Neurological soft signs and structural network changes: a longitudinal analysis in first-episode schizophrenia.

BACKGROUND: Neurological soft signs (NSS) are often reported in patients with schizophrenia and may vary with psychopathological symptoms during the course of disease. Many cross-sectional neuroimaging studies have shown that NSS are associated with disturbed network connectivity in schizophrenia. However, it remains unclear how these associations change over time during the course of disorder. METHODS: In present study, 20 patients with first-episode schizophrenia and 20 controls underwent baseline structural magnetic resonance imaging (MRI) scan and at one-year follow-up. Structural network characteristics of patients and controls were analyzed using graph theoretical approach based on MRI data. NSS were assessed using the Heidelberg scale. RESULTS: At baseline, patients demonstrated significant changes of the local network properties mainly involving regions of the cortical-subcortical-cerebellar circuits compared to healthy controls. For further analysis, the whole patient group was dichotomized into a NSS-persisting and NSS-decreasing subgroup. After one-year follow-up, the NSS-persisting subgroup showed decreased betweenness in right inferior opercular frontal cortex, left superior medial frontal cortex, left superior temporal cortex, right putamen and cerebellum vermis and increased betweenness in right lingual cortex. However, the NSS-decreasing subgroup exhibited only localized changes in right middle temporal cortex, right insula and right fusiform with decreased betweenness, and in left lingual cortex with increased betweenness. CONCLUSIONS: These findings provide evidence for brain network reorganization subsequent to clinical disease manifestation in patients with first-episode schizophrenia, and support the hypothesis that persisting NSS refer to progressive brain network abnormalities in patients with schizophrenia. Therefore, NSS could help to establish a better prognosis in first-episode schizophrenia patients.

Neurological soft signs and brain morphology in people living with HIV.

Neurological soft signs (NSS) are a common feature of severe psychiatric disorders such as schizophrenia but are also prevalent in organic brain diseases like HIV-associated neurocognitive disorder (HAND) or Alzheimer's disease. While distinct associations between NSS, neurocognition, and cerebral regions were demonstrated in schizophrenia, these associations still have to be elucidated in HIV. Therefore, we investigated 36 persons with HIV of whom 16 were neurocognitively healthy and 20 were diagnosed with HAND. NSS were assessed using the Heidelberg scale. NSS scores were correlated with gray matter (GM) using whole brain voxel-based morphometry. Results showed significantly elevated NSS in the HAND group when compared to the neurocognitively healthy with respect to NSS total score and the subscores "orientation" and "complex motor tasks". While the two groups showed only minor, non-significant GM differences, higher NSS scores (subscales "motor coordination", "orientation") were significantly correlated with GM reduction in the right insula and cerebellum (FWE-corrected). Our results corroborate elevated NSS in HIV+ patients with HAND in contrast to cognitively unimpaired patients. In addition, cerebral correlates of NSS with GM reductions in insula and cerebellum were revealed. Taken together, NSS in this patient group could be considered a marker of cerebral damage and neurocognitive deficits.

Neurological soft signs and cognition in the late course of chronic schizophrenia: a longitudinal study.

Neurological soft signs (NSS) are minor ('soft') neurological abnormalities in sensory and motor performances, which are frequently reported in patients with schizophrenia at any stage of their illness. It has been demonstrated that NSS vary in the clinical course of the disorder: longitudinally NSS decrease in parallel with remission of psychopathological symptoms, an effect which mainly applies to patients with a remitting course. These findings are primarily based on patients with a first episode of the disorder, while the course of NSS in patients with chronic schizophrenia and persisting symptoms is rather unknown. Therefore, we investigated NSS twice in 21 patients with chronic schizophrenia (initial mean duration of illness: 23 ± 11 years) with a mean follow-up interval of 7 years. NSS were evaluated by the Heidelberg Scale, established instruments were used to rate neuropsychological performance and psychopathological symptoms. NSS showed significant increases on the subscales "motor coordination" and "integrative functions", while positive and negative symptoms, including apathy, showed only minor, non-significant changes. Verbal memory, verbal fluency, and cognitive flexibility along with severity of global cognitive deficits demonstrated a significant deterioration. Regression analyses identified executive dysfunction (cognitive flexibility and verbal fluency) at baseline as significant predictors of NSS increase at follow-up. Our findings indicate that NSS deteriorate in the long-term course of chronic schizophrenia. This effect may be accounted for by a decrease of executive functions and logical memory, which can be attributed to premature brain aging.

Association of cortical thickness and neurological soft signs in patients with chronic schizophrenia and healthy controls.

