Metabotropic glutamate receptor 5 binding in patients with obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is a disabling, mostly chronic, psychiