Cognitive load and autonomic response patterns under negative priming demand in depersonalization-derealization disorder.

Previous studies have yielded evidence for cognitive processing abnormalities and alterations of autonomic functioning in depersonalization-derealization disorder (DPRD). However, multimodal neuroimaging and psychophysiology studies have not yet been conducted to test for functional and effective connectivity under cognitive stress in patients with DPRD. DPRD and non-referred control subjects underwent a combined Stroop/negative priming task, and the neural correlates of Stroop interference effect, negative priming effect, error rates, cognitive load span and average amplitude of skin conductance responses were ascertained for both groups. Evoked haemodynamic responses for basic Stroop/negative priming activations were compared. For basic Stroop to neutral contrast, patients with DPRD differed in the location (inferior vs. superior lobule) of the parietal region involved, but showed similar activations in the left frontal region. In addition, patients with DPRD also co-activated the dorsomedial prefrontal cortex (BA9) and posterior cingulate cortex (BA31), which were also found to be the main between-group difference regions. These regions furthermore showed connectivity with frequency of depersonalization states. Evoked haemodynamic responses drawn from regions of interest indicated significant between-group differences in 30-40% of time points. Brain-behaviour correlations differed mainly in laterality, yet only slightly in regions. A reversal of autonomic patterning became evident in patients with DPRD for cognitive load spans, indicating less effective arousal suppression under cognitive stress - patients with DPRD showed positive associations of cognitive load with autonomic responses, whereas controls exhibit respective inverse association. Overall, the results of the present study show only minor executive cognitive peculiarities, but further support the notion of abnormalities in autonomic functioning in patients with DPRD.

Dissociable brain correlates for depression, anxiety, dissociation, and somatization in depersonalization-derealization disorder.

OBJECTIVE: The cerebral mechanisms of traits associated with depersonalization-derealization disorder (DPRD) remain poorly understood. METHOD: Happy and sad emotion expressions were presented to DPRD and non-referred control (NC) subjects in an implicit event-related functional magnetic resonance imaging (fMRI) design, and correlated with self report scales reflecting typical co-morbidities of DPRD: depression, dissociation, anxiety, somatization. RESULTS: Significant differences between the slopes of the two groups were observed for somatization in the right temporal operculum (happy) and ventral striatum, bilaterally (sad). Discriminative regions for symptoms of depression were the right pulvinar (happy) and left amygdala (sad). For dissociation, discriminative regions were the left mesial inferior temporal gyrus (happy) and left supramarginal gyrus (sad). For state anxiety, discriminative regions were the left inferior frontal gyrus (happy) and parahippocampal gyrus (sad). For trait anxiety, discriminative regions were the right caudate head (happy) and left superior temporal gyrus (sad). Discussion The ascertained brain regions are in line with previous findings for the respective traits. The findings suggest separate brain systems for each trait. CONCLUSION: Our results do not justify any bias for a certain nosological category in DPRD.

Aberrant function of learning and cognitive control networks underlie inefficient cognitive flexibility in anorexia nervosa: a cross-sectional fMRI study.

OBJECTIVES: People with Anorexia Nervosa exhibit difficulties flexibly adjusting behaviour in response to environmental changes. This has previously been attributed to problematic behavioural shifting, characterised by a decrease in fronto-striatal activity. Additionally, alterations of instrumental learning, which relies on fronto-striatal networks, may contribute to the observation of inflexible behaviour. The authors sought to investigate the neural correlates of cognitive flexibility and learning in Anorexia Nervosa. METHOD: Thirty-two adult females with Anorexia Nervosa and thirty-two age-matched female control participants completed the Wisconsin Card Sorting Task whilst undergoing functional magnetic resonance imaging. Event-related analysis permitted the comparison of cognitive shift trials against those requiring maintenance of rule-sets and allowed assessment of trials representing learning. RESULTS: Although both groups performed similarly, we found significant interactions in the left middle frontal gyrus, precuneus and superior parietal lobule whereby blood-oxygenated-level dependent response was higher in Anorexia Nervosa patients during shifting but lower when maintaining rule-sets, as compared to healthy controls. During learning, posterior cingulate cortex activity in healthy controls decreased whilst increasing in the Anorexia Nervosa group, whereas the right precuneus exhibited the opposite pattern. Furthermore, learning was associated with lower blood-oxygenated-level dependent response in the caudate body, as compared to healthy controls. CONCLUSIONS: People with Anorexia Nervosa display widespread changes in executive function. Whilst cognitive flexibility appears to be associated with aberrant functioning of the fronto-parietal control network that mediates between internally and externally directed cognition, fronto-striatal alterations, particularly within the caudate body, were associated with instrumental learning. Together, this shows how perseverative tendencies could be a substrate of multiple high-order processes that may contribute to the maintenance of Anorexia Nervosa.

