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Neurological soft signs (NSS) and cognitive impairment in chronic schizophrenia

Recent studies indicate that neurological soft signs (NSS) in schizophrenia are associated with generalized cognitive impairments rather than changes in specific neuropsychological domains. However, the majority of studies solely included first-episode patients or patients with a remitting course and did not consider age, course, education or severity of global cognitive deficits as potential confounding variables. Therefore, we examined NSS with respect to cognitive deficits in chronic schizophrenia, i.e. patients who are particularly vulnerable to both, NSS and cognitive impairments. Eighty patients with chronic schizophrenia (43.36 ± 15a) and 60 healthy controls (47.52 ± 14.8a) matched for age, sex and years of education were examined on the Heidelberg NSS scale and a broad neuropsychological battery including short term, working, logical and autobiographic memory (AM), theory of mind (ToM), psychomotor speed and cognitive flexibility. When contrasted with the controls, patients showed significantly higher NSS scores and impairments in all neuropsychological domains but short-term memory. NSS were significantly associated with all neuropsychological domains considered but short-term memory and semantic AM. Except for episodic AM (which was significantly correlated with NSS in patients only) these correlations applied to both groups and were confirmed when age, years of education and severity of global cognitive deficits (Mini Mental State Examination) were controlled for. Results demonstrate that NSS reflect a rather wide range of cognitive impairments in schizophrenia, which also involves episodic AM and ToM. These associations were not accounted for by age, education or severity of global cognitive deficits and facilitate the clinical usage of NSS as a screening instrument.


Introduction
Neurological soft signs (NSS) or subtle motor and sensory deficits are frequently found in a wide range of psychiatric conditions, in particular schizophrenia (for review see: Bombin et al., 2005;Chan et al., 2010;Heuser, 2011;Schröder et al., 1992). NSS vary in the clinical course with severity of the condition as demonstrated by decreasing scores with remission of psychopathological symptoms (for review see: Bachmann et al., 2014;Bachmann and Schröder, 2018). Hence, one may hypothesize that NSS reflect acuity and severity of schizophrenia rather than specific dysfunctions.
In patients with chronic schizophrenia NSS scores were found to be significantly associated with neuropsychological impairments (overview see Table 1), which are one of the core features of the disorder (Bora and Pantelis, 2016;Fioravanti et al., 2012;Herold, 2011;Herold et al., 2017). In our table we solely cited studies focusing on patients with chronic schizophrenia with > 40 years of age and a duration of illness of > 20 years. These rigorous selection criteria were applied to especially focus on older patients with a chronic course of the disorder. According to the given literature (King et al., 1991;Owens and Johnstone, 1980) NSS seem to be associated with general cognitive functioning in this patient group. This was also the case when neuropsychological functions were assessed in detail (Chan and Chen, 2004b;Liddle et al., 1993): NSS showed correlations with verbal and visual memory, short term and working memory as well as executive functions and general intelligence. However, some studies focused only on selected cognitive domains such as executive functions or attention (Chan and Chen, 2004a;Sewell et al., 2010;Smith et al., 1999).
In a seminal paper Quitkin et al. (1976) examined 350 patients from 6 diagnostic groups. However, this study was not cited in Table 1, since it did not include patients older than 50 years. Results show negative correlations between the total number of soft signs and IQ scores.