BACKGROUND: Neurological soft signs (NSS), i.e. subtle neurological abnormalities, have been frequently found in schizophrenia. Neuroimaging studies in schizophrenia have shown abnormal cortical thickness changes across the cortical mantle. However, few studies have examined relationships between NSS and cortical thickness abnormalities in schizophrenia. METHOD: A sample of 18 patients with chronic schizophrenia and 20 age-matched healthy controls were included. Cortical thickness was assessed on high-resolution 3-tesla magnetic resonance imaging by using FreeSurfer software and NSS were rated on the Heidelberg Scale. RESULTS: Significant negative correlations between NSS and cortical thickness were found in the prefrontal, inferior temporal, superior parietal, postcentral, and supramarginal cortices in the schizophrenia patients. In the controls, however, this negative correlation was found in the anterior cingulate, pericalcarine and superior/middle temporal regions. CONCLUSION: Our results not only confirmed the association between NSS and cortical thickness in chronic schizophrenia but also indicated that patients and controls have different anatomical substrates of NSS.

Autobiographical memory impairment in chronic schizophrenia: Significance and clinical correlates.

Previous studies of autobiographical memory (AM) in schizophrenia yielded a reduction of specificity, richness of details and conscious recollection, which indicate both, quantitative and qualitative AM changes. However, their associations with psychopathological symptoms and neuropsychological deficits were not resolved. Therefore, we sought to investigate AM with respect to psychopathology and neuropsychology in patients with chronic schizophrenia to rule out the influence of different courses of the disease. AM of four lifetime periods was examined in 75 patients and 50 healthy controls by using a semi-structured interview. The recalled episodes were rated for memory specificity. Subsequently, one single event of each period of life was rated for details and experiential aspects of reliving (originality, vividness/visual imagery, emotional re-experiencing and emotional valence). When contrasted with healthy controls, patients recalled a significantly reduced number of episodes and personal semantic facts; moreover, memory specificity of AM was significantly lower in patients than controls. While the richness of details calculated for single events showed only minor, non-significant group differences, vividness and emotional re-experiencing were significantly less pronounced in the patient group. Along with this, AM performance correlated significantly with negative symptoms including apathy as well as verbal memory and executive functions. Our results underline the significance of overgenerality as a key feature of AM in schizophrenia as well as a dissociation between intact number of details of single events and reduced vividness and emotional re-experiencing. The extent of negative symptoms including apathy and impairments of verbal memory/executive functions may explain AM deficits in chronic schizophrenia.

Autobiographical memory in chronic schizophrenia: A follow-up study.

Chronic schizophrenia is a very disabling disease and patient's social integration remains difficult. One important aspect is autobiographical memory (AM) as it is impaired in schizophrenia and highly correlated to patient's outcome, since its closely linked to self and identity. Reduced specificity and lack of details are characteristics of patients' AM, but its longitudinal course in schizophrenia remains unclear. We examined 21 patients who underwent our protocol twice with an interval of 7 years. AM was assessed using a semi-structured interview, covering four periods of life and addressing semantic knowledge and autobiographical episodes as well as their details. The results can be divided into three parts, separating semantic memories, specific autobiographical memories and details describing the latter. While a significant deterioration of semantic AM over time could be revealed, the specificity of the free recalled autobiographical episodes remained rather stable - albeit on a low level. In contrast, unique events were remembered with significantly less details at follow-up than at the first examination. While floor-effects given a relatively small number of unique events have to be considered, semantic AM and episodic details seem to be a valuable target for AM remediation given their further deterioration over time.

Structural brain networks in schizophrenia based on nonnegative matrix factorization.

Schizophrenia is a severe mental disease with significant morphometric reductions in gray matter volume and cortical thickness in a variety of brain regions. However, most studies only focused on the voxel level alterations in specific cerebral regions and ignored the spatial relationship between voxels. In the present study, we used a novel, data-driven technique-nonnegative matrix factorization (NMF) to group voxels with similar information into a network, and studied the structural covariance at the network level in schizophrenia. Our sample included 36 patients with schizophrenia and 21 healthy controls. Compared with healthy controls, patients with schizophrenia showed significant gray matter volume reductions in six structural covariance networks (dorsal striatum, thalamus, hippocampus-parahippocampus, supplementary motor area-fusiform, middle/inferior temporal network, frontal-parietal-occipital network). Our findings confirmed the assumption of a disturbance in the cortical-subcortical circuit in schizophrenia and suggested that NMF is a useful multivariate method to identify brain networks, which provides a new perspective to study the neural mechanism in schizophrenia.

Neural Correlates of Autobiographical Memory: Evidence From a Positron Emission Tomography Study in Patients With Mild Cognitive Impairment and Alzheimer's Disease.

Background: Autobiographical memory (AM) changes are the hallmark of Alzheimer's disease (AD) and mild cognitive impairment (MCI). In recent neuroimaging studies, AM changes have been associated with numerous cerebral sites, such as the frontal cortices, the mesial temporal lobe, or the posterior cingulum. Regional glucose uptake in these sites was investigated for underlying subdimensions using factor analysis. Subsequently, the factors were examined with respect to AM performance in a subgroup of patients. Methods: Data from 109 memory clinic referrals, who presented with MCI (n = 60), mild AD (n = 49), or were cognitively intact, were analyzed. The glucose metabolic rates determined by positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) in 34 cerebral sites important for AM were investigated for underlying subdimensions by calculating factor analysis with varimax rotation. Subsequently, the respective factor scores were correlated with the episodic and semantic AM performance of 22 patients, which was measured with a semi-structured interview assessing episodic memories (characterized by event-related emotional, sensory, contextual, and spatial-temporal details) and personal semantic knowledge from three periods of life (primary school, early adulthood, and recent years). Results: Factor analysis identified seven factors explaining 69% of the variance. While patients with MCI and AD showed lower values than controls on the factors frontal cortex, mesial temporal substructures, and occipital cortex, patients with MCI presented with increased values on the factors posterior cingulum and left temporo-prefrontal areas. The factors anterior cingulum and right temporal cortex showed only minor, non-significant group differences. Solely, the factor mesial temporal substructures was significantly correlated with both episodic memories (r = 0.424, p < 0.05) and personal semantic knowledge (r = 0.547, p < 0.01) in patients with MCI/AD. Conclusions: The factor structure identified corresponds by large to the morphological and functional interrelations of the respective sites. While reduced glucose uptake on the factors frontal cortex, mesial temporal substructures, and occipital cortex in the patient group may correspond to neurodegenerative changes, increased values on the factors posterior cingulum and left temporo-prefrontal areas in MCI may result from compensatory efforts. Interestingly, changes of the mesial temporal substructures were correlated with both semantic and episodic AM. Our findings suggest that AM deficits do not only reflect neurodegenerative changes but also refer to compensatory mechanisms as they involve both quantitative losses of specific memories and qualitative changes with a semantization of memories.

Neurological soft signs (NSS) and brain morphology in patients with chronic schizophrenia and healthy controls.

Subtle abnormalities in sensory integration, motor coordination and sequencing of complex motor acts or neurological soft signs (NSS) are characteristic phenomena in patients with schizophrenia at any stage of the illness. Previous MRI studies in schizophrenia found NSS to be associated with cortical, thalamic and cerebellar changes. Since these studies mainly focused on first-episode or recent onset schizophrenia, the cerebral correlates of NSS in chronic schizophrenia remained rather unclear. 49 middle-aged patients with chronic schizophrenia with a mean duration of illness of 20.3 ± 14.0 years and 29 healthy subjects matched for age and sex were included. NSS were examined on the Heidelberg Scale and correlated to grey matter (GM) by using whole brain high resolution magnetic resonance imaging (3 Tesla) with SPM12/CAT12 analyses. As expected, NSS in patients were significantly (p≤0.001) elevated in contrast to healthy controls, a finding, which not only applied to NSS total score, but also to the respective subscales "motor coordination", "sensory integration", "complex motor tasks", "right/left and spatial orientation" and "hard signs". Within the patient group NSS total scores were significantly correlated to reduced GM in right lingual gyrus, left parahippocampal gyrus, left superior temporal gyrus, left thalamus (medial dorsal nucleus) and left posterior lobe of the cerebellum (declive). Respective negative associations could also be revealed for the subscales "motor coordination", "complex motor tasks" and "right/left and spatial orientation". These findings remained significant after FWE-correction for multiple comparisons and were confirmed when years of education, chlorpromazine-equivalents or variables indicating the severity of psychopathology were introduced as additional covariates. According to our results lingual, parahippocampal, superior temporal, inferior and middle frontal gyri, thalamus and cerebellum have to be considered as important sites of NSS in chronic schizophrenia. That these findings only applied for patients but not healthy controls may indicate a different pathogenesis of NSS.

Neurological soft signs (NSS) and gray matter volume (GMV) in first-episode psychosis: An analysis of NSS motor subscores.

We aimed to study the correlations between gray matter volume and the motor subscores of NSS in first-episode psychosis patients with both, whole brain and region of interest analyses. The structural MRIs of 81 first-episode psychosis patients were analyzed by using voxel-based morphometry (VBM) for SPM. NSS were assessed using the Heidelberg scale. Significant decreases of gray matter volume were correlated to high NSS total scores and, more specifically, frontal, subcortical and cerebellar areas were significantly correlated with increased scores of the subscores Motor Coordination (MoCo) and Complex Motor Tasks (CMT). When applying a stricter statistical correction, only the frontal gyrus and caudate nucleus survived for MoCo; whereas the precentral and superior frontal gyri survived for CMT. When doing regional analyses, using as masks the structures deemed as significant by the whole brain analyses and applying the FWE-correction, the superior frontal gyrus, thalamus and caudate nucleus correlated negatively with MoCo; and the precentral and superior frontal gyri, thalamus and caudate nucleus showed inverse correlations with CMT. These results suggest that cerebral cortex, subcortical structures (thalamus and striatum) and cerebellum are inversely correlated to both motor NSS subscores, the first time a study describes this relationship for all the relevant structures simultaneously. For its part, ROI proves to be effective demonstrating that subcortical structures (thalamus and caudate) are the most affected by motor NSS.

Neurological Soft Signs and Brain Network Abnormalities in Schizophrenia.

Neurological soft signs (NSS) are often found in patients with schizophrenia. A wealth of neuroimaging studies have reported that NSS are related to disturbed cortical-subcortical-cerebellar circuitry in schizophrenia. However, the association between NSS and brain network abnormalities in patients with schizophrenia remains unclear. In this study, the graph theoretical approach was used to analyze brain network characteristics based on structural magnetic resonance imaging (MRI) data. NSS were assessed using the Heidelberg scale. We found that there was no significant difference in global network properties between individuals with high and low levels of NSS. Regional network analysis showed that NSS were associated with betweenness centrality involving the inferior orbital frontal cortex, the middle temporal cortex, the hippocampus, the supramarginal cortex, the amygdala, and the cerebellum. Global network analysis also demonstrated that NSS were associated with the distribution of network hubs involving the superior medial frontal cortex, the superior and middle temporal cortices, the postcentral cortex, the amygdala, and the cerebellum. Our findings suggest that NSS are associated with alterations in topological attributes of brain networks corresponding to the cortical-subcortical-cerebellum circuit in patients with schizophrenia, which may provide a new perspective for elucidating the neural basis of NSS in schizophrenia.

Associations between brain structural networks and neurological soft signs in healthy adults.

Neurological soft signs (NSS), as minor neurological deficits, have been identified in several psychiatric disorders, especially in schizophrenia. However, it's unclear how the neuropathological processes of the disease affect NSS related brain morphological changes and whether it is confounded by the use of medication. As NSS also exist in healthy people, the potential confounding effects of psychopathology or medication will be excluded if NSS are investigated in healthy people. Therefore, we applied a novel multivariate approach, source-based morphometry (SBM), to study structural networks in relation to NSS in healthy adults based on structural magnetic resonance imaging (MRI) data. The Heidelberg Scale was applied to evaluate NSS. Using SBM, we constructed structural networks and investigated their associations with NSS in healthy adults. Six grey matter (GM) structural networks were identified. Sensory integration subscores were associated with the cerebellar component and the cortico-basal ganglia-thalamic component. Motor coordination subscores and total NSS scores were associated with the sensorimotor component. The present findings indicated that structural network abnormalities in cerebellar, subcortical and cortical sensorimotor areas contribute to NSS performance in healthy adults.

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 ±â€¯15a) and 60 healthy controls (47.52 ±â€¯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.

Neurological soft signs and grey matter abnormalities in individuals with ultra-high risk for psychosis.

Neurological soft signs (NSSs), conventionally defined as subtle neurological abnormalities, are frequently found in individuals with schizophrenia. Many neuroimaging studies have also reported that NSSs are associated with grey matter changes in patients with schizophrenia at different stages of the illness. However, these findings may be confounded by the effect of antipsychotic medications, chronicity, and duration of untreated psychosis. Examining NSSs in individuals with ultra-high risk (UHR) for psychosis may help to identify the neuroanatomical substrates of NSSs related to the illness itself and to avoid these potential confounding effects. A sample of 21 individuals with UHR were included in the present study. NSSs were rated using the abridged version of the Cambridge Neurological Inventory. Grey matter volume was assessed using optimized voxel-based morphometry on images acquired by a high-resolution 3-T magnetic resonance imaging scanner. We found that higher NSS scores in individuals with UHR were associated with decreased grey matter volume at the superior and medial frontal cortex, the rectal cortex, the pre- and post-central cortex, the insula, the caudate, and the cerebellum. Our results suggest that these brain structural characteristics may represent the neuroanatomical substrate of NSSs in individuals with UHR. These findings contribute to the understanding of the intrinsic features of psychosis associated with NSSs and may provide insights into pre-schizophrenia pathophysiology.

