Investigating psychobiological causes and mechanisms in functional seizures and functional motor symptoms: Study protocol.

INTRODUCTION: Advances have been made in understanding the aetiology of functional neurological disorder (FND); however, its pathophysiological mechanisms have not been definitively demonstrated. Evidence suggests interacting roles for altered emotional processing and interoception, elevated autonomic arousal, and dissociation, but there is limited evidence demonstrating their causal influence on specific FND symptoms. Our superordinate aim is to elucidate potentially shared and distinct aetiological factors and mechanisms in two common FND subtypes, functional seizures (FS) and functional motor symptoms (FMS). METHODS: This study has a multimodal, mixed between- and within-groups design. The target sample is 50 individuals with FS, 50 with FMS, 50 clinical controls (anxiety/depression), and 50 healthy controls. Potential aetiological factors (e.g., adverse life events, physical/mental health symptoms, dissociative tendencies, interoceptive insight/sensibility) will be assessed with a detailed medical history interview and self-report questionnaires. A laboratory session will include a neurocognitive battery, psychophysiological testing, cardiac interoception and time estimation tasks and an isometric handgrip task. A subsample will undergo magnetic resonance imaging, including structural, resting-state and task-based scans combined with psychophysiological recording. Remote monitoring with ecological momentary assessment and wearables will measure variability in FND symptoms and their potential predictors/correlates for ≥2 weeks in patients' daily lives. Longitudinal follow-ups at 3, 6, and 12-months will monitor longer-term outcomes in the clinical groups. DISCUSSION: This study employs multimodal research methods to rigorously examine several putative mechanisms in FND, at subjective/experiential, behavioural, and physiological levels. The study will test causal hypotheses about the role of altered emotional processing, autonomic arousal, dissociation and interoception in the initiation or exacerbation of FND symptoms, directly comparing these processes in FS and FMS to healthy and clinical controls. This is the first study of its kind, with potential to reveal important targets for prevention and treatment of FND in future.

MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods. Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

Neurodevelopmental origins of abnormal cortical morphology in dissociative identity disorder.

OBJECTIVE: To examine the two constitutes of cortical volume (CV), that is, cortical thickness (CT) and surface area (SA), in individuals with dissociative identity disorder (DID) with the view of gaining important novel insights into the underlying neurobiological mechanisms mediating DID. METHODS: This study included 32 female patients with DID and 43 matched healthy controls. Between-group differences in CV, thickness, and SA, the degree of spatial overlap between differences in CT and SA, and their relative contribution to differences in regional CV were assessed using a novel spatially unbiased vertex-wise approach. Whole-brain correlation analyses were performed between measures of cortical anatomy and dissociative symptoms and traumatization. RESULTS: Individuals with DID differed from controls in CV, CT, and SA, with significantly decreased CT in the insula, anterior cingulate, and parietal regions and reduced cortical SA in temporal and orbitofrontal cortices. Abnormalities in CT and SA shared only about 3% of all significantly different cerebral surface locations and involved distinct contributions to the abnormality of CV in DID. Significant negative associations between abnormal brain morphology (SA and CV) and dissociative symptoms and early childhood traumatization (0 and 3 years of age) were found. CONCLUSIONS: In DID, neuroanatomical areas with decreased CT and SA are in different locations in the brain. As CT and SA have distinct genetic and developmental origins, our findings may indicate that different neurobiological mechanisms and environmental factors impact on cortical morphology in DID, such as early childhood traumatization.

Is it Trauma- or Fantasy-based? Comparing dissociative identity disorder, post-traumatic stress disorder, simulators, and controls.

OBJECTIVE: The Trauma Model of dissociative identity disorder (DID) posits that DID is etiologically related to chronic neglect and physical and/or sexual abuse in childhood. In contrast, the Fantasy Model posits that DID can be simulated and is mediated by high suggestibility, fantasy proneness, and sociocultural influences. To date, these two models have not been jointly tested in individuals with DID in an empirical manner. METHOD: This study included matched groups [patients (n = 33) and controls (n = 32)] that were compared on psychological Trauma and Fantasy measures: diagnosed genuine DID (DID-G, n = 17), DID-simulating healthy controls (DID-S, n = 16), individuals with post-traumatic stress disorder (PTSD, n = 16), and healthy controls (HC, n = 16). Additionally, personality-state-dependent measures were obtained for DID-G and DID-S; both neutral personality states (NPS) and trauma-related personality states (TPS) were tested. CONCLUSION: For Trauma measures, the DID-G group had the highest scores, with TPS higher than NPS, followed by the PTSD, DID-S, and HC groups. The DID-G group was not more fantasy-prone or suggestible and did not generate more false memories. Malingering measures were inconclusive. Evidence consistently supported the Trauma Model of DID and challenges the core hypothesis of the Fantasy Model.