Table 1
Overview of studies showing NSS-cognition correlates in old-age patients with chronic schizophrenia.
Author Cambridge Neurological Inventory (CNI, Chen et al., 1995) "When the group was further divided into two subgroups by taking the lower and upper quartiles of their blink rate, patients at the upper quartiles exhibited significantly more disinhibition signs than those at the lower quartiles. There was also a trend for those patients at the upper quartiles to commit more error in a sustained attention task." "Intense blinkers demonstrated significantly more disinhibition soft signs and commission error of the SART than the rare blinkers." Chan and Chen (2004b)  (continued on next page) C.J. Herold, et al. Schizophrenia Research: Cognition 16 (2019) 17-24 Barnes et al. (1995) solely considered primitive reflexes in a sample of 48 patients with schizophrenia (mean age: 51 ± 10 years) which were not found to be significantly correlated with current IQ or estimated IQ decline from premorbid to current level. Another study (Poole et al., 1999) found motor dyscoordination (i.e. inaccurate, dysfluent motor sequencing) not to be significantly related to semantic processing, intelligence, or symptoms in 26 patients with schizophrenia (mean age: 40 ± 10 years). In a large genetic study which involved 471 patients aged 18 to 60 years, Chen et al. (2001) reported a trend association between the genotype 102T/102C and better verbal fluency performance and less motor coordination NSS. Especially the older studies could not rely on standardized instruments for NSS assessments (King et al., 1991;Liddle et al., 1993;Owens and Johnstone, 1980;Quitkin et al., 1976); others used the NES scale, which, besides NSS in a strict sense, also includes memory tasks (Buchanan and Heinrichs, 1989). According to the results of a metaanalysis (Chan et al., 2010) cognitive variables and NSS share about 10% of their variance, thus indicating that these parameters "reflect associated, but distinct, aspects of neurobehavioral function in schizophrenia". The respective studies included patients in all stages of the disease from first manifestation to chronic schizophrenia. While these studies confirmed the importance of NSS and their association with neurocognitive impairments in schizophrenia, confounding effects due to the heterogeneity of the patients' samples under investigation or the instruments for the assessment of NSS and cognition cannot be excluded.
We therefore sought to analyze NSS and cognitive impairment in a large sample of patients with chronic schizophrenia and in healthy controls. We solely included patients with chronic schizophrenia to reduce the potential impact of different clinical courses of the disorder (i.e. chronic vs. remitting) and thereby circumstances of life. Since NSS may be ameliorated by cognitive reserve (Urbanowitsch et al., 2015) years of school education, i.e. its established proxy, was considered as a covariate. Similarly, age (Herold et al., 2017) and severity of global cognitive deficits (King et al., 1991;Owens and Johnstone, 1980) had to be considered. To address the wide range of associations hypothesized between NSS levels and cognitive impairment we used a broad test battery, which also included domains rather scarcely investigated like theory of mind (ToM) and autobiographic memory (AM).
We expected NSS scores to be associated with a broad range of neuropsychological impairments from memory, psychomotor speed and cognitive flexibility to ToM even if age, years of education, and severity of global cognitive deficits were considered as covariates.

Subjects
80 patients with subchronic 1 (n = 14) or chronic 2 (n = 66) schizophrenia (N = 76) or schizoaffective disorder (N = 4) according to DSM-III/DSM-IV criteria (American Psychiatric Association, 1987, 2000 from three psychiatric long-term units (n = 36) and a mental state hospital (n = 44) were included. 60 healthy participants matched for age, years of education and sex were selected as control group (Table 2). Age at disease onset was determined on basis of the patients' history and case notes. None of the participants had a lifetime history of neurological or severe systemic illness, head injury or substance dependence. Along with this, patients with late onset schizophrenia as defined by an age of onset > 40 years were excluded (Schmid et al., began to show signs of the illness (including prodromal, active, and residual phases) more or less continuously, is less than two years but at least six months." (DSM-III, p.192) 2 "Same as above, but greater than two years" (DSM-III, p.192) 2011), just as patients with pronounced extrapyramidal symptoms were. The investigations were approved by the ethics committee of the Medical Faculty of Heidelberg University and written informed consent was obtained from all participants after the procedures of the study had been fully explained in accordance with the Declaration of Helsinki.

Clinical assessments
Psychopathological symptoms were rated on the Brief Psychiatric Rating Scale (BPRS, Overall and Gorham, 1962), the Scales for the Assessment of Positive and Negative Symptoms (SAPS and SANS, Andreasen, 1984aAndreasen, , 1984b and -to especially address apathetic symptoms -the Apathy Evaluation Scale (AES, Lueken et al., 2006).