Visually induced nausea causes characteristic changes in cerebral, autonomic and endocrine function in humans.

An integrated understanding of the physiological mechanisms involved in the genesis of nausea remains lacking. We aimed to describe the psychophysiological changes accompanying visually induced motion sickness, using a motion video, hypothesizing that differences would be evident between subjects who developed nausea in comparison to those who did not. A motion, or a control, stimulus was presented to 98 healthy subjects in a randomized crossover design. Validated questionnaires and a visual analogue scale (VAS) were used for the assessment of anxiety and nausea. Autonomic and electrogastrographic activity were measured at baseline and continuously thereafter. Plasma vasopressin and ghrelin were measured in response to the motion video. Subjects were stratified into quartiles based on VAS nausea scores, with the upper and lower quartiles considered to be nausea sensitive and resistant, respectively. Twenty-eight subjects were exposed to the motion video during functional neuroimaging. During the motion video, nausea-sensitive subjects had lower normogastria/tachygastria ratio and cardiac vagal tone but higher cardiac sympathetic index in comparison to the control video. Furthermore, nausea-sensitive subjects had decreased plasma ghrelin and demonstrated increased activity of the left anterior cingulate cortex. Nausea VAS scores correlated positively with plasma vasopressin and left inferior frontal and middle occipital gyri activity and correlated negatively with plasma ghrelin and brain activity in the right cerebellar tonsil, declive, culmen, lingual gyrus and cuneus. This study demonstrates that the subjective sensation of nausea is associated with objective changes in autonomic, endocrine and brain networks, and thus identifies potential objective biomarkers and targets for therapeutic interventions.

Interoceptive-reflective regions differentiate alexithymia traits in depersonalization disorder.

It is unclear to what degree depersonalization disorder (DPD) and alexithymia share abnormal brain mechanisms of emotional dysregulation. We compared cerebral processing of facial expressions of emotion in individuals with DPD to normal controls (NC). We presented happy and sad emotion expressions in increasing intensities from neutral (0%) through mild (50%) to intense (100%) to DPD and non-referred NC subjects in an implicit event-related fMRI design, and correlated respective brain activations with responses on the 20-item Toronto Alexithymia Scale (TAS-20) and its three subscales F1-F3. The TAS-20 predicts clinical diagnosis of DPD with a unique variance proportion of 38%. Differential regression analysis was utilized to ascertain brain regions for each alexithymia subscale. Differential regions of total alexithymia severity for happy emotion were the globus pallidus externus; for identifying feelings (TAS-20 F1 subscale), the right anterior insula; for description of feelings (F2), the right dorsal mid-anterior cingulate gyrus (BA 24); and for externally oriented cognitive style (F3), the left paracingulate gyrus (BA 32). For sad emotion, the differential region for the total TAS-20 score was the dorsal anterior cingulate gyrus (BA 24); for TAS-20 F1, the left inferior anterior insula; for TAS-20 F2, the right PCC (BA 31); and for TAS-20 F3, the right orbital gyrus (BA 10). Supporting our hypotheses, the ascertained brain regions for TAS-20 subscales subserve interoception, monitoring and reflection of internal states and emotion. The presented analyses provide evidence that alexithymia plays a substantial role in emotional dysregulation in DPD, presumably based on restrictions in interoception.

A comparison of automated anatomical-behavioural mapping methods in a rodent model of stroke.

Neurological damage, due to conditions such as stroke, results in a complex pattern of structural changes and significant behavioural dysfunctions; the automated analysis of magnetic resonance imaging (MRI) and discovery of structural-behavioural correlates associated with these disorders remains challenging. Voxel lesion symptom mapping (VLSM) has been used to associate behaviour with lesion location in MRI, but this analysis requires the definition of lesion masks on each subject and does not exploit the rich structural information in the images. Tensor-based morphometry (TBM) has been used to perform voxel-wise structural analyses over the entire brain; however, a combination of lesion hyper-intensities and subtle structural remodelling away from the lesion might confound the interpretation of TBM. In this study, we compared and contrasted these techniques in a rodent model of stroke (n=58) to assess the efficacy of these techniques in a challenging pre-clinical application. The results from the automated techniques were compared using manually derived region-of-interest measures of the lesion, cortex, striatum, ventricle and hippocampus, and considered against model power calculations. The automated TBM techniques successfully detect both lesion and non-lesion effects, consistent with manual measurements. These techniques do not require manual segmentation to the same extent as VLSM and should be considered part of the toolkit for the unbiased analysis of pre-clinical imaging-based studies.