Bilateral hippocampal increase following first-episode psychosis is associated with good clinical, functional and cognitive outcomes.

BACKGROUND: Hippocampal pathology has been proposed to underlie clinical, functional and cognitive impairments in schizophrenia. The hippocampus is a highly plastic brain region; examining change in volume, or change bilaterally, over time, can advance understanding of the substrate of recovery in psychosis. METHOD: Magnetic resonance imaging and outcome data were collected at baseline and 6-year follow-up in 42 first-episode psychosis subjects and 32 matched controls, to investigate whether poorer outcomes are associated with loss of global matter and hippocampal volumes. Bilateral hippocampal increase (BHI) over time, as a marker of hippocampal plasticity was hypothesized to be associated with better outcomes. Regression analyses were performed on: (i) clinical and functional outcomes with grey matter volume change and BHI as predictor variables; and (ii) cognitive outcome with BHI as predictor. RESULTS: BHI was present in 29% of psychosis participants. There was no significant grey matter loss over time in either patient or control groups. Less severe illness course and lesser symptom severity were associated with BHI, but not with grey matter change. Employment and global function were associated with BHI and with less grey matter loss. Superior delayed verbal recall was also associated with BHI. CONCLUSIONS: BHI occurs in a minority of patients following their first psychotic episode and is associated with good outcome across clinical, functional and cognitive domains.

Fact or factitious? A psychobiological study of authentic and simulated dissociative identity states.

BACKGROUND: Dissociative identity disorder (DID) is a disputed psychiatric disorder. Research findings and clinical observations suggest that DID involves an authentic mental disorder related to factors such as traumatization and disrupted attachment. A competing view indicates that DID is due to fantasy proneness, suggestibility, suggestion, and role-playing. Here we examine whether dissociative identity state-dependent psychobiological features in DID can be induced in high or low fantasy prone individuals by instructed and motivated role-playing, and suggestion. METHODOLOGY/PRINCIPAL FINDINGS: DID patients, high fantasy prone and low fantasy prone controls were studied in two different types of identity states (neutral and trauma-related) in an autobiographical memory script-driven (neutral or trauma-related) imagery paradigm. The controls were instructed to enact the two DID identity states. Twenty-nine subjects participated in the study: 11 patients with DID, 10 high fantasy prone DID simulating controls, and 8 low fantasy prone DID simulating controls. Autonomic and subjective reactions were obtained. Differences in psychophysiological and neural activation patterns were found between the DID patients and both high and low fantasy prone controls. That is, the identity states in DID were not convincingly enacted by DID simulating controls. Thus, important differences regarding regional cerebral bloodflow and psychophysiological responses for different types of identity states in patients with DID were upheld after controlling for DID simulation. CONCLUSIONS/SIGNIFICANCE: The findings are at odds with the idea that differences among different types of dissociative identity states in DID can be explained by high fantasy proneness, motivated role-enactment, and suggestion. They indicate that DID does not have a sociocultural (e.g., iatrogenic) origin.

Individualized prediction of illness course at the first psychotic episode: a support vector machine MRI study.

BACKGROUND: To date, magnetic resonance imaging (MRI) has made little impact on the diagnosis and monitoring of psychoses in individual patients. In this study, we used a support vector machine (SVM) whole-brain classification approach to predict future illness course at the individual level from MRI data obtained at the first psychotic episode. METHOD: One hundred patients at their first psychotic episode and 91 healthy controls had an MRI scan. Patients were re-evaluated 6.2 years (s.d.=2.3) later, and were classified as having a continuous, episodic or intermediate illness course. Twenty-eight subjects with a continuous course were compared with 28 patients with an episodic course and with 28 healthy controls. We trained each SVM classifier independently for the following contrasts: continuous versus episodic, continuous versus healthy controls, and episodic versus healthy controls. RESULTS: At baseline, patients with a continuous course were already distinguishable, with significance above chance level, from both patients with an episodic course (p=0.004, sensitivity=71, specificity=68) and healthy individuals (p=0.01, sensitivity=71, specificity=61). Patients with an episodic course could not be distinguished from healthy individuals. When patients with an intermediate outcome were classified according to the discriminating pattern episodic versus continuous, 74% of those who did not develop other episodes were classified as episodic, and 65% of those who did develop further episodes were classified as continuous (p=0.035). CONCLUSIONS: We provide preliminary evidence of MRI application in the individualized prediction of future illness course, using a simple and automated SVM pipeline. When replicated and validated in larger groups, this could enable targeted clinical decisions based on imaging data.

Detecting fearful and neutral faces: BOLD latency differences in amygdala-hippocampal junction.

