Decline in working memory in stable schizophrenia may be related to attentional impairment: mediating effects of negative symptoms

doi:10.21203/rs.3.rs-3224248/v1

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Decline in working memory in stable schizophrenia may be related to attentional impairment: mediating effects of negative symptoms

https://doi.org/10.21203/rs.3.rs-3224248/v1

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Objective:

Cognitive deficits and negative symptoms are prevalent in individuals with schizophrenia and are crucial indicators of functional recovery. However, the specific relationship between attention, working memory, and negative symptoms in stable schizophrenia remains unclear. This study aims to explore these associations and provide valuable insights for the subsequent treatment of schizophrenia.

Methods:

We conducted a comprehensive assessment of 145 patients with stable schizophrenia using the Chinese Brief Neurocognitive Suite of Tests (C-BCT) and the Positive and Negative Symptom Scale (PANSS).

Results:

Patients with abnormal cognition exhibited significantly higher PANSS total scores, cognitive symptom scores, and negative symptom scores than those with normal cognition（P<0.05）.Pearson's correlation analysis revealed significant positive correlations between digital breadth and sustained operation（r=0.389，P<0.001）,as well as a significant negative correlation between digital breadth and negative symptoms（r=-0.291，P<0.001）.Moreover, continuous manipulation showed a negative correlation with negative symptoms（r=-0.173，P<0.05）.However, no significant correlations were found between the digital breadth conformity score and persistent manipulation or negative symptoms（r=0.148，P>0.05；r=-0.068，P>0.05）. Notably, negative symptoms were identified as a mediator in the relationship between attention and working memory (effect size=0.024).

Conclusion:

Our findings highlight significant associations between working memory, attention, and negative symptoms in individuals with stable-phase schizophrenia. Moreover, attention not only directly impacts working memory but also indirectly influences it through negative symptoms. Addressing cognitive deficits and negative symptoms in the treatment of schizophrenia may lead to improved overall outcomes for affected individuals.

Stable schizophrenia

Working memory

Attention

Negative symptom

Intermediary effect

Cognitive deficits are prominent and treatment-resistant symptoms of schizophrenia (SCZ) and serve as prominent indices of patient functioning and treatment outcomes. [1]. Numerous studies have demonstrated measurable cognitive deficits in individuals with SCZ, including impairments in working memory (WM), attention, information processing speed, and executive functioning [2]. Notably, working memory performance has emerged as the most robust predictor of functional outcomes [3]. Moreover, attention and working memory are closely intertwined [4, 5], and individual differences in these abilities are dependent on their interrelated variations [6]. Lapses in working memory performance have been associated with differences in individuals' attention[7], wherein low-ability individuals exhibit more frequent mind-wandering, particularly during cognitively demanding tasks, and this phenomenon demonstrates synchronized behavior [4].

The negative symptoms of SCZ, such as emotional flattening, social withdrawal, lack of pleasure, apathy, and reduced emotional expression, significantly impair social functioning [8]. The underlying mechanisms are complex and may involve reduced gray matter volume in the prefrontal, medial, and superior temporal lobes [9] Dysregulation of multiple neurotransmitters, especially dopamine release, plays a pivotal role in these pathologic changes [10] .Furthermore, these alterations are closely associated with impairments in executive function, attention, and working memory [11] .Previous studies have found that the link between cognitive function and functional outcomes is mediated by clinical symptoms, primarily negative symptoms [12].Interestingly, we observed that medication showed limited effectiveness in alleviating negative and cognitive symptoms. Thus, it is imperative to investigate the relationship between these factors to better manage symptom progression.

The main objective of this study was to explore the relationship between working memory, attention, and negative symptoms using a mediation model. We hypothesized that attention influences working memory, and that negative symptoms may mediate the association between attention and working memory. The inclusion of a mediation model will help elucidate the intricate interactions among these cognitive and symptomatic aspects of SCZ, paving the way for more targeted and effective interventions.

2.1 Participants

In this study, 145 patients with stable schizophrenia who were hospitalized at Anhui Mental Health Center from June 2022 to June 2023 were selected, and all participants and guardians provided informed consent.

2.2 Inclusion and exclusion criteria

Inclusion criteria were as follows:

(1) Those who meet the DSM-V diagnostic criteria for schizophrenia;

(2) Symptomatic stabilizers: clinically stable for ≥ 3 months, with P1, P2, P3, and P6 items ≤ 3 on the PANSS scale, and taking regular antipsychotic single-agent therapy and remaining stable for ≥ 3 months;

(3) Age 18–60 years;

(4) Obtain informed consent, agree to take cognitive function tests, be able to understand and read Chinese, understand the test program, be able to understand the voice introduction, and be able to operate a simple iPad.

