Katharina M. Kubera

Motor dysfunction within the schizophrenia-spectrum: A dimensional step towards an underappreciated domain

At the beginning of the 20th century, genuine motor abnormalities (GMA) were considered to be intricately linked to schizophrenia. Subsequently, however, GMA have been increasingly regarded as unspecific transdiagnostic phenomena or related to side effects of antipsychotic treatment. Despite possible medication confounds, within the schizophrenia spectrum GMA have been categorized into three broad categories, i.e. neurological soft signs, abnormal involuntary movements and catatonia. Schizophrenia patients show a substantial overlap across a broad range of distinct motor signs and symptoms suggesting a prominent involvement of the motor system in disease pathophysiology. There have been several attempts to increase reliability and validity in diagnosing schizophrenia based on behavior and neurobiology, yet relatively little attention has been paid to the motor domain in the past. Nevertheless, accumulating neuroscientific evidence suggests the possibility of a motor endophenotype in schizophrenia, and that GMA could represent a specific dimension within the schizophrenia-spectrum. Here, we review current neuroimaging research on GMA in schizophrenia with an emphasis on distinct and common mechanisms of brain dysfunction. Based on a dimensional approach we show that multimodal neuroimaging combined with fine-grained clinical examination can result in a comprehensive characterization of structural and functional brain changes that are presumed to underlie core GMA in schizophrenia. We discuss the possibility of a distinct motor domain, together with its implications for future research. Investigating GMA by means of multimodal neuroimaging can essentially contribute at identifying novel and biologically reliable phenotypes in psychiatry.

Local brain gyrification as a marker of neurological soft signs in schizophrenia

Patients with psychiatric disorders of significant neurodevelopmental origin, such as schizophrenia and autism frequently experience genuine motor abnormalities, such as neurological soft signs (NSS). Previous MRI studies in patients with schizophrenia have shown that NSS are associated with abnormal cortical, thalamic and cerebellar structure and function. So far, however, no neuroimaging study focused on the role of the local gyrification index (LGI) in the pathophysiology of NSS. This study sought to explore the relationship between NSS and folding patterns of the cerebral cortex that are thought to be established during early brain development. In this study, whole brain high-resolution magnetic resonance imaging (MRI) at 3 Tesla was used to investigate the LGI in 33 patients with recent-onset schizophrenia. Cortical reconstruction was performed with the Freesurfer image analysis suite. NSS were examined on the Heidelberg Scale and related to LGI. Age, gender, years of education and medication were considered as potential confounding variables. In summary, higher NSS scores were positively associated with morphological changes of LGI predominantly in parietal and occipital areas. Our results confirm the hypothesis of a significant relationship between LGI changes and the NSS expression in schizophrenia. Investigation of LGI may help to explain subtle motor symptoms such as NSS in schizophrenia.

Multiparametric mapping of neurological soft signs in healthy adults

Minor motor and sensory deficits or neurological soft signs (NSS) are frequently found in patients with schizophrenia at any stage of their illness. Although previous studies have reported that NSS are associated with altered structure and function within fronto-parietal areas, it remains unclear whether the neuroanatomical basis of NSS may be confounded by underlying pathological processes, and by antipsychotic treatment. Morphological brain correlates of NSS in healthy subjects have seldom been investigated. This study evaluated the relationship between NSS levels and abnormalities of subcortical and cortical structures in healthy individuals. High-resolution MRI data at 3 Tesla were obtained from 68 healthy individuals. Automated segmentation of caudate nucleus, putamen, globus pallidus, thalamus, and brainstem was performed using both FSL-FIRST and Freesurfer. The surface-based analysis via Freesurfer enabled calculation of cortical thickness, area and folding (local gyrification index). NSS were examined on the Heidelberg Scale and related to both subcortical and cortical measurements. Using two fully automated brain segmentations methods, we found no significant association between NSS levels and morphological changes in subcortical structures. Higher NSS scores were associated with morphological changes of cortical thickness, area and folding in multiple areas comprising superior frontal, middle temporal, insular and postcentral regions. Our findings demonstrate the benefit of surface-based approaches when investigating brain correlates of NSS. The data lend further support to the hypothesis that NSS in healthy individuals involve multiple cortical rather than subcortical brain regions.

