Disrupted Working Memory Circuitry in Schizophrenia: Disentangling fMRI Markers of Core Pathology vs Other Aspects of Impaired Performance

Abstract

Working memory (WM) impairment, a core feature of schizophrenia, is often associated with aberrant dorsolateral prefrontal cortex (dlPFC) activation. Reduced resting-state connectivity within the frontoparietal control network (FPCN) has also been reported in schizophrenia. However, interpretation of WM-related dlPFC dysfunction has been limited by performance differences between patients and controls, and by uncertainty over the relevance of resting-state connectivity to network engagement during task. We contrasted brain activation in 40 schizophrenia patients and 40 controls during verbal WM performance, and evaluated underlying functional connectivity during rest and task. During correct trials, patients demonstrated normal FPCN activation, despite an inverse relationship between positive symptoms and activation. FPCN activation differed between the groups only during error trials (controls4patients). In contrast, controls demonstrated stronger deactivation of the ventromedial prefrontal cortex (vmPFC) during correct and error trials. Functional connectivity analysis indicated impaired resting-state FPCN connectivity in patients, but normal connectivity during task. However, patients showed abnormal connectivity among regions such as vmPFC, lateral orbitofrontal cortex, and parahippocampal gyrus (PHG) during both rest and task. During task, patients also exhibited altered thalamic connectivity to PHG and FPCN. Activation and connectivity patterns that were more characteristic of controls generally correlated with better performance. In summary, patients demonstrated normal FPCN activation when they remained on-task, and exhibited normal FPCN connectivity during WM, whereas vmPFC deactivation differences persisted regardless of WM performance. Our findings suggest that altered FPCN activation in patients reflects performance difference, and that limbic and thalamic dysfunction is critically involved in WM deficits in schizophrenia.

A Novel Multisensory Integration Task Reveals Robust Deficits in Rodent Models of Schizophrenia: Converging Evidence for Remediation via Nicotinic Receptor Stimulation of Inhibitory Transmission in the Prefrontal Cortex

“…This finding suggests that nAChR activation rescues CMOR performance by enhancing GABAergic activity. In support of this, electrophysiological findings show that activation of nAChRs increases GABAergic currents in the cortex and hippocampus (Alkondon and Albuquerque, 2001;Couey et al, 2007;Aracri et al, 2010). Moreover, the GABAergic system is severely affected in schizophrenia patients because GABAergic markers such as parvalbumin (PV) are reduced in the hippocampus and prefrontal cortex (PFC) (Lewis et al, 2005;Lewis et al, 2012).…”

“…In nontreated rodents, activation of ␣ 4 ␤ 2 nAChRs increases GABAergic currents (Alkondon and Albuquerque, 2001;Couey et al, 2007;Aracri et al, 2010). We assessed GABAergic currents in ketamine-treated (rats: n ϭ 5; neurons: n ϭ 27) and saline-treated (rats: n ϭ 7; neurons: n ϭ 31) rats by recording GABAergic sEPSCs in pyramidal neurons located within OFC layer 2/3 at baseline and after the application of 1 mM ACh (in the presence of 200 nM atropine and 10 nM MLA to block muscarinic and ␣ 7 ACh receptors, respectively).…”

“…GABAergic spontaneous EPSCs (sEPSCs) were recorded for each neuron during a 30 s baseline period and then in the presence of 1 mM acetylcholine (ACh; 15 s application). Under these recording conditions, the observed sEPSCs were completely blocked by the addition of the GABA A receptor competitive antagonist BIC at a concentration of 10 M (Couey et al, 2007;Bailey et al, 2010). Analysis of GABAergic sEPSC frequency and amplitude at baseline and during the application of ACh was performed using the Mini Analysis Program (Synaptosoft).…”

“…The use of this high-chloride intracellular solution in neurons held at Ϫ75 mV allows for the observation GABA A receptor activation via positive inward currents that result from chloride exiting the open ligand-gated ion channel (Couey et al, 2007;Bailey et al, 2010). All recordings were performed in layer 2/3 of the OFC, which was visualized by recording immediately dorsal to the apex of layer 1 in the OFC (Van De Werd and Uylings, 2008).…”

“…Activation of pharmacologically isolated ␣ 4 ␤ 2 nAChRs in the OFC restored inhibitory currents without affecting GABAergic amplitude, suggesting that presynaptic ␣ 4 ␤ 2 nAChRs rescued GABAergic function. ␣ 4 ␤ 2 nAChRs have been shown to be localized presynaptically on GABAergic interneurons (Porter et al, 1999;Gulledge et al, 2007) and to enhance inhibitory currents (Alkondon and Albuquerque, 2001;Couey et al, 2007;Aracri et al, 2010). Moreover, chronic ketamine administration in rodents upregulates nAChR expression in the cortex (Chatterjee et al, 2012), potentially explaining why nAChRs have greater efficacy in restoring MSO performance and increasing GABAergic currents in ketamine-treated rats compared with saline-treated rats.…”