Working Memory in Schizophrenia: Behavioral and Neural Evidence for Reduced Susceptibility to Item-Specific Proactive Interference

Kaller, Christoph P.; Loosli, Sandra; Rahm, Benjamin; Gössel, Astrid; Schieting, Stephan; Hornig, Tobias; Hennig, Jürgen; Elst, Ludger Tebartz van; Weiller, Cornelius; Katzev, Michael

doi:10.1016/j.biopsych.2014.03.012

Cited by 24 publications

(14 citation statements)

References 52 publications

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“…These findings suggest that PTSD is not associated with increased intrusion of irrelevant representations into WM when simple, non-emotional stimuli are used. The results also add to the neuropsychological literature indicating that executive components of WM can be dissociated from WM maintenance (Thompson-Schill et al., 2002; Kaller et al, 2014). …”

Section: Discussionsupporting

confidence: 74%

Dissociation between working memory performance and proactive interference control in post-traumatic stress disorder

et al. 2017

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Deficits in working memory (WM) and cognitive control processes have been reported in post-traumatic stress disorder (PTSD), in addition to clinical symptoms such as hypervigilance, re-experiencing, and avoidance of trauma reminders. Given the uncontrollable nature of intrusive memories, an important question is whether PTSD is associated with altered control of interference in WM. Some studies also suggest that episodic memory shows a material-specific dissociation in PTSD, with greater impairments in verbal memory and relative sparing of nonverbal memory. It is unclear whether this dissociation applies to WM, as no studies have used identical task parameters across material. Here we tested 29 combat Veterans with PTSD and 29 age-matched control Veterans on a recent probes WM task with words and visual patterns in separate blocks. Participants studied four-item sets, followed by a probe stimulus that had been presented in the previous set (recent probe) or not (nonrecent probe). Participants with PTSD made more errors than controls, and this decrement was similar for verbal and visual stimuli. Proactive interference from items recently presented, but no longer relevant, was not significantly different in the PTSD group and showed no relationship to re-experiencing symptom severity. These results demonstrate that PTSD is not reliably associated with increased intrusions of irrelevant representations into WM when non-emotional stimuli are used. Future studies that use trauma-related material may provide insight into the flashbacks and intrusive thoughts that plague those with PTSD.

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Section: Discussionsupporting

confidence: 74%

Dissociation between working memory performance and proactive interference control in post-traumatic stress disorder

et al. 2017

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“…Alternatively, serial biases could be the mere by-product of long-lasting cellular or synaptic mechanisms that support memory stabilization during working memory delays 30 . Our study is in line with previous findings of reduced susceptibility to proactive interference in schizophrenia 31 . However, while proactive interference is mainly discussed in the context of cognitive control, the limited complexity of our task restricts possible interpretations of reduced between-trial interference and supports the role of reduced residual memory traces.…”

Section: Methodssupporting

confidence: 94%

Disrupted serial dependence suggests deficits in synaptic potentiation in anti-NMDAR encephalitis and schizophrenia