NSS and neuropsychological testing
NSS were rated on the Heidelberg scale (Schröder et al., 1992;Schröder et al., 1993), which comprises 16 items on five factors (motor coordination, sensory integration, complex motor tasks, right/left and spatial orientation and hard signs). Ratings are protocolled on a 0-3 point scale (no/slight/moderate/marked abnormality). The psychometric properties of the Heidelberg scale are well established (Bachmann et al., 2005;Schröder et al., 1992).
The neuropsychological test battery included the Mini Mental State Examination (MMSE) as cognitive screening instrument to assess global cognitive deficits (Folstein et al., 1975), verbal and AM, short-term and working memory, psychomotor speed, cognitive flexibility and ToM by applying the subtests Logical Memory I (immediate recall) and II (delayed recall) from the Wechsler Memory Scale-Revised (WMS-R, Härting et al., 2000), a semi-structured AM inventory (Fast et al., 2006;Fast et al., 2007), the digit span forward and backward tasks from the WMS-R (Härting et al., 2000), the Trail Making Test version A and B (TMT, Reitan, 1992), the Reading Mind in the Eyes test (RMIE, Baron-Cohen et al., 2001;Bölte, 2005) and a ToM-test consisting of a picture sequencing task and a questionnaire (Brüne, 2005). In consideration of the age of the younger subjects, the assessment of AM was restricted to memories from the first three lifetime periods. A detailed description of the AM interview is given in former publications of our group (Herold et al., 2013.

Statistical analyses
All statistical analyses were performed using SPSS version 23 (IBM SPSS Statistics). Group differences concerning the variables "age" and "years of education" were investigated by analysis of variance (univariate ANOVA), or chi 2 test (variable "sex"). Paired samples t-test was used to compare SAPS and SANS global scores. When group differences of NSS and neuropsychological test results were analyzed, multivariate analyses of covariance (MANCOVA) with age as covariate were calculated.
Pearson correlation coefficients were performed to evaluate the relationships between NSS scores and CPZ equivalents, age, years of education or MMSE scores as well as between the variables of cognitive performance and years of education or age to identify potential confounding variables.
To assess the associations between NSS scores and the neuropsychological domains considered, Pearson correlation coefficients were calculated while controlling for age. Subsequently, these analyses were repeated with years of education, age/years of education and age/ years of education/MMSE as covariates. Subsequently, the Bonferroni correction was applied.

Clinical characteristics
The patients' clinical characteristics are given in Table 3. Negative symptoms were predominating in our patient group as revealed by a comparison of SAPS (5.77 ± 4.59) and SANS (7.92 ± 5.43) global scores (T = −2.77, df = 78, p = 0.007). All but 2 patients were under neuroleptic treatment according to their psychiatrist's choice.

NSS and cognition -group comparisons
As to be expected, patients showed significantly higher NSS scores than healthy controls (F [6130] = 14,570; p < 0.001; η 2 = 0.402); this difference was significant for the total score as well as the five subscales (Table 4). No significant correlations between NSS scores and CPZ equivalents arose (p > 0.15).
When compared to healthy controls, patients demonstrated significant impairments in all neuropsychological domains but short-term memory (Table 5).  Data are means (standard deviations), unless otherwise indicated. AES apathy evaluation scale; AT atypical antipsychotics; AT + T atypical and typical antipsychotics; BPRS brief psychiatric rating scale; CPZ chlorpromazine; SANS scale for the assessment of negative symptoms; SAPS scale for the assessment of positive symptoms; T typical antipsychotics.

NSS and cognition -correlations
As summarized in Table 6, NSS total scores were significantly correlated with performance on logical memory, digit span backward and TMT A and B (p ≤ 0.003). In the control group a similar pattern of significant correlations between NSS scores and neuropsychological parameters arose with NSS total scores being significantly correlated to logical memory, digit span backward, TMT A and B (p < 0.05).
With respect to AM, solely the quality of autobiographic episodes recalled (specificity and details scores), but not semantic memory, was significantly correlated with NSS total scores and the subscales "motor coordination", "complex motor tasks" and "right/left/spatial orientation" in the patient group (p < 0.02). In the controls no significant associations between NSS and AM arose.
ToM total scores and the subscores "questions" and "order" were significantly associated with NSS total scores and all subscales (p < 0.03) except for "hard signs" in the patients. In the control group ToM total scores and the respective subscores correlated significantly to NSS total scores and the subscales "complex motor tasks" and "right/ left/spatial orientation" (p ≤ 0.05). The RMIE test scores were significantly correlated with NSS total scores and the subscales "motor coordination", "complex motor tasks" and "right/left/spatial orientation" (p ≤ 0.002) in the patient but not in the control group.
After Bonferroni correction (α: 0.05/78 = 0.00064) the correlations between NSS and logical memory I and II, TMT A and B, ToM (total and questions, RMIE) remained significant in the patient group, while in the control group only the correlations between NSS and TMT A and B and ToM (total and questions) were confirmed.
These results were replicated when years of education and both, age and years of education were partialled out, since age and years of education were significantly correlated with variables of NSS and cognition (NSS total score and education: r = −0.208, p = 0.014; NSS total score and age: r = 0.316, p ≤ 0.001; cognitive performance and education −0.44 < r < 0.48, p ≤ 0.005, cognitive performance and age −0.37 < r < 0.42, 0.001 ≤ p < 0.16). In a next step MMSE scores were additionally entered as covariate in the calculation of correlations between NSS scores and cognition due to significant negative associations between MMSE and NSS scores (−0.38 > r > −0.60, p < 0.001). The correlations between NSS scores and cognitive impairments were confirmed when age, years of education and MMSE were partialled out as covariates.