Candidates were excluded for:

(1) Alcohol or substance dependence in the past six months;

(2) Significant clinical neurologic disorders; head trauma (loss of consciousness for more than an hour), Parkinson's disease, dementia;

(3) Pregnant or breastfeeding women;

(4) Presence of a family history of mental retardation;

(5) Combined other mental disorders;

(6) Their level of visual or auditory functioning affects the test.

2.3 Measures

2.3.1 General demographic information

Data on demographics and indicators, such as sex, age, height, weight, body mass index (BMI), duration of illness, years of schooling, and chlorpromazine equivalents, were collected.[13, 14].

2.3.2 Cognitive function assessment

The Chinese Brief Neurocognitive Compact Test (C-BCT) is a localized cognitive assessment tool for schizophrenia adapted for China [15].The target patients are those who have cognitive impairment and those who have been treated with medication to observe the effects of the treatment. A total of four tests are included, including the connectivity test, symbol encoding, sustained manipulation, and numerical breadth. The patients were tested for information processing speed, executive function, attention, and working memory. Each measure shows its T score, deficit, degree of impairment, and percentile (%) in the Chinese test population as a means of assessing the patient's cognitive function.

2.3.3 Positive and Negative Symptom Scale

Analysis was performed using a 5-factor model, which included cognitive factors (P2, N5, N7, G10, G11), excitability factors (P4, P7, G4, G8, G14), depression factors (G2, G3, G6), negative factors (N1-N7), and positive factors (P1-P7). Rated by 2 consistency-trained psychiatric clinicians, the higher the symptom score, the more severe the symptom.

2.4. Statistical analysis

Statistical analyses were performed using SPSS 26.0, first checking whether the measured data were characterized by a normal distribution as well as consistency of variance. Normal distribution was represented by(\(\stackrel{-}{x}\)±s) and skewed distribution was represented by M(P₂₅, P₇₅). General data such as age, height, weight, body mass (BMI), duration of disease, years of education, and chlorpromazine equivalents were analyzed using the independent samples t-test, while gender was studied using the chi-square test. Comparisons of 2 groups of measured data that conformed to a normal distribution were performed using 2 independent samples t-test; Pearson's correlation analysis was used in this study to explore the correlation between the variables; the difference was considered statistically significant at P < 0.05. For the mediation analysis, attention (sustained operation) was set as the independent variable ,and working memory (numerical breadth) was set as the dependent variable. The coefficient of variation test was applied to explore the mediating effect of the model.

3.1 General demographic information and analysis of variance

A total of 145 patients with stable schizophrenia were included in this study. Based on the results of the Chinese Brief Neurocognitive Suite of Tests (CBCT), 68 patients exhibited normal cognition, while 77 patients had abnormal cognition. Importantly, there were no significant differences in sex, age, body mass index (BMI), illness duration, years of education, or chlorpromazine equivalents between the two groups (P>0.05). However, the PANSS total score, negative symptom scores, and cognitive symptom scores showed statistically significant differences between the groups (P<0.05). For detailed information, refer to Table 1.

Table 1 Comparison of general demographic information and PANSS scores of cognitively normal and cognitively abnormal patients

	Cognitively normal group（n=68）	Cognitive abnormalities group（n=77）	t/X²	P
N	68	77
Age（years）	31.37±10.64	32.84±9.96	-0.859	0.392
Gender Men	27	28
Women	39	48	0.727	0.695
BMI（Kg/m²）	23.28±5.12	24.13±4.84	-1.016	0.311
Years of Education	11.44±3.38	11.45±3.32	-0.024	0.981
Course of a Disease	7.73±6.96	8.39±5.49	-0.627	0.532
Chlorpromazine Equivalent	396.08±204.23	379.44±169.34	0.530	0.597
PANSS Total	79.43±15.72	85.64±19.62	-2.086	0.039
Positive Symptoms	16.56±3.69	15.86±3.06	1.253	0.212
Negative Symptoms	18.99±8.48	24.61±7.46	-4.251	<0.001
Cognitive Symptoms	11.12±3.23	12.38±3.75	-2.151	0.033
Depressive Symptoms	6.62±4.70	6.09±3.11	0.805	0.422
Excitatory Symptoms	14.75±4.35	14.75±5.86	-0.004	0.997

3.2 A study of relevance

The associations between working memory (WM) (digit breadth paralleling and retrograde) and attention (sustained operation) and negative symptoms in schizophrenic patients are summarized in Table 2. According to Pearson correlation analysis, digit breadth became significantly positively correlated with sustained operation (r=0.389, p<0.001) and negatively correlated with negative symptoms (r=-0.291, p<0.001). Sustained operation was found to be negatively correlated with negative symptoms (r=-0.173, p<0.05). However, digital breadth conformity scores were not significantly correlated with sustained manipulation and negative symptoms (r=0.148, p>0.05; r=-0.068, p>0.05).