Stein

Barbosa

Rosa-Justicia

et al. 2019

Preprint

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We report markedly reduced working memory-related serial dependence with preserved memory accuracy in anti-NMDAR encephalitis and schizophrenia. We argue that NMDAR-related changes in cortical excitation, while quickly destabilizing persistent neural activity, cannot fully account for a reduction of memory-dependent biases. Rather, our modeling results support a disruption of a memory mechanism operating on a longer timescale, such as short-term potentiation.The NMDA receptor (NMDAR) subserves memory mechanisms at several timescales, including sustained working memory delay activity 1,2 and different temporal components of synaptic potentiation 3,4 . In addition, hypofunction of NMDARs is linked to psychiatric disease, in particular schizophrenia 5 , and it possibly contributes to abnormal working memory function in patients with schizophrenia 6,7 . Indeed, reduced prefrontal NMDAR density characterizes this disease 8 . Yet, the specific neural alterations by which NMDAR hypofunction could lead to memory deficits in schizophrenia are still under debate 6,7 . Here, we studied working memory function in healthy controls, patients with schizophrenia, and patients recovering from anti-NMDAR encephalitis ( Methods , Supplementary Table 1). Anti-NMDAR encephalitis is characterized by an antibody-mediated reduction of NMDARs, accompanied by initial psychosis and long-lasting memory deficits 9,10 , resembling clinical features of schizophrenia 11 .Consequently, we expected working memory deficits in anti-NMDAR encephalitis to parallel those in schizophrenia. This correspondence allows linking alterations in working memory to the NMDAR in both patient groups.We assessed memory alterations in a visuospatial delayed-response task (Fig. 1a) on two coexisting temporal scales: single-trial working memory accuracy as a proxy of active memory maintenance during short delays, and serial dependence of responses on previously memorized stimuli 12,13 (serial biases, Fig. 1b) as a read-out of passive information maintenance across trials. Neural correlates of this task have been identified in monkey prefrontal cortex 14,15 , inspiring computational models that can capture key aspects of neural dynamics and behavior [15][16][17][18][19] . The biophysical detail of these models permits to investigate how NMDAR hypofunction at different synaptic sites affects circuit dynamics and working memory.Candidate mechanisms are a disturbed balance between cortical excitation and inhibition (E/I balance), as it is observed in schizophrenia and in studies using NMDAR antagonists (e.g. ketamine) 2,5,20,21 , and alterations in NMDAR-regulated short-term synaptic potentiation 3,4,22 . In the modeling section of this study (Figs. 2,3), we systematically tested the potential of these candidate mechanisms for explaining experimentally observed memory alterations in schizophrenia and anti-NMDAR encephalitis.First, we sought to identify alterations in single-trial working memory accuracy, as an indication of a possible dysfunction of activity-based memory...

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“…This process has been shown to involve plasticity in the DG (Malleret et al, 2010), with a particular role for neurogenesis (Saxe et al, 2007), including circuit-dependent integration of immature neurons in effective DG function (Rangel et al, 2013). Schizophrenia cases show diminished vulnerability to proactive interference owing to their greater loss of previous working memory traces and disruption of coupling between PFC and subcortical (limbic/thalamic) regions, shown with functional imaging (Anticevic et al, 2012;Kaller et al, 2014), that would confer greater autonomy to temporal lobe regions.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of Specialized Delay/Interference-Dependent Working Memory Following Loss of Dysbindin-1A in Schizophrenia-Related Phenotypes

Petit

Michalak

Cox

et al. 2016

Neuropsychopharmacol

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Dysbindin-1, a protein that regulates aspects of early and late brain development, has been implicated in the pathobiology of schizophrenia. As the functional roles of the three major isoforms of dysbindin-1, (A, B, and C) remain unknown, we generated a novel mutant mouse, dys-1A, with selective loss of dysbindin-1A and investigated schizophrenia-related phenotypes in both males and females. Loss of dysbindin-1A resulted in heightened initial exploration and disruption in subsequent habituation to a novel environment, together with heightened anxiety-related behavior in a stressful environment. Loss of dysbindin-1A was not associated with disruption of either long-term (olfactory) memory or spontaneous alternation behavior. However, dys-1A showed enhancement in delay-dependent working memory under high levels of interference relative to controls, ie, impairment in sensitivity to the disruptive effect of such interference. These findings in dys-1A provide the first evidence for differential functional roles for dysbindin-1A vs dysbindin-1C isoforms among phenotypes relevant to the pathobiology of schizophrenia. Future studies should investigate putative sex differences in these phenotypic effects.

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Working Memory in Schizophrenia: Behavioral and Neural Evidence for Reduced Susceptibility to Item-Specific Proactive Interference

Cited by 24 publications

References 52 publications

Dissociation between working memory performance and proactive interference control in post-traumatic stress disorder

Dissociation between working memory performance and proactive interference control in post-traumatic stress disorder

Disrupted serial dependence suggests deficits in synaptic potentiation in anti-NMDAR encephalitis and schizophrenia

Dysregulation of Specialized Delay/Interference-Dependent Working Memory Following Loss of Dysbindin-1A in Schizophrenia-Related Phenotypes

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