Dataset Information

Fiber pathway pathology, synapse loss and decline of cortical function in schizophrenia.

ABSTRACT: A quantitative cortical model is developed, based on both computational and simulation approaches, which relates measured changes in cortical activity of gray matter with changes in the integrity of longitudinal fiber pathways. The model consists of modules of up to 5,000 neurons each, 80% excitatory and 20% inhibitory, with these having different degrees of synaptic connectiveness both within a module as well as between modules. It is shown that if the inter-modular synaptic connections are reduced to zero while maintaining the intra-modular synaptic connections constant, then activity in the modules is reduced by about 50%. This agrees with experimental observations in which cortical electrical activity in a region of interest, measured using the rate of oxidative glucose metabolism (CMRglc(ox)), is reduced by about 50% when the cortical region is isolated, either by surgical means or by transient cold block. There is also a 50% decrease in measured cortical activity following inactivation of the nucleus of Meynert and the intra-laminar nuclei of the thalamus, which arise either following appropriate lesions or in sleep. This occurs in the model if the inter-modular synaptic connections require input from these nuclei in order to function. In schizophrenia there is a 24% decrease in functional anisotropy of longitudinal fasciculi accompanied by a 7% decrease in cortical activity (CMRglc(ox)).The cortical model predicts this, namely for a 24% decrease in the functioning of the inter-modular connections, either through the complete loss of 24% of axons subserving the connections or due to such a decrease in the efficacy of all the inter-modular connections, there will be about a 7% decrease in the activity of the modules. This work suggests that deterioration of longitudinal fasciculi in schizophrenia explains the loss of activity in the gray matter.

SUBMITTER: Bennett MR

PROVIDER: S-EPMC3620229 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Fiber pathway pathology, synapse loss and decline of cortical function in schizophrenia.

Bennett Max R MR Farnell Les L Gibson William G WG

PloS one 20130408 4

A quantitative cortical model is developed, based on both computational and simulation approaches, which relates measured changes in cortical activity of gray matter with changes in the integrity of longitudinal fiber pathways. The model consists of modules of up to 5,000 neurons each, 80% excitatory and 20% inhibitory, with these having different degrees of synaptic connectiveness both within a module as well as between modules. It is shown that if the inter-modular synaptic connections are red ...[more]

PMID: 23593232

Similar Datasets

Project description:BackgroundCortical atrophy is associated with cognitive decline, but the association is not perfect. We aimed to identify factors explaining the discrepancy between the degree of cortical atrophy and cognitive decline in cognitively unimpaired elderly.MethodsThe discrepancy between atrophy and cognitive decline was measured using the residuals from a linear regression analysis between change in whole brain cortical thickness over time and change in a cognitive composite measure over time in 395 cognitively unimpaired participants from the Swedish BioFINDER study. We tested for bivariate associations of this residual measure with demographic, imaging, and fluid biomarker variables using Pearson correlations and independent-samples t-tests, and for multivariate associations using linear regression models. Mediation analyses were performed to explore possible paths between the included variables.ResultsIn bivariate analyses, older age (r = -0.11, p = 0.029), male sex (t = -3.00, p = 0.003), larger intracranial volume (r = -0.17, p < 0.001), carrying an APOEe4 allele (t = -2.71, p = 0.007), larger white matter lesion volume (r = -0.16, p = 0.002), lower cerebrospinal fluid (CSF) β-amyloid (Aβ) 42/40 ratio (t = -4.05, p < 0.001), and higher CSF levels of phosphorylated tau (p-tau) 181 (r = -0.22, p < 0.001), glial fibrillary acidic protein (GFAP; r = -0.15, p = 0.003), and neurofilament light (NfL; r = -0.34, p < 0.001) were negatively associated with the residual measure, i.e., associated with worse than expected cognitive trajectory given the level of atrophy. In a multivariate analysis, only lower CSF Aβ42/40 ratio and higher CSF NfL levels explained cognition beyond brain atrophy. Mediation analyses showed that associations between the residual measure and APOEe4 allele, CSF Aβ42/40 ratio, and CSF GFAP and p-tau181 levels were mediated by levels of CSF NfL, as were the associations with the residual measure for age, sex, and WML volume.ConclusionsOur results suggest that axonal degeneration and amyloid pathology independently affect the rate of cognitive decline beyond the degree of cortical atrophy. Furthermore, axonal degeneration mediated the negative effects of old age, male sex, and white matter lesions, and in part also amyloid and tau pathology, on cognition over time when accounting for cortical atrophy.

Project description:Prior studies have demonstrated reduced dendritic spine density in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia. However, it remains unclear how generalizable this finding is in schizophrenia and if it is seen in bipolar disorder, a historically distinct psychiatric condition.To assess whether spine loss is present in the DLPFC of individuals with schizophrenia and individuals with bipolar disorder.This study used postmortem human brain tissue from individuals with schizophrenia (n=14), individuals with bipolar disorder (n=9), and unaffected control participants (n=19). Tissue samples containing the DLPFC (Brodmann area 46) were Golgi-stained, and basilar dendrites of pyramidal cells in the deep half of layer III were reconstructed.The number of spines per dendrite, spine density, and dendrite length were compared across groups. We also assessed for the potential effects of clinical and demographic variables on dendritic parameters.The mean (SD) spine density was significantly reduced (ie, by 10.5%) in individuals with bipolar disorder (0.28 [0.04] spines/?m) compared with control participants (0.31 [0.05] spines/?m) (P=.02). In individuals with schizophrenia, the mean (SD) spine density was also reduced (by 6.5%; 0.29 [0.03] spines/?m) but just missed significance when compared with control participants (P=.06). There was a significant reduction in the mean (SD) number of spines per dendrite in both individuals with schizophrenia (72.8 [24.9] spines per dendrite) and individuals with bipolar disorder (68.9 [12.9] spines per dendrite) compared with controls (92.8 [31.1] spines per dendrite) (individuals with schizophrenia vs controls: 21.6% reduction [P=.003]; individuals with bipolar disorder vs controls: 25.8% reduction [P=.005]). In addition, both individuals with schizophrenia and individuals with bipolar disorder had a reduced mean (SD) dendrite length (246.5 [67.4] and 245.6 [29.8] ?m, respectively) compared with controls (301.8 [75.1] ?m) (individuals with schizophrenia vs controls: 18.3% reduction [P=.005]; individuals with bipolar disorder vs controls: 18.6% reduction [P=.005]).Dendritic spine loss in the DLPFC was seen in both individuals with schizophrenia and individuals with bipolar disorder, suggesting that the 2 disorders may share some common pathophysiological features.

Dataset Information

Fiber pathway pathology, synapse loss and decline of cortical function in schizophrenia.

Publications

Fiber pathway pathology, synapse loss and decline of cortical function in schizophrenia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets