Executive Function with a Focus on Working Memory in Schizophrenia

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Executive Function with a Focus on Working Memory in Schizophrenia

Executive function with a focus on working memory in schizophrenia Schizophrenia is a complex disorder with a large heterogeneity within its clinical handbook. Categorised as a disorder of psychosis, it remains an abstract chronic illness that affects one percent of the global population (Nordqvist, C. 2017). With a vast variety of clinical presentations, the exact nature of the neuropsychology of schizophrenia continues to remain elusive. Ongoing research and continuous technological advances, however, brings clarity to a multifactorial aetiology and the spectrum of symptoms the patient’s display. Divided into 3 categories, schizophrenia manifests into positive, negative and cognitive symptoms, and arise as the fundamental aspects of the disorder.

Positive symptoms, the addition of a behaviour, thought or feeling seemingly coincides with emotional and social reactivity in schizophrenia (Mueser & Jeste, 2011). This is presented as delusions and hallucinations. Negative symptoms, which take away a behaviour thought or feeling can include, specific impaired motivation, drop in spontaneous speech and social withdrawal (Fatani, Aldawod & Alhawaj, 2017). Cognitive symptoms can include deficits in executive functioning, attention, and working memory (Glausier & Lewis, 2013). In this review, cognitive dysfunction has been highlighted as a core domain of schizophrenia, reported in almost 98% (Tripathi, Kar, & Shukla, 2018) of schizophrenic patients. Impairments can include disorganized speech, attention and thought, poor memory and higher-order functions eventually impairing the capacity to communicate effectively (Fatani, Aldawod & Alhawaj, 2017).

Through an exploration of a possible pathway, the light will be shed on executive dysfunction and more specifically working memory, a limited capacity that temporarily holds information available for processing, in schizophrenia. Disrupted component processes and underlying abnormalities in neural architecture and connectivity in combination with altered functional activity forms the basis to explain such changes (Eisenberg & Berman, 2009). However due to it heterogeneous nature, sometimes broad or specific, and manifested by different patterns of performance (Kuperberg & Heckers, 2000) there remains no general consensus. Executive function refers to the ability to coordinate thought and action and directing it toward obtaining a set of goals. Simply it allows us to invoke voluntary control of our behavioural responses to allow human beings to develop and carry out plans, obey social rules, solve problems, adapt to unexpected circumstances, multitask and locate episodes in time and place (Orellana & Slachevsky, 2013).

Deficits in executive function can occur in various stages over the progression of schizophrenia. Adolescent at risk of developing the disease, patients with their first episode of schizophrenia, relatives and aged patients with more severe cognitive impairment all present signs of executive dysfunction (Breton et al., 2011; Kuperberg & Heckers, 2000). Based on the traditional medical model, executive function was construed as a single construct as a central executive in charge of high-level cognitive skills (Della Sala et al., 1998; Shallice, 1990).

However, as our understanding continues to evolve, executive function is a model of multiple process related systems that is inter-related, inter-dependent and work together as an integrated supervisory system (Stuss & Alexander, 2000). Working memory (WM) is a limited capacity system that enables us to temporarily hold, update and work with relevant information, playing a significant component in higher-order thinking, language and goal directed behaviour (Baddeley, 2003). It confers the ability to direct behaviour by the sole representations of the outside world rather than by immediate stimulation and thus to base behaviour on ideas and thoughts (Lichter & Cummings, 2001). Noted by (Salzinger, 1984), schizophrenic behaviour was excessively dominated by immediate stimulation rather than by a balance of current, internal and past information. Well-documented in several researches are deficits in WM of patients with schizophrenia (Barch, Csernansky, Conturo & Snyder, 2002; (Callicott et al., 2000)

Deficits shown by schizophrenic patients on a variety of neuropsychological tests become the foundation to illustrate such points. The PFC mediated tasks on which schizophrenic patients perform poorly share a common feature, the involvement of working memory (Goldman-Rakic, 1987). Most widely recognised is the Wisconsin Card Sorting Test which is particularly sensitive to dorsolateral prefrontal cortex (DLPFC) abnormalities. Patients are reported to have difficulties in switching from one category to another, where they preserve the choice even when it is no longer correct. Further illustrated by (Weinberger, Berman, & Zec, 1986), they observed the blood flow of medication free schizophrenic patients under various conditions (at rest, during performance of WCST). It was seen blood flow to the DLPFC did not increase in comparison to the control. Similar findings are seen while performing the Tower of London task (Andreasen et al., 1992).

However, more studies are needed to integrate structural and functional imaging to further investigate WM abnormalities and their relationship to other variables like age and medication effects. Anatomically these functions are linked to the prefrontal cortex as deficits in executive skills often are correlated to damage to the PFC (Grattan & Eslinger, 1991).Supporting this comes a plethora of functional neuroimaging studies (Honey, Bullmore, & Sharma, 2002) that have observed increased activation of the prefrontal cortex when performing tasks specifically designed for executive functioning (Morris, Ahmed, Syed, & Toone, 1993). In addition negative symptoms are frequently linked to symptoms of patients with lesions of the DLPFC and related structures (Freedman & Brown, 2011). The PFC is subdivided into four main regions, the ventromedial PFC, largely involved in the integration of emotional information kept in memory and external stimuli, the dorsolateral PFC related to working memory, reasoning and thematic understanding, the medial PFC involved in attentional control and planning and the frontal pole involved in adaptive planning and self-awareness (Orellana & Slachevsky, 2013). As demonstrated above schizophrenic patients most commonly show deficits in tasks (working memory) related to the DLPFC (Manoach et al., 2000; Perlstein, Carter, Noll, & Cohen, 2001).

Described not as an anatomical structure, but rather defined by its functional attributions it is located in the middle of the frontal gyrus of the cortex (BA9+46) with its main functions including conceptualization, cognitive flexibility and working memory (McCabe, Roediger, McDaniel, Balota, & Hambrick, 2010). Although this has been highly replicated, behavioural abnormalities in schizophrenia remain poorly understood (Yoon et al., 2008). With numerous lines of evidence continuing to point towards abnormalities of the DLPFC, it does not implicate degeneration or to a possible lesion, but instead highlights alterations in neuronal and dendritic spine density and/or decreases in the neuropil (axons+ dendrites+ glia) (Boksa, 2012). Therefore suggests there is no loss of axons or cortical neurons but rather a decline in neuronal processes (Garey, 2010). The disturbances in the molecular mechanisms that underlie neuronal processes; spine formation, pruning, and/or maintenance(Glausier & Lewis, 2013) consequently impact the circuitry with multiple cortical regions. These processes are vital to streamline neural circuits through their shared function for an effective neural network.

Therefore, functional connectivity abnormalities may constitute a final common pathway for executive dysfunction and WM impairment. Suspected to occur during adolescence from a deficit of synaptic elimination programmed to occur during adolescence (Feinberg, 1982) , disruptions in neurodevelopment may bring about these deficits (Ho et al., 2003). Imaging studies of high-risk adolescent reveal an enhanced grey matter volume reduction in prefrontal cortex (Gogtay, Vyas, Testa, Wood, & Pantelis, 2011). Consistent with this, is evidence suggesting that the brains of adult patients have decreased grey matter, such that synaptic pruning may be analogous to the decline (Andreasen et al., 2011; Feinberg, 1982). Post-mortem brain studies (Moyer, Shelton, & Sweet, 2015) have similarly reported decreased spine density on cortical pyramidal cells from patients with schizophrenia compared with controls. Pyramidal spine density, small protrusions joined to the main dendrite, are often targeted during elimination in developmental synaptic pruning (Gogtay et al., 2011).

The vast majority of excitatory synapses (80-95%), which facilitates the transmission of an action potential, provide input to dendritic spines. They serve to specifically connect inputs in circuitry and therefore underlies the disruption of normal connectivity (Yuste & Majewska, 2001). The prefrontal cortex is a component of a larger network of cortical areas with numerous synapses translating the signal across, with dysfunction in any part of the network it gives rise to aberrant functional outcomes. The application of newly developed techniques and electron microscope studies has revealed a strong correlation between spine size and efficacy of synaptic transmission (Lee, Soares, & Béïque, 2012). Dendritic spine alterations have been identified in multiple brain regions in schizophrenia but are best characterized in cortical layer 3 (Glausier & Lewis, 2013). Parallel studies have both reported that small spine density had significantly reduced pyramidal neurons in layer 3 of the PFC in the schizophrenic brains. Small spines, due to its empirical link with synaptic function, correlates with neural plasticity, therefore effective circuitry involving PFC (Hung et al., 2008).

Seen in several experimental models, spine deficits are also associated vastly with impairments in working memory, attention and sociability (Brennaman et al., 2011; Liston et al., 2006)further suggesting deficits in dendritic spines may be contributors to the clinical features of schizophrenia. In neuropsychological testing, impaired cognitive flexibility demonstrated on the Wisconsin Card Sorting Test (Milner, 1963)is linked to spine density. Though less well studied, the ventrolateral prefrontal cortex (VLPFC), is noted to be involved in working memory storage and rehearsal processes (Wager & Smith, 2003). With less cellular abnormalities than DLPFC, patients have still shown increased VLPFC activation in conjunction with reduced DLPFC activation in a verbal working memory task (Tan, Choo, Fones, & Chee, 2005). There is no conclusive agreement as to whether the cognitive impairments can be attributed to a single or multiple disrupted system. The prefrontal cortex receives many connections from other cerebral structures. To carry out its functions it requires interactions between a complex array of anatomically and functionally related areas(Goldman-Rakic, 1987; Selemon, Rajkowska, & Goldman-Rakic, 1995).

Patients with schizophrenia have shown altered activity in the DLPFC, anterior cingulate cortex, basal ganglia, hippocampus and mediodorsal nucleus of the thalamus (Eisenberg & Berman, 2009;(Unschuld et al., 2013).Hence it is important to understand how information processing within PFC influences and is influenced by activity of other regions and how disconnection of these neural networks such as white matter damage or impairment to other brain regions (Stuss & Alexander, 2000) may explain cognitive deficits and neuroimaging findings. Functional neuroimaging of patients during EF tasks shows abnormal activation not only in the frontal lobes, but in other distributed brain regions typically recruited by executive task demands (Jansma, Ramsey, van der Wee, & Kahn, 2004). Moreover, working memory tasks; nonmatching to sample are associated with lesions of the hippocampus(Yoon, Okada, Jung, & Kim, 2008), observed in a rat study. In studies on WM in schizophrenia there was seen abnormal connectivity among different circuits connected to the frontal lobes (parietal, cerebellum, hippocampus) (Ruiz, Birbaumer, & Sitaram, 2013).

Therefore, suggests executive function requires the integration of prefrontal and subcortical activity where disrupted PFC function and related aberrant interactions contribute to executive dysfunction in schizophrenia. It is however a concern that functional connectivity measures are unable to differentiate between whether abnormal functional is due to abnormal function in anatomical connections or within regions. Due to the profound interconnectivity between the thalamus and PFC, the subcortical structure must play a large role in cognition. The thalamus facilitates connections and filters input and output from cortical and sub cortical regions. It has various connections with the prefrontal cortex and additionally, the mediodorsal nucleus of the thalamus provides projections to and from various regions of the PFC, serving as the major relay station to the PFC (Andreasen, 1997). As a filter, the thalamus receives sensory information from multiple sources, simplifies it by excluding redundant stimuli, and forwarding or receiving the relevant information to the PFC to formulate the appropriate decisions or responses in a rapid and well-coordinated manner required in executive skills. Through the application of stereology techniques obtained relatively precise quantitative estimates of cell loss in the medial dorsal nucleus of the thalamus. Observed was both a decrease in neuronal density and a reduction in volume (Alelú-Paz & Giménez-Amaya, 2008).

Working memory tasks, have also provided support for thalamic abnormalities. In one study comparing schizophrenic patients with healthy volunteers during practised and novel recall of complex narrative material, we observed decreased thalamic flow in patients suffering from schizophrenia (Cohen & Yurgelun-Todd, 2001). In summary, schizophrenia continues to remain a convoluted mystery. Through an exploration of changes seen in executive function and working we are able to begin to recognise and understand the complex pathophysiology. Indicated by series of converging evidence on the neuronal processes, neural architecture and connectivity of the prefrontal cortex it forms the basis to explain such dysfunction.

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