Neurological Soft Signs and Psychopathology in Chronic Schizophrenia: A Cross-Sectional Study in Three Age Groups.

As established in a wealth of studies subtle motor and sensory neurological abnormalities or neurological soft signs (NSS) are frequently found in patients with schizophrenia at any stage of their illness. However, the potential impact of chronicity and age on NSS was scarcely investigated. Therefore, we assessed NSS in 90 patients with subchronic (n = 22) or chronic (n = 68) schizophrenia and in 60 healthy controls who were assigned to three age groups (18-29, 30-49, and +50 years). NSS were measured on the Heidelberg Scale, psychopathological symptoms including apathy were rated on established instruments. As demonstrated by analysis of variance, NSS scores in patients were significantly (p < 0.05) increased relative to healthy controls. Significant age effects arose in all NSS subscores, with older subjects scoring well above the younger ones. These age effects were more pronounced in patients than controls, indicating that NSS in chronic schizophrenia exceed age-associated changes. Moreover, the NSS scores in patients were significantly associated with duration of illness, thought disturbance, positive symptoms, and apathy. These results were confirmed after age/duration of illness and years of education were partialed out and via regression analyses. Our findings conform to the hypothesis that NSS are associated with chronicity of the disorder as indicated by the correlations of NSS with both, duration of illness and apathy. The correlations between NSS and positive symptoms/thought disturbance correspond to the fluctuation of positive symptoms during the course of the disorder. The significantly more pronounced age effects on NSS in patients may either point to ongoing cerebral changes or to a greater susceptibility of patients toward physiological age effects, which may be mediated among other factors by a lower cognitive reserve.

Comparison of grey matter volume and thickness for analysing cortical changes in chronic schizophrenia: a matter of surface area, grey/white matter intensity contrast, and curvature.

Grey matter volume and cortical thickness are the two most widely used measures for detecting grey matter morphometric changes in various diseases such as schizophrenia. However, these two measures only share partial overlapping regions in identifying morphometric changes. Few studies have investigated the contributions of the potential factors to the differences of grey matter volume and cortical thickness. To investigate this question, 3T magnetic resonance images from 22 patients with schizophrenia and 20 well-matched healthy controls were chosen for analyses. Grey matter volume and cortical thickness were measured by VBM and Freesurfer. Grey matter volume results were then rendered onto the surface template of Freesurfer to compare the differences from cortical thickness in anatomical locations. Discrepancy regions of the grey matter volume and thickness where grey matter volume significantly decreased but without corresponding evidence of cortical thinning involved the rostral middle frontal, precentral, lateral occipital and superior frontal gyri. Subsequent region-of-interest analysis demonstrated that changes in surface area, grey/white matter intensity contrast and curvature accounted for the discrepancies. Our results suggest that the differences between grey matter volume and thickness could be jointly driven by surface area, grey/white matter intensity contrast and curvature.

Autobiographical memory: a clinical perspective.

Autobiographical memory (ABM) comprises memories of one's own past that are characterized by a sense of subjective time and autonoetic awareness. Although ABM deficits are among the primary symptoms of patients with major psychiatric conditions such as mild cognitive impairment (MCI) and Alzheimer Disease (AD) or chronic schizophrenia large clinical studies are scarce. We therefore summarize and discuss the results of our clinical studies on ABM deficits in the respective conditions. In these studies ABM was assessed by using the same instrument - i.e., the Erweitertes Autobiographisches Gedächtnis Inventar (E-AGI) - thus allowing a direct comparison between diagnostic groups. Episodic ABM, especially the richness of details was impaired already in MCI and in beginning AD. Semantic memories were spared until moderate stages, indicating a dissociation between both memory systems. A recency effect was detectable in cognitively unimpaired subjects and vanished in patients with AD. A similar pattern of deficits was found in patients with chronic schizophrenia but not in patients with major depression. These ABM deficits were not accounted for by gender, or education level and did not apply for the physiological ageing process in otherwise healthy elderly. In conclusion, ABM deficits are frequently found in AD and chronic schizophrenia and primarily involve episodic rather than semantic memories. This dissociation corresponds to the multiple trace theory which hypothesized that these memory functions refer to distinct neuronal systems. The semi-structured interview E-AGI used to discern ABM changes provided a sufficient reliability measures, moreover potential effects of a number of important confounders could be falsified so far. These findings underline the relevance of ABM-assessments in clinical practice.