Psychophysiological responses to pain identify reproducible human clusters.

Pain is a ubiquitous yet highly variable experience. The psychophysiological and genetic factors responsible for this variability remain unresolved. We hypothesised the existence of distinct human pain clusters (PCs) composed of distinct psychophysiological and genetic profiles coupled with differences in the perception and the brain processing of pain. We studied 120 healthy subjects in whom the baseline personality and anxiety traits and the serotonin transporter-linked polymorphic region (5-HTTLPR) genotype were measured. Real-time autonomic nervous system parameters and serum cortisol were measured at baseline and after standardised visceral and somatic pain stimuli. Brain processing reactions to visceral pain were studied in 29 subjects using functional magnetic resonance imaging (fMRI). The reproducibility of the psychophysiological responses to pain was assessed at year. In group analysis, visceral and somatic pain caused an expected increase in sympathetic and cortisol responses and activated the pain matrix according to fMRI studies. However, using cluster analysis, we found 2 reproducible PCs: at baseline, PC1 had higher neuroticism/anxiety scores (P ≤ 0.01); greater sympathetic tone (P<0.05); and higher cortisol levels (P ≤ 0.001). During pain, less stimulus was tolerated (P ≤ 0.01), and there was an increase in parasympathetic tone (P ≤ 0.05). The 5-HTTLPR short allele was over-represented (P ≤ 0.005). PC2 had the converse profile at baseline and during pain. Brain activity differed (P ≤ 0.001); greater activity occurred in the left frontal cortex in PC1, whereas PC2 showed greater activity in the right medial/frontal cortex and right anterior insula. In health, 2 distinct reproducible PCs exist in humans. In the future, PC characterization may help to identify subjects at risk for developing chronic pain and may reduce variability in brain imaging studies.

Sex differences in brain response to anticipated and experienced visceral pain in healthy subjects.

Women demonstrate higher pain sensitivity and prevalence of chronic visceral pain conditions such as functional gastrointestinal disorders than men. The role of sex differences in the brain processing of visceral pain is still unclear. In 16 male and 16 female healthy subjects we compared personality, anxiety levels, skin conductance response (SCR), and brain processing using functional MRI during anticipation and pain induced by esophageal distension at pain toleration level. There was no significant difference in personality scores, anxiety levels, SCR, and subjective ratings of pain between sexes. In group analysis, both men and women demonstrated a similar pattern of brain activation and deactivation during anticipation and pain consistent with previous reports. However, during anticipation women showed significantly greater activation in the cuneus, precuneus, and supplementary motor area (SMA) and stronger deactivation in the right amygdala and left parahippocampal gyrus, whereas men demonstrated greater activation in the cerebellum. During pain, women demonstrated greater activation in the midcingulate cortex, anterior insula, premotor cortex, and cerebellum and stronger deactivation in the caudate, whereas men showed increased activity in the SMA. The pattern of brain activity suggests that, during anticipation, women may demonstrate stronger limbic inhibition, which is considered to be a cognitive modulation strategy for impending painful stimulation. During pain, women significantly activate brain areas associated with the affective and motivation components of pain. These responses may underlie the sex differences that exist in pain conditions, whereby women may attribute more emotional importance to painful stimuli compared with men.

Somatization severity associated with postero-medial complex structures.

Somatisation is a frequent problem in various psychiatric disorders, yet the cerebral mechanisms of somatisation remain unexamined. To test if somatisation is susceptible to emotional states, we investigated relationships between somatisation severity, neural effective connectivity, and autonomic responses to emotional facial expressions. Volunteering participants (N = 20) were presented with facial expressions of happy and sad emotion at three intensity levels (0%-50%-100%) in a fast implicit ER-fMRI design with concurrent derivation of skin conductance levels (SCL). Self-reported somatisation severity as assessed with Rief's SOMS-2 index was correlated with neural response controlling for other clinical traits to ascertain brain bases of somatisation. Regression analyses estimated effective connectivity of main clusters so determined with peripheral autonomic responses. Regions in which magnitude of activity correlated with somatisation severity consisted in both happy and sad conditions of the anterior ventral precuneus (BA7), along with posterior cingulate gyrus (PCC, BA23, sad condition) and anteromedial thalamus (happy condition).

The effects of reality distortion syndrome on salient stimuli processing in patients with schizophrenia: an fMRI study.

