched healthy comparison subjects (HCS) who performed a spatial WM task designed to test the computational model. Specifically, we manipulated delay duration and distractor distance presented during the delay. Subjects used a high-sensitivity joystick to indicate the remembered location, yielding a continuous response measure. Results largely followed model predictions, whereby patients exhibited increased variance and less WM precision as the delay period increased relative to HCS. Schizophrenia patients also exhibited increased WM distractibility, with reports biased toward distractors at specific spatial locations, as predicted by the model. Finally, the magnitude of the WM drift and distractibility were significantly correlated, indicating a possibly shared underlying mechanism. Effects are consistent with elevated E/I ratio in schizophrenia, establishing a framework for translating neural circuit computational model of cognition to human experiments, explicitly testing mechanistic behavioral hypotheses of cellular-level neural deficits in patients.
| S-EPMC5901719 | biostudies-literature
Project description:Schizophrenia is a neurodevelopmental disorder with high heritability. Several lines of evidence indicate that the PRODH gene may be related to the disorder. Therefore, our study investigates the effects of 12 polymorphisms of PRODH on schizophrenia and its phenotypes. To further evaluate the roles of the associated variants in the disorder, we have conducted magnetic resonance imaging (MRI) scans to assess cortical volumes and thicknesses. A total of 192 patients were evaluated using the Structured Clinical Interview for DSM-IV (SCID), Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, Global Assessment of Functioning (GAF) and Clinical Global Impression (CGI) instruments. The study included 179 controls paired by age and gender. The samples were genotyped using the real-time polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP)-PCR and Sanger sequencing methods. A sample of 138 patients and 34 healthy controls underwent MRI scans. One polymorphism was associated with schizophrenia (rs2904552), with the G-allele more frequent in patients than in controls. This polymorphism is likely functional, as predicted by PolyPhen and SIFT, but it was not associated with brain morphology in our study. In summary, we report a functional PRODH variant associated with schizophrenia that may have a neurochemical impact, altering brain function, but is not responsible for the cortical reductions found in the disorder.
| S-EPMC3912045 | biostudies-literature
Project description:Schizotypal disorder is characterized by odd behavior and attenuated forms of schizophrenic features without the manifestation of overt and sustained psychoses. Past studies suggest that schizotypal disorder shares biological and psychological commonalties with schizophrenia. Structural magnetic resonance imaging (MRI) studies have demonstrated both common and distinct regional gray matter changes between schizophrenia and schizotypal disorder. However, no study has compared cortical thickness, which is thought to be a specific indicator of cortical atrophy, between schizophrenia and schizotypal disorder. The subjects consisted of 102 schizophrenia and 46 schizotypal disorder patients who met the International Classification of Diseases, 10th edition criteria and 79 gender- and age-matched healthy controls. Each participant underwent a T1-weighted 3-D MRI scan using a 1.5-Tesla scanner. Cortical thickness was estimated using FreeSurfer. Consistent with previous studies, schizophrenia patients exhibited wide-spread cortical thinning predominantly in the frontal and temporal regions as compared with healthy subjects. Patients with schizotypal disorder had a significantly reduced cortical thickness in the left fusiform and parahippocampal gyri, right medial superior frontal gyrus, right inferior frontal gyrus, and right medial orbitofrontal cortex as compared with healthy controls. Schizophrenia patients had thinner cortices in the left precentral and paracentral gyri than those with schizotypal disorder. Common cortical thinning patterns observed in schizophrenia and schizotypal disorder patients may be associated with vulnerability to psychosis. Our results also suggest that distinct cortical changes in schizophrenia and schizotypal disorder may be associated with the differences in the manifestation of clinical symptoms among these disorders.
| S-EPMC7406196 | biostudies-literature