Table 2 Correlations between WM (digit breadth paralleling, retrograde) and attention (sustained manipulation) and negative symptoms in patients with schizophrenia

	Number breadth-anterograde score	Digital breadth-retrograde score	Digital breadth	Continuous operation
Digital breadth-retrograde score	.413**
Digital breadth	.743**	.798**
Continuous operation	0.148	.402**	.389**
Negative Symptoms	-0.068	-.357**	-.291**	-.173*

3.3 Negative Symptoms Mediate the Relationship Between WM and Attention Associations

Based on the correlation analyses described above, mediating effects were examined using the SPSS macro program PROCESS developed by Hayes. A mediation model based on negative symptoms was constructed by creating a structural equation with persistent manipulation as the independent variable in the model 4 condition (Table 3、Table 4). In Step 1, regression analyses revealed an estimated effect size of 0.229 (P < 0.05) for persistent manipulation on digit breadth. In Step 2, the regression coefficients were standardized, and the estimated effect size of continuous manipulation on digit breadth was 0.205 (P < 0.05). A difference-in-difference coefficient test indicated that negative symptoms mediated the association between persistent manipulation and digit breadth, with an effect size of 0.024 (Figure). Thus, it appears that sustained manipulation scores not only directly influence digit breadth scores but also have an indirect effect through negative symptoms.

Table 3 Mediating Effects of Negative Symptoms on the Relationship Between Sustained Operations and Digit Breadth

		R	R2	SE	β	estimate	t	p
Digital breadth	Continuous operation	0.451	0.203	0.045	0.349	0.205	4.593	0.000
	Negative Symptoms			0.080	-0.230	-0.230	-3.026	0.003
Negative Symptoms	Continuous operation	0.174	0.030	0.046	-0.174	-0.173	-2.106	0.037

Table 4 Total, Direct, and Indirect Effects of Negative Symptoms on the Relationship Between Continuous Operations and Digit Breadth

	Effect	BootSE	BootLLCI	BootULCI	Relative effect
Indirect effect	0.024	0.013	0.002	0.052	10.27%
Direct effect	0.205	0.050	0.111	0.307	89.77%
Total effect	0.229	0.051	0.133	0.331

The primary objective of this study was to explore the intricate relationship between attention, working memory, and negative symptoms in stable schizophrenia. Our findings revealed a strong association between attention, as assessed by the C-BCT, and working memory in patients with stable schizophrenia. Moreover, we observed that negative symptoms, as evaluated using the PANSS scale, were also closely related to and mediated the association between attention and working memory. This suggests that impaired attention directly or indirectly contributes to a decline in working memory through negative symptoms. These significant findings offer a valuable theoretical basis for advancing the treatment and prevention of cognitive impairment in schizophrenia.

Historically, the treatment of schizophrenia has primarily focused on managing hallucinations and delusions, while negative and cognitive symptoms have proven more challenging to address than positive symptoms[16].However, numerous previous studies have underscored that negative and cognitive symptoms serve as the most robust predictors of functional outcomes in schizophrenia [17-19]. Consequently, targeted improvement of patients' negative symptoms may lead to concurrent enhancements in cognitive impairment symptoms. Our study corroborates these previous findings, as we observed that patients with schizophrenia exhibiting notable cognitive abnormalities had higher PANSS scale scores and elevated negative symptom scores than those with normal cognition. This finding aligns with previous research, indicating that patients with higher levels of negative symptoms exhibit reduced engagement and face greater difficulty in completing cognitive tests. Overall, these results further support the association between negative symptoms and cognitive impairment in individuals with schizophrenia [20, 21].

A significant negative correlation has been reported between negative symptoms and prior cognitive functioning, and this correlation has been associated with poorer daily functioning [22-24] . However, there is limited research exploring how negative symptoms specifically impact cognitive functioning subfields. In light of this, our study aimed to examine the relationship between negative symptoms, attention, and working memory. We found that negative symptoms were negatively correlated with attention and working memory, while attention and working memory showed a positive correlation. These findings suggest that targeting negative symptoms may lead to improvements in attention and working memory, thereby benefiting overall cognition. Neurobiological evidence further supports the connection between negative symptoms and executive/attentional dysfunction in schizophrenia, involving biochemical, structural, and functional abnormalities in the frontal cortex and related subcortical circuits [25-27]. Additionally, significant negative correlations were observed between intrinsic hippocampal activity in schizophrenia, a broad range of cognitive measures, and its association with negative symptoms [28] . Considering that medications often show limited effectiveness in treating negative symptoms and cognitive deficits in schizophrenia, which substantially impact patients' quality of life, planned aerobic exercise may offer significant benefits [29].