Neurological Abnormalities in Recent-Onset Schizophrenia and Asperger-Syndrome

Background: Neurological abnormalities including a variety of subtle deficits such as discrete impairments in sensory integration, motor coordination (MOCO), and sequencing of complex motor acts are frequently found in patients with schizophrenia (SZ) and commonly referred to as neurological soft signs (NSS). Asperger-syndrome (AS) is characterized by sensory-motor difficulties as well. However, the question whether the two disorders share a common or a disease-specific pattern of NSS remains unresolved. Method: A total of 78 age- and education-matched participants [26 patients with recent-onset SZ, 26 individuals with AS, and 26 healthy controls (HC)] were recruited for the study. Analyses of covariance (ANCOVAs), with age, years of education, and medication included as covariates, were used to examine group differences on total NSS and the five subscale scores. Discriminant analyses were employed to identify the NSS subscales that maximally discriminate between the three groups. Results: Significant differences among the three groups were found in NSS total score and on the five NSS subscales. The clinical groups differed significantly in the NSS subscale MOCO. The correct discriminant rate between patients with SZ and individuals with AS was 61.5%. The correct discriminant rate was 92.3% between individuals with AS and HC, and 80.8% between SZ patients and HC, respectively. Conclusion: Our findings provide new evidence for the presence of NSS in AS and lend further support to previously reported difficulties in movement control in this disorder. According to the present results, SZ and AS seem to be characterized by both quantitative and qualitative NSS expression.

Cortical features of distinct developmental trajectories in patients with delusional infestation

Background: Although there is strong neuroimaging evidence that cortical alterations are a core feature of schizophrenia spectrum disorders, it still remains unclear to what extent such abnormalities occur in monothematic delusional disorders. In individuals with delusional infestation (DI), the delusional belief to be infested with pathogens, previous structural MRI studies have shown prefrontal, temporal, parietal, insular, thalamic and striatal gray matter volume changes. Differential contributions of cortical features of evolutionary and genetic origin (such as cortical thickness, area and folding) which may distinctly contribute to DI pathophysiology are unclear at present. Methods: In this study, 18 patients with DI and 20 healthy controls (HC) underwent MRI scanning at 1.0 T. Using surface‐based analyses we calculated cortical thickness, surface area and local gyrification index (LGI). Whole‐brain differences between patients and controls were investigated. Results: Surface analyses revealed frontoparietal patterns exhibiting altered cortical thickness, surface area and LGI in DI patients compared to controls. Higher cortical thickness was found in the right medial orbitofrontal cortex (p < 0.05, cluster‐wise probability [CWP] corrected). Smaller surface area in patients was found in the left inferior temporal gyrus, the precuneus, the pars orbitalis of the right frontal gyrus, and the lingual gyrus (p < 0.05, CWP corr.). Lower LGI was found in the left postcentral, bilateral precentral, right middle temporal, inferior parietal, and superior parietal gyri (p < 0.01, CWP corr.). Conclusion: This study lends further support to the hypothesis that cortical features of distinct evolutionary and genetic origin differently contribute to the pathogenesis of delusional disorders. Regions in which atrophy was observed are part of neural circuits associated with perception, visuospatial control and self‐awareness. The data are in line with the notion of a content‐specific neural signature of DI. HighlightsDI patients have higher cortical thickness in the medial orbitofrontal cortex.DI patients have lower surface area and LGI in temporo‐parietal regions.Cortical features of distinct evolutionary origin differently contribute to DI.

White matter microstructure variations contribute to neurological soft signs in healthy adults

Neurological soft signs (NSS) are core features of psychiatric disorders with significant neurodevelopmental origin. However, it is unclear whether NSS correlates are associated with neuropathological processes underlying the disease or if they are confounded by medication. Given that NSS are also present in healthy persons (HP), investigating HP could reveal NSS correlates, which are not biased by disease‐specific processes or drug treatment. Therefore, we used a combination of diffusion MRI analysis tools to provide a framework of specific white matter (WM) microstructure variations underlying NSS in HP.

Hippocampal formation alterations differently contribute to autobiographic memory deficits in mild cognitive impairment and Alzheimer's disease

Autobiographical memory (AM) is part of declarative memory and includes both semantic and episodic aspects. AM deficits are among the major complaints of patients with Alzheimers disease (AD) even in early or preclinical stages. Previous MRI studies in AD patients have showed that deficits in semantic and episodic AM are associated with hippocampal alterations. However, the question which specific hippocampal subfields and adjacent extrahippocampal structures contribute to deficits of AM in individuals with mild cognitive impairment (MCI) and AD patients has not been investigated so far. Hundred and seven participants (38 AD patients, 38 MCI individuals and 31 healthy controls [HC]) underwent MRI at 3 Tesla. AM was assessed with a semi‐structured interview (E‐AGI). FreeSurfer 5.3 was used for hippocampal parcellation. Semantic and episodic AM scores were related to the volume of 5 hippocampal subfields and cortical thickness in the parahippocampal and entorhinal cortex. Both semantic and episodic AM deficits were associated with bilateral hippocampal alterations. These associations referred mainly to CA1, CA2‐3, presubiculum, and subiculum atrophy. Episodic, but not semantic AM loss was associated with cortical thickness reduction of the bilateral parahippocampal and enthorinal cortex. In MCI individuals, episodic, but not semantic AM deficits were associated with alterations of the CA1, presubiculum and subiculum. Our findings support the crucial role of CA1, presubiculum, and subiculum in episodic memory. The present results implicate that in MCI individuals, semantic and episodic AM deficits are subserved by distinct neuronal systems.

