Neurological Soft Signs Are Not "Soft" in Brain Structure and Functional Networks: Evidence From ALE Meta-Analysis

Neuropsychology and Applied Cognitive Neuroscience Laboratory, Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
Schizophrenia Bulletin (Impact Factor: 8.45). 05/2013; 40(3). DOI: 10.1093/schbul/sbt063
Source: PubMed


Neurological soft signs (NSS) are associated with schizophrenia and related psychotic disorders. NSS have been conventionally considered as clinical neurological signs without localized brain regions. However, recent brain imaging studies suggest that NSS are partly localizable and may be associated with deficits in specific brain areas.

We conducted an activation likelihood estimation meta-analysis to quantitatively review structural and functional imaging studies that evaluated the brain correlates of NSS in patients with schizophrenia and other psychotic disorders. Six structural magnetic resonance imaging (sMRI) and 15 functional magnetic resonance imaging (fMRI) studies were included.

The results from meta-analysis of the sMRI studies indicated that NSS were associated with atrophy of the precentral gyrus, the cerebellum, the inferior frontal gyrus, and the thalamus. The results from meta-analysis of the fMRI studies demonstrated that the NSS-related task was significantly associated with altered brain activation in the inferior frontal gyrus, bilateral putamen, the cerebellum, and the superior temporal gyrus.

Our findings from both sMRI and fMRI meta-analyses further support the conceptualization of NSS as a manifestation of the "cerebello-thalamo-prefrontal" brain network model of schizophrenia and related psychotic disorders.

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    • "Indeed, items such as the 'Fist-Edge-Palm' sign, which has strong theoretical association with frontal lobe functions (Luria, 1966), has specific functional connectivity linking the right inferior prefrontal cortex and the right middle prefrontal cortex in healthy volunteers (Rao et al. 2008), and may capture similar higher cortical functions in patients with schizophrenia (Chan et al. 2009). Given the brevity (10 min), sensitivity and specificity (Chan et al. 2009; Zhao et al. 2013) of the CNI, as well as the strong neural underpinnings of NSS (Chan & Gottesman, 2008; Rao et al. 2008; Zhao et al. 2014), it may be worthwhile to include at least some NSS items in the endophenotype assessment regimen for schizophrenia (Chan et al. 2010a). This study has several limitations. "
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    ABSTRACT: Background: Neurological soft signs (NSS) have long been considered potential endophenotypes for schizophrenia. However, few studies have investigated the heritability and familiality of NSS. The present study examined the heritability and familiality of NSS in healthy twins and patient-relative pairs. Method: The abridged version of the Cambridge Neurological Inventory was administered to 267 pairs of monozygotic twins, 124 pairs of dizygotic twins, and 75 pairs of patients with schizophrenia and their non-psychotic first-degree relatives. Results: NSS were found to have moderate but significant heritability in the healthy twin sample. Moreover, patients with schizophrenia correlated closely with their first-degree relatives on NSS. Conclusions: Taken together, the findings provide evidence on the heritability and familiality of NSS in the Han Chinese population.
    Psychological Medicine 09/2015; DOI:10.1017/S0033291715001580 · 5.94 Impact Factor
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    • "A recent metaanalysis of structural and functional imaging findings suggests that NeuroImage: Clinical 9 (2015) 411–417 NSS are associated with volume reductions of the pre-central gyrus, the cerebellum, the inferior frontal gyrus and the thalamus. Furthermore, the same meta-analysis also suggests that functional imaging studies support an association between NSS and altered neural activation in the inferior frontal gyrus, the bilateral putamen, the cerebellum and the superior temporal gyrus in patients with schizophrenia (Zhao et al., 2014). Taken together, these findings support the presence of a dysfunction of neural circuitry that underlies the presence of these minor neurological abnormalities, which are already present at illness onset. "
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    ABSTRACT: Neurological soft signs have been considered one of the promising neurological endophenotypes for schizophrenia. However, most previous studies have employed clinical rating data only. The present study aimed to examine the neurobiological basis of one of the typical motor coordination signs, the Fist-Edge-Palm task (FEP), in patients with first-episode schizophrenia and their non-psychotic first degree relatives. Thirteen patients with first-episode schizophrenia, 14 non-psychotic first-degree relatives and 14 healthy controls were recruited. All of them were instructed to perform the FEP task in a 3T GE Machine. Psychophysiological interaction (PPI) analysis was used to evaluate the functional connectivity between the sensorimotor cortex and frontal regions when participants performed the FEP task compared to simple motor tasks. In the contrast of palm-tapping (PT) vs. rest, activation of the left frontal-parietal region was lowest in the schizophrenia group, intermediate in the relative group and highest in the healthy control group. In the contrast of FEP vs. PT, patients with schizophrenia did not show areas of significant activation, while relatives and healthy controls showed significant activation of the left middle frontal gyrus. Moreover, with increase in task complexity, significant functional connectivity was observed between the sensorimotor cortex and the right frontal gyrus in healthy controls but not in patients with first episode schizophrenia. These findings suggest that activity of the left frontal-parietal and frontal regions may be neurofunctional correlates of neurological soft signs, which in turn may be a potential endophenotype of schizophrenia. Moreover, the right frontal gyrus may play a specific role in the execution of the FEP task in schizophrenia spectrum disorders.
    Clinical neuroimaging 09/2015; 9. DOI:10.1016/j.nicl.2015.09.008 · 2.53 Impact Factor
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    • "In particular, studies suggest the NSS might predict abnormalities within the cerebellar–thalamo–prefrontal circuitry [4] [5] and be viewed as an index of " cognitive dysmetria " [5] [6]. NSS assessment encompasses different domains, such as motor coordination (e.g., finger-to-nose test or diadochokinesis), up to complex motor sequences (e.g., Ozeretzki's or Luria's tests), and often include also sensory integration (e.g., stereognosis or graphesthesia). "
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    ABSTRACT: Neurological soft signs (NSS) are semeiotic anomalies not assessed by the standard neurological examination, primarily developed in psychiatric settings and recently proposed as potential markers of minor brain circuit alterations, especially the cerebellar-thalamic-prefrontal network. Primary headache patients present with normal neurological examination and frequent psychiatric comorbidity. Aim of this exploratory study consisted in assessing NSS in 20 episodic frequent migraine (MH) and in 10 tension-type headache (ETTH) outpatients compared to 30 matched healthy controls. NSS were assessed by the Heidelberg scale; clinical characteristics and brain MRI were additionally obtained in all patients. NSS were increased by ∼70 and ∼90%, in ETTH and MH, respectively, with respect to controls (p<0.001) and the difference remained significant even after controlling for age and education. Headache type and characteristics did not influence NSS presentation, while headache patients with white matter hyperintensities (WMH) at brain MRI had higher NSS scores compared both to normal controls and patients without WMH. NSS identify a subset of primary headache patients sharing the same comorbidities or minimal brain anomalies, suggesting that tailored prophylactic options might apply. Copyright © 2015. Published by Elsevier Ireland Ltd.
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