The present study aimed to construct a mediation model using attention (sustained manipulation score) and working memory (numerical breadth score), wherein negative symptom scores play a mediating role. Specifically, we found that attention indirectly or directly influences working memory by affecting negative symptoms. As argued by Brazo[26] , primary and secondary negative symptoms may be linked to varying degrees of executive/attentional dysfunction. In our study, we explored this relationship and aimed to contribute to future cognitive improvements by addressing negative symptoms. Lam[30] suggested that social cognition mediates the relationship between neurocognition and symptoms, and neurocognitive deficits predispose individuals with schizophrenia to more severe psychiatric symptoms through impairments in social cognition. However, in our study, we focused on subdividing cognitive functioning into attention and working memory rather than social cognition.

This study has several limitations that should be acknowledged. First, the mediation analysis of attention, working memory, and negative symptoms was based on cross-sectional data, and follow-up observations of the enrolled patients were not conducted. Nevertheless, this study represents a crucial initial step toward longitudinal and more comprehensive research. Second, the present study serves as a preliminary investigation and did not delve into subdivisions of cognitive functions, such as neurocognitive and social cognition, verbal and spatial working memory, and even sub-programs of negative symptoms. Future studies should explore these aspects in greater depth. Additionally, the measurement instrument used in this study was the Chinese Brief Neurocognitive Suite of Tests (C-BCT), which may introduce bias in the measurement process, an inherent limitation that future studies should address. Moreover, cognitive functioning in schizophrenia is influenced by various complex factors, and in this study, we focused solely on the relationship between attention and working memory. To gain a comprehensive understanding of the effects of cognition and symptoms in schizophrenia, as well as depression and other disorders, further exploration of the mechanisms and influencing factors of cognitive decline and symptom onset is warranted. Such research will provide essential theoretical support for identifying potent drug targets and developing effective behavioral interventions in the future.

Based on our investigation of the relationship between cognitive function and negative symptoms, we found that both attention deficit and negative symptoms significantly contribute to the decline in working memory. Moreover, noteworthy research indicates that attention deficit can impact negative symptoms, subsequently exacerbating the decline in working memory, either directly or indirectly. This suggests that effectively addressing negative symptoms can lead to more comprehensive treatment of cognitive deficits. For example, aerobic exercise has shown promise in treating both cognitive deficits and negative symptoms in schizophrenia, making it a potentially valuable therapeutic intervention [31, 32].

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of The Anhui Mental Health Centre. Informed consent was obtained from all the subjects. The trial registration number was HSY-IRB-PJ-JZB-001.

Consent for publication

Not applicable.

Availability of data and materials

The data that support the findings of this study are available from Hefei Fourth People’ Hospital but restrictions apply to the availability of those data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Hefei Fourth People’ Hospital. To obtain the data in this study, the researchers may be contacted at [email protected].

Competing interest

All authors declare no conflict of interest.

Funding

Funding this work was supported by the Scientific and technological research project of Anhui Provincial Science and Technology Department(201904a07020009).

Authors' contributions

Nan Du performed the statistical processing of the data, interpretation and analysis of the results, and wrote and revised the paper; Nan Du, Long Chen, Lihui Yao, Xiaojing Meng, Li Shi, and Jingwei Li collected and organized the data; Nan Du and XuLai Zhang performed the feasibility analysis and were responsible for the quality control and review; and XuLai Zhang was responsible for the conceptualization and design of the article, as well as for the overall management and supervision.

Acknowledgements

We would like to thank the support of Hefei Fourth People’s Hospital.

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No competing interests reported.

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Decline in working memory in stable schizophrenia may be related to attentional impairment: mediating effects of negative symptoms

Status:

Version 1

Abstract

Figures

1. Introduction

2. Methods

2.1 Participants

2.2 Inclusion and exclusion criteria

2.3 Measures

2.3.1 General demographic information

2.3.2 Cognitive function assessment

2.3.3 Positive and Negative Symptom Scale

2.4. Statistical analysis

3 Results

4 Discussion

5 Limitations and prospects

6 Conclusion

Declarations

References

Additional Declarations

Status:

Version 1