Cortical folding patterns are associated with impulsivity in healthy young adults

Impulsivity is associated with distinct mental disorders but is also considered as a personality trait exhibited by healthy individuals. Current studies suggest that early stressful life events might cause higher impulsivity in the adulthood. Morphological features, which reflect early brain development, could provide valuable information regarding the origin of impulsive behavior. However, none of the previous MRI studies employed a methodology specifically designed to investigate the relationship between impulsivity and markers of brain development. In this regard, we aimed to investigate the relationship between cortical folding and the three distinct factors of impulsivity (attention, motor, and non-planning) in young healthy adults. Fifty-four right-handed healthy individuals were recruited for the study and underwent magnetic resonance imaging (MRI) at 3 Tesla. A surface-based analysis was used to calculate a local gyrification index (LGI). Impulsivity was examined by the Barratt Impulsiveness Scale (BIS-11) and related to LGI. Associations between LGI and BIS-11 scores were assessed using within-group correlations (p < 0.05, “cluster-wise probability” [CWP] corr.). BIS subscores were positively correlated with cortical folding in several distinct areas: Total and attention scores were positively correlated with LGI in the left postcentral gyrus, cingulate gyrus, precentral gyrus, pars opercularis of the inferior frontal gyrus, right middle temporal gyrus, superior parietal gyrus, pericalcarine gyrus, and lateral occipital gyrus (each p < 0.05 CWP corr.). BIS motor score was positively correlated with LGI in the left superior temporal, lingual and supramarginal gyrus (each p < 0.05 CWP corr.). BIS non-planning score showed a positive correlation with LGI in the pars opercularis of the right inferior frontal gyrus and the left middle temporal, precentral and superior parietal gyrus (each p < 0.05 CWP corr.). Furthermore, we found gender-specific differences in BIS-11-LGI-correlation in the middle and inferior frontal gyrus. Our findings illustrate the advantages of cortical folding as a marker of early brain development when investigating structural brain correlates of impulsivity in young adulthood. Further, they lend additional support to the notion that alterations in early neurodevelopment comprising fronto-temporo-parietal regions might give rise to higher impulsivity in healthy individuals.

Motor dysfunction as research domain in the period preceding manifest schizophrenia: A systematic review

HighlightsMotor dysfunction precedes the onset of manifest schizophrenia.Motor deficits reflect vulnerability for developing schizophrenia.Motor dysfunction is an intermediate phenotype candidate for schizophrenia. &NA; Schizophrenia is a severe behavioral syndrome of neurodevelopmental nature marked by primary or genuine motor abnormalities (GMA), which refer to spontaneous and medication‐independent motor phenomena. Since motor dysfunction thus might be a consequence of events occurring during early childhood and adolescence, GMA can be detected in the period preceding manifest schizophrenia. However, the question whether motor system dysfunction might be a promising motor intermediate phenotype for schizophrenia remains unanswered. In this review, we systematically evaluate the evidence on GMA in healthy persons, individuals with schizotypal personality traits, persons at ultra‐high risk for psychosis, and unaffected first‐degree relatives of schizophrenia patients. What becomes evident is a continuum of GMA expression, which appears to be linked to abnormalities of cerebello‐thalamo‐cortical, fronto‐parietal, and cortico‐subcortical motor circuits. According to current evidence, motor dysfunction is a key aspect of the neurodevelopmental risk factor model of schizophrenia. Insights provided by this research will help promoting the RDoC Motor System construct and expand the clinical relevance of the motor domain in the period preceding manifest schizophrenia.

Noninvasive brain stimulation for the treatment of auditory verbal hallucinations in schizophrenia: methods, effects and challenges

This mini-review focuses on noninvasive brain stimulation techniques as an augmentation method for the treatment of persistent auditory verbal hallucinations (AVH) in patients with schizophrenia. Paradigmatically, we place emphasis on transcranial magnetic stimulation (TMS). We specifically discuss rationales of stimulation and consider methodological questions together with issues of phenotypic diversity in individuals with drug-refractory and persistent AVH. Eventually, we provide a brief outlook for future investigations and treatment directions. Taken together, current evidence suggests TMS as a promising method in the treatment of AVH. Low-frequency stimulation of the superior temporal cortex (STC) may reduce symptom severity and frequency. Yet clinical effects are of relatively short duration and effect sizes appear to decrease over time along with publication of larger trials. Apart from considering other innovative stimulation techniques, such as transcranial Direct Current Stimulation (tDCS), and optimizing stimulation protocols, treatment of AVH using noninvasive brain stimulation will essentially rely on accurate identification of potential responders and non-responders for these treatment modalities. In this regard, future studies will need to consider distinct phenotypic presentations of AVH in patients with schizophrenia, together with the putative functional neurocircuitry underlying these phenotypes.