Discussion
The present study yielded the following findings: (i) NSS were significantly elevated in elderly patients with chronic schizophrenia who also showed significant neurocognitive impairments in almost every domain considered when contrasted to healthy controls, and (ii) significant associations between NSS scores and a wide range of neuropsychological parameters emerged in both, the patients and the control group.
The present study of patients with chronic schizophrenia, demonstrated significantly increased NSS scores in the patient group when compared to a control group carefully matched for age, education and sex. Despite methodological differences, increased NSS scores in "old" patients with chronic schizophrenia were also reported in previous studies (Table 1). This result confirmed and extended previous studies in young or middle-aged patients with schizophrenia, which yielded significant higher NSS scores than in age-adjusted controls, a finding, which was particularly pronounced in patients with a chronic course of the disorder (Schröder et al., 1992;Schröder et al., 1996) and could already be demonstrated one year after manifestation of the disease (Bachmann et al., 2005). Since the differences between patients and controls could be demonstrated in all age groups (Bombin et al., 2005;Chan et al., 2010), these findings also correspond to the hypothesis that NSS are not subject to age-related changes per se, as demonstrated in a population-based study (Urbanowitsch et al., 2015). Similarly, the neuropsychological impairments found in the patient group correspond to the results of a wealth of studies (for review see: Herold et al., 2017) as neuropsychological deficits are considered to be among the core features of schizophrenia.
In the patient group, increased NSS scores were significantly  Data are means (standard deviations).
C.J. Herold, et al. Schizophrenia Research: Cognition 16 (2019) 17-24 correlated with various cognitive impairments ranging from different memory functions (logical and working memory), psychomotor speed, cognitive flexibility to AM and ToM. Except for AM performance, these correlations also applied to the control group and were confirmed after Bonferroni correction by large. These correlations do not appear to be accounted for by age, education or severity of global cognitive deficits since they were confirmed when the respective variables were partialled out. That NSS in chronic schizophrenia are associated with a wide range of neuropsychological impairments rather than specific changes in discrete domains is supported by a number of studies (for review see Table 1). Along with this, Chan et al. (2015) suggested that "neurological signs capture more or less the same construct captured by conventional neurocognitive tests in patients with schizophrenia". These significant associations of NSS scores with cognition performance facilitate the possibility to use NSS as a screening instrument for the assessment of neurocognitive impairments in patients with chronic schizophrenia. This may be of particular importance, as cognitive deficits have a high predictive value for everyday functioning in schizophrenia (Fett et al., 2011;Green et al., 2004;Shamsi et al., 2011), while human resources for neuropsychological examinations and the motivation and/ or capacity of patients for such longer cognitive test procedures are often limited.
In addition, a noticeable number of reports focused exclusively on specific neuropsychological domains. In accordance with our results, significant relationships between NSS scores and verbal logical memory impairments (WMS, Arango et al., 1999;Chan and Chen, 2004b;Chan et al., 2009;Liddle et al., 1993), between NSS and impairments of psychomotor speed/cognitive flexibility (TMT-A/B, Arango et al., 1999;Braun et al., 1995;Cuesta et al., 1996;Flashman et al., 1996;Liddle et al., 1993;but see: Smith et al., 1999) were repeatedly described in chronic schizophrenia. With respect to the significant associations between NSS and cognitive flexibility as assessed on the TMT-B one may argue that the latter shares a psychomotor component with motor NSS. However, such a component is not involved when cognitive flexibility is assessed by using the WCST which was also found to be significantly correlated with NSS (Bersani et al., 2004;Braun et al., 1995;Jahn et al., 2006;Karr et al., 1996;Mohr et al., 1996;Smith et al., 1999). In addition, it has also been reported that NSS in patients with chronic schizophrenia are associated with ToM deficits (Romeo et al., 2014). However, significant associations between NSS and logical memory performance were not confirmed by Flashman et al. (1996), while Liddle et al. (1993) revealed significant correlations between NSS scores and corsi blocks (as a spatial analogue of digit span), but not digit span performance (WMS) (see also : Smith et al., 1999).