Evolutionary survival and procreation are augmented if an individual organism quickly detects environmental threats and rapidly initiates defensive behavioral reactions. Thus, facial emotions signaling a potential threat, e.g., fear or anger, should be perceived rapidly and automatically, possibly through a subcortical processing route which includes the amygdala. Using event-related functional magnetic resonance imaging (fMRI), we investigated the time course of the response in the amygdala to neutral and fearful faces, which appear from dynamically decreasing random visual noise. We aimed to detect differences of the amygdala response between fearful and neutral faces by estimating the latency of the blood oxygenation level-dependent (BOLD) response. We found that bilateral amygdala-hippocampal junction activation occurred earlier for fearful than for neutral faces. Our findings support the theory of a dual route architecture in which the subcortical thalamic-hippocampal-amygdala route serves fast preconscious threat perception.

The robustness of perception.

The natural environment around us, which is often crowded, cluttered or even foggy, is subject to a dynamically changing composition of objects and events. The human brain is continuously perceiving, recognizing and evaluating this dynamic scene composition. If the perception of degraded visual objects is important, e.g. in the case of potential threat stimuli, the brain needs to be more sensitive in detecting these objects from the natural environment. It is therefore hypothesized that reacting to the dynamically changing environment involves a robust and quick processing of salient information, which can be either with or without conscious awareness. We investigated the dynamics and robustness of perception using pictures of three salience levels, i.e. fearful faces (most salient), neutral faces (salient) and houses (nonsalient), which appear from dynamically decreasing random visual noise. Stimuli were matched for luminance, contrast, brightness and spatial frequency information. Reaction times show a significantly earlier response for faces than for houses. Fearful faces were significantly more quickly detected than neutral faces. The neural correlates sustaining robust perception were investigated with event-related functional magnetic resonance imaging (fMRI). The amygdala showed a significant perception-related response for faces, as compared to houses, that was further enhanced for fearful faces as compared to neutral faces. Our data indicate that emotionally salient information processing is (i) mediated by the amygdala and (ii) more robust than for nonsalient stimuli as it shows a significantly lower perceptual threshold.

One brain, two selves.

Having a sense of self is an explicit and high-level functional specialization of the human brain. The anatomical localization of self-awareness and the brain mechanisms involved in consciousness were investigated by functional neuroimaging different emotional mental states of core consciousness in patients with Multiple Personality Disorder (i.e., Dissociative Identity Disorder (DID)). We demonstrate specific changes in localized brain activity consistent with their ability to generate at least two distinct mental states of self-awareness, each with its own access to autobiographical trauma-related memory. Our findings reveal the existence of different regional cerebral blood flow patterns for different senses of self. We present evidence for the medial prefrontal cortex (MPFC) and the posterior associative cortices to have an integral role in conscious experience.

Interscan displacement-induced variance in PET activation data is excluded by a scan-specific attenuation correction.

In PET activation studies, linear changes in regional cerebral blood flow may be caused by subject interscan displacements rather than by changes in cognitive state. The aim of this study was to investigate the impact of these artifacts and to assess whether they can be removed by applying a scan-specific calculated attenuation correction (CAC) instead of the default measured attenuation correction (MAC). Two independent data sets were analyzed, one with large (data I) and one with small (data II) interscan displacements. After attenuation correction (CAC or MAC), data were analyzed using SPM99. Interscan displacement parameters (IDP), obtained during scan realignment, were included as additional regressors in the General Linear Model and their impact was assessed by variance statistics revealing the affected brain volume. For data I, this volume reduced dramatically from 579 to 12 cm(3) (approximately 50-fold) at P(uncorr)

Iterative versus filtered backprojection reconstruction for statistical parametric mapping of PET activation measurements: a comparative case study.

The significance of task-induced cerebral blood flow responses, assessed using statistical parametric mapping, depends, among other things, on the signal-to-noise ratio (SNR) of these responses. Generally, positron emission tomography sinograms of H(2)(15)O activation studies are reconstructed using filtered backprojection (FBP). Alternatively, the acquired data can be reconstructed using an iterative reconstruction procedure. It has been demonstrated that the application of iterative reconstruction methods improves image SNR as compared with FBP. The aim of this study was to compare FBP with iterative reconstruction, to assess the statistical power of H(2)(15)O-PET activation studies using statistical parametric mapping. For this case study, PET data originating from a bimanual motor task were reconstructed using both FBP and maximum likelihood expectation maximization (ML-EM), an iterative algorithm. Both resulting data sets were statistically analyzed using statistical parametric mapping. It was found, with this dataset, that the statistical analysis of the iteratively reconstructed data confirm the a priori expected physiological response. In addition, increased Z scores were obtained in the iteratively reconstructed data. In particular, for the expected task-related response, activation of the posterior border of the left angular gyrus, the Z score increased from 3.00 to 3.96. Furthermore, the number of statistically significant clusters doubled while their volume increased by more than 50%. In conclusion, iterative reconstruction has the potential to increase the statistical power in H(2)(15)O-PET activation studies as compared with FBP reconstruction.