Schizophrenia is associated with interpersonal difficulties related to impairments in the processing of facial emotional expressions. The aim of the present study was to identify brain regions associated with reality distortion syndrome reduction in a group of patients with schizophrenia during processing of emotionally salient stimuli. We used functional magnetic resonance imaging to measure cerebral blood oxygenation changes during an implicit emotional task in 11 patients with schizophrenia, who were scanned twice with an interval of 6-8 weeks. We found that reality distortion syndrome reduction was associated with increases in the activation of the affective division of the anterior cingulate and lateral prefrontal cortices. Our findings may indicate that changes in the activation of these regions during processing of emotionally salient stimuli may represent neural markers of patients' symptomatic improvement.

Amygdala activation to masked happy facial expressions.

The amygdala has a key role in automatic non-conscious processing of emotions. Highly salient emotional stimuli elicit amygdala activity, and happy faces are among the most rapidly perceived facial expressions. In backward masking paradigms, an image is presented briefly and then masked by another stimulus. However, reports of amygdala responses to masked happy faces have been mixed. In the present study, we used functional magnetic resonance imaging (fMRI) to examine amygdala activation to masked happy, sad, and neutral facial expressions. Masked happy faces elicited greater amygdala activation bilaterally as compared to masked sad faces. Our findings indicate that the amygdala is highly responsive to non-consciously perceived happy facial expressions.

Diffusion tensor imaging in sporadic and familial (D90A SOD1) forms of amyotrophic lateral sclerosis.

BACKGROUND: The basis of heterogeneity in the clinical presentation and rate of progression of amyotrophic lateral sclerosis (ALS) is poorly understood. OBJECTIVES: To use diffusion tensor imaging as a measure of axonal pathologic features in vivo in ALS and to compare a homogeneous form of familial ALS (homozygous D90A SOD1 [superoxide dismutase 1]) with sporadic ALS. DESIGN: Cross-sectional diffusion tensor imaging study. SETTING: Tertiary referral neurology clinic. PATIENTS: Twenty patients with sporadic ALS, 6 patients with homozygous D90A SOD1 ALS, and 21 healthy control subjects. MAIN OUTCOME MEASURE: Fractional anisotropy in cerebral white matter. RESULTS: Patients with homozygous D90A SOD1 ALS showed less extensive pathologic white matter in motor and extramotor pathways compared with patients with sporadic ALS, despite similar disease severity assessed clinically using a standard functional rating scale. Fractional anisotropy correlated with clinical measures of severity and upper motor neuron involvement. CONCLUSION: In vivo diffusion tensor imaging measures demonstrate differences in white matter degeneration between sporadic ALS and a unique familial form of the disease, indicating that genotype influences the distribution of cerebral pathologic features in ALS.

Cerebral and autonomic responses to emotional facial expressions in depersonalisation disorder.

BACKGROUND: Depersonalisation disorder is characterised by emotion suppression, but the cerebral mechanisms of this symptom are not yet fully understood. AIMS: To compare brain activation and autonomic responses of individuals with the disorder and healthy controls. METHOD: Happy and sad emotion expressions in increasing intensities (neutral to intense) were presented in an implicit event-related functional magnetic resonance imaging (fMRI) design with simultaneous measurement of autonomic responses. RESULTS: Participants with depersonalisation disorder showed fMRI signal decreases, whereas the control group showed signal increases in response to emotion intensity increases in both happy and sad expressions. The analysis of evoked haemodynamic responses from regions exhibiting functional connectivity between central and autonomic nervous systems indicated that in depersonalisation disorder initial modulations of haemodynamic response occurred significantly earlier (2 s post-stimulus) than in the control group (4-6 s post-stimulus). CONCLUSIONS: The results suggest that fMRI signal decreases are possible correlates of emotion suppression in depersonalisation disorder.

Facial fear processing and psychotic symptoms in schizophrenia: functional magnetic resonance imaging study.

BACKGROUND: The recognition of negative facial affect is impaired in people with schizophrenia. The neural underpinnings of this deficit and its relationship to the symptoms of psychosis are still unclear. AIMS: To examine the association between positive and negative psychotic symptoms and activation within the amygdala and extrastriate visual regions of patients with schizophrenia during fearful and neutral facial expression processing. METHOD: Functional magnetic resonance imaging was used to measure neural responses to neutral and fearful facial expressions in 11 patients with schizophrenia and 9 healthy volunteers during an implicit emotional task. RESULTS: No association between amygdala activation and positive symptoms was found; the activation within the left superior temporal gyrus was negatively associated with the negative symptoms of the patients. CONCLUSIONS: Our results indicate an association between impaired extrastriate visual processing of facial fear and negative symptoms, which may underlie the previously reported difficulties of patients with negative symptoms in the recognition of facial fear.

Multisite fMRI reproducibility of a motor task using identical MR systems.

PURPOSE: To estimate between-scanner functional MRI (fMRI) reproducibility in a multisite study. MATERIALS AND METHODS: A total of five identical 1.5T MR systems were used to repeatedly scan five subjects while performing a finger tapping task. A two-way (scanners, subjects) random effects analysis of variance (ANOVA) was used to estimate between-scanner and between-subject variability on two outcome variables: task-related mean blood oxygenation level dependent (BOLD) signal change and volume of activation within a motor region-of-interest (ROI). RESULTS: Between-scanner variability of fMRI data accounted for a small proportion of the total variation in the BOLD signal change (8.34%, P = 0.114) and volume of activation (5.46%, P = 0.203). Between-subject variation accounted for more than half of the total variation for both measurements (57.17% and 54.46%, respectively, P < 0.01). CONCLUSION: These results support the feasibility of multisite studies using identical scanner systems.

Cortical activation during motor imagery is reduced in Amyotrophic Lateral Sclerosis.

The neural correlates of motor execution in Amyotrophic Lateral Sclerosis (ALS) are challenging to investigate due to muscle weakness. Alternatives to traditional motor execution paradigms are therefore of great interest. This study tested the hypothesis that patients with Amyotrophic Lateral Sclerosis (ALS) would show increased cortical activation during motor imagery compared to healthy controls, as seen in studies of motor execution. Functional MRI was used to measure activation during a block design paradigm contrasting imagery of right hand movements against rest in 16 patients with ALS and 17 age-matched healthy controls. Patients with ALS showed reduced activation during motor imagery in the left inferior parietal lobule, and in the anterior cingulate gyrus and medial pre-frontal cortex. This reduction in cortical activation during motor imagery contrasts with the pattern seen during motor execution. This may represent the disruption of normal motor imagery networks by ALS pathology outside the primary motor cortex.

Limbic and prefrontal responses to facial emotion expressions in depersonalization.

Depersonalization disorder, characterized by emotional detachment, has been associated with increased prefrontal cortical and decreased autonomic activity to emotional stimuli. Event-related fMRI with simultaneous measurements of skin conductance levels occurred in nine depersonalization disorder patients and 12 normal controls to neutral, mild and intense happy and sad facial expressions. Patients, but not controls, showed decreases in subcortical limbic activity to increasingly intense happy and sad facial expressions, respectively. For both happy and sad expressions, negative correlations between skin conductance measures in bilateral dorsal prefrontal cortices occurred only in depersonalization disorder patients. Abnormal decreases in limbic activity to increasingly intense emotional expressions, and increases in dorsal prefrontal cortical activity to emotionally arousing stimuli may underlie the emotional detachment of depersonalization disorder.

Human attachment security is mediated by the amygdala: evidence from combined fMRI and psychophysiological measures.

The neural basis of human attachment security remains unexamined. Using event-related functional magnetic resonance imaging (fMRI) and simultaneous recordings of skin conductance levels, we measured neural and autonomic responses in healthy adult individuals during a semantic conceptual priming task measuring human attachment security "by proxy". Performance during a stress but not a neutral prime condition was associated with response in bilateral amygdalae. Furthermore, levels of activity within bilateral amygdalae were highly positively correlated with attachment insecurity and autonomic response during the stress prime condition. We thereby demonstrate a key role of the amygdala in mediating autonomic activity associated with human attachment insecurity.

Functional magnetic resonance imaging of verbal fluency and confrontation naming using compressed image acquisition to permit overt responses.

Verbal fluency and confrontation naming, two tests of word retrieval, are of great utility in the field of cognitive neuroscience. However, in the context of functional magnetic resonance imaging (fMRI), movement artefact has necessitated the use of covert paradigms, which has limited clinical application. We developed two overt fMRI paradigms that allowed for performance measurement and hence were appropriate for use with patient groups. The paradigms incorporated a blocked-design and compressed-acquisition methodology where cues were presented and responses made in a "silent" period allowing for performance measurement. The slow response pace was specifically designed for older and potentially cognitively impaired participants. Verbal fluency was associated with activation in the middle frontal gyrus (Brodmann areas 46 and 9), anterior cingulate gyrus and inferior frontal gyrus (area 44 and 45). Confrontation naming activated areas of the temporo-occipital cortices (areas 18, 19, and 37) and the inferior frontal gyrus. The two paradigms successfully activated regions involved in executive and word retrieval processes and overcame the potential artefacts resulting from overt speech during image acquisition, providing useful neuropsychological tools to investigate cognitive deficits in clinical populations.