Even more so, a similar pattern of associations between NSS and cognitive performance emerged in the healthy control group investigated here; a finding which does not only apply to healthy subjects (e.g. Arabzadeh et al., 2014;Arango et al., 1999;Chan et al., 2011;Chen and Chan, 2003), but also to otherwise healthy first-degree relatives of patients with schizophrenia (Solanki et al., 2012). That NSS correspond to a rather global cognitive deficit is further supported by a recent investigation in patients with HIV associated neurocognitive disorder (HAND), which clearly involved an increase of NSS scores with more pronounced cognitive impairments (Toro et al., 2018). From this perspective, the present findings underline the transdiagnostic character of NSS.
Age has to be considered as a potential confounding variable since both, NSS and cognitive impairments in schizophrenia increase with age, as has been demonstrated in the present study, and two recent publications of our group Herold et al., 2017). However, the associations found between NSS and cognitive performance were confirmed when age was partialled out as a covariate. With respect to neuroleptic side effects, significant associations between CPZ equivalents and NSS scores did not arose. Since the patients with chronic schizophrenia investigated in our study had a mean duration of illness of 20 years, a detailed summary of all medication prescribed to the patients in the past was not feasible. As it was argued already by Heinrichs and Buchanan (1988) the notion that antipsychotic medication exerts a protective effect on NSS is widely supported by the results of longitudinal studies (Bachmann et al., 2014;Bachmann and Schröder, 2018). Moreover, NSS were also demonstrated in patients who did not receive any neuroleptic medication (Dazzan and Murray, 2002;Schröder and Heuser, 2008), as well as in first-degree relatives of patients with schizophrenia (Neelam et al., 2011) or in patients with HAND (Toro et al., 2018). The significant inverse correlations between years of education and NSS scores/cognition deficits refer to a protective effect of this variable -generally used as a proxy for cognitive reserve -as it may ameliorate cognitive deficits by facilitating compensational mechanisms (Urbanowitsch et al., 2015). However, the associations between NSS and cognitive performance were confirmed when school education was partialled out. Even more so, the respective associations proofed to be independent of global cognitive deficits since they were confirmed when MMSE scores were entered as additional covariate.
This character of NSS as correlates of a wide range of neuropsychological impairments corresponds to the results of neuroimaging studies Kong et al., 2015;Thomann et al., 2008; for overview see: Zhao et al., 2014). The latter characterized NSS as a correlate of a wide range of structural cerebral changes, i.e. in the frontal cortices, thalamus and sensorimotor cortex, which are vice versa also involved in important neuropsychological deficits (Antonova et al., 2004;Crespo-Facorro et al., 2007a). Vast proportions of the frontal cortices involve aspects of imagery, planning, execution, monitoring and evaluation of motor acts (de la Vega et al., 2016;Miller and Cohen, 2001;Petrides, 2005). More specifically, thalamic changes may lead to both, increased NSS scores and impaired neurocognition (Andrews et al., 2006;Crespo-Facorro et al., 2007b;Hirjak et al., 2012;Thomann et al., 2008). In addition, changes in the sensorimotor cortex are associated with NSS and via mirror neurons with ToM Kong et al., 2015;McCormick et al., 2012;Pineda, 2008;Schröder et al., 1999;Thomann et al., 2008). Hence, NSS refer to a large variety of structural and functional brain alterations and therefore are associated to global cognitive limitations.
Taken together the present study supported our hypothesis that NSS are associated with a broad range of neurocognitive impairments in patients with chronic schizophrenia as well as healthy controls. With Chan et al. (2015) these findings underline the usability of NSS as a screening instrument for cognitive impairment. From a clinical perspective, these findings facilitate the use of NSS as a marker for severity of the disease and of poor prognosis (Bachmann et al., 2014;Bachmann and Schröder, 2018).

Role of the funding source
Funding source had no role in this publication.