The association between cognitive deficits and prefrontal hemodynamic responses during performance of working memory task in patients with schizophrenia

Abstract

Schizophrenia-associated cognitive deficits are resistant to treatment and thus pose a lifelong burden. The Brief Assessment of Cognition in Schizophrenia (BACS) provides reliable and valid assessments across cognitive domains. However, because the prefrontal functional abnormalities specifically associated with the level of cognitive deficits in schizophrenia have not been examined, we explored this relationship. Patients with schizophrenia (N = 87) and matched healthy controls (N = 50) participated in the study. Using near-infrared spectroscopy (NIRS), we measured the hemodynamic responses in the prefrontal and superior temporal cortical surface areas during a working memory task. Correlation analyses revealed a relationship between the hemodynamics and the BACS composite and domain scores. Hemodynamic responses of the left dorsolateral prefrontal cortex (DLPFC) and left frontopolar cortex (FPC) in the higher-level-of-cognitive-function schizophrenia group were weaker than the responses of the controls but similar to those of the lower-level-of-cognitive-function schizophrenia group. However, hemodynamic responses in the right DLPFC, bilateral ventrolateral PFC (VLPFC), and right temporal regions decreased with increasing cognitive deficits. In addition, the hemodynamic response correlated positively with the level of cognitive function (BACS composite scores) in the right DLPFC, bilateral VLPFC, right FPC, and bilateral temporal regions in schizophrenia. The correlation was driven by all BACS domains. Our results suggest that the linked functional deficits in the right DLPFC, bilateral VLPFC, right FPC, and bilateral temporal regions may be related to BACS-measured cognitive impairments in schizophrenia and show that linking the neurocognitive deficits and brain abnormalities can increase our understanding of schizophrenia pathophysiology.

Introduction

Schizophrenia is associated with deficits in multiple cognitive domains, including selective and sustained attention, working memory, episodic memory, processing speed, executive function, and social cognition (Green et al., 2004). Because of the lack of effective treatments for these deficits, schizophrenia often continues to exact a devastating toll, with 80% of patients remaining unemployed and less than 30% living independently (Torrey, 2006).

In order to advance the development of therapies aimed at ameliorating the cognitive deficits in schizophrenia, biomarkers must be identified that can be used to determine whether therapeutic candidates elicit the targeted biological effects. In neuropsychiatric research, a biomarker is an indicator of neuronal function — hypothesized to be related to disease mechanisms — that can serve as an immediate and objective measure of the biological effects of therapeutic candidates (Tregellas et al., 2014).

Impairments in working memory and other cognitive functions are cardinal neuropsychological symptoms in schizophrenia, and the prefrontal cortex (PFC) is important for mediating and executing these functions (Badre and D'Esposito, 2009, D'Esposito et al., 1995, Senkowski and Gallinat, 2015, Takizawa et al., 2008). The cognitive impairment associated with schizophrenia stems mainly from abnormalities of the PFC (Green et al., 2004), as supported by the results of functional magnetic resonance imaging (fMRI) studies performed during neurocognitive tasks (Minzenberg et al., 2009, Senkowski and Gallinat, 2015). Previous studies using the n-back neurocognitive assessment task, which is a well-known working memory task, have indicated that patients with schizophrenia have decreased dorsolateral prefrontal cortex (DLPFC) activation (Callicott et al., 2003, Callicott et al., 2000, Jansma et al., 2004, Perlstein et al., 2001, Schneider et al., 2007). On the other hand, other studies have shown that patients with schizophrenia have greater PFC activation compared with healthy controls (HCs), suggesting that the relationship between PFC activation and neuronal function follows an inverted U-curve activity pattern (Callicott et al., 2003, Jansma et al., 2004, Potkin et al., 2009), or a compensatory response using preserved functions (Callicott et al., 2003, Minzenberg et al., 2009, Potkin et al., 2009, Schneider et al., 2007). Therefore, working memory impairment may result from reduced function in specific brain regions related to a given cognitive task (Lett et al., 2014). Elucidating the relationship between working memory-related PFC neural activity and cognitive ability could help clarify the mechanism(s) of cognitive impairment.

The Brief Assessment of Cognition in Schizophrenia (BACS) (Keefe et al., 2004) is an instrument used to evaluate the elements of cognition that are most commonly impaired and strongly connected with everyday functioning in patients with schizophrenia (Keefe et al., 2006). The BACS includes five cognitive domains (verbal memory, working memory, motor speed, verbal fluency, attention and speed of information processing, and executive function) and can be administered by a wide range of mental health professionals. Despite the battery's comprehensive nature, high test–retest reliability, predictive value, relationship to functional outcome, and utility in clinical trials (Kaneda et al., 2007, Keefe et al., 2006, Keefe et al., 2008, Melau et al., 2015), to our knowledge, no study has reported an association between BACS scores and brain function in schizophrenia. Understanding the brain abnormalities related to BACS performance may allow imaging assessments to help accelerate the development of new therapies.

In our previous pilot study (Pu et al., 2014), we investigated the effects of a cognitive remediation therapy on neurocognitive functioning assessed by BACS and on working memory-related PFC neural activity using 52-channel near-infrared spectroscopy (NIRS). The cognitive remediation therapy group, in comparison with the control group, showed significant improvement on the BACS and a significant increase in brain activation in the right frontopolar area, which is associated with working memory, in comparison with the control group. In addition, the amount of enhancement in cognitive subcomponents such as verbal memory and verbal fluency was positively correlated with the magnitude of the increase in the hemodynamic response during the working memory task predominantly in the right hemisphere. These findings suggest that NIRS may be a useful tool for assessing the changes in neural activity that underlie the neurocognitive functioning improvements elicited by neurocognitive rehabilitation. However, the relationship between the working memory-related PFC neural activity and neurocognitive functioning is not yet clear.

Our goals in the present study were to test the hypotheses that (1) relative to healthy subjects, patients with schizophrenia have detectable abnormalities in working memory-related PFC neural activity, as measured using multi-channel NIRS imaging, and (2) this neural activity is related to cognitive ability, in particular the working memory or verbal memory and verbal fluency cognitive domains, as the improvement in these subcomponents in BACS was associated with increase in the hemodynamic response caused by cognitive remediation therapy in our previous study (Pu et al., 2014). Findings supporting these hypotheses would suggest that working memory-related PFC neural activity may be a useful biomarker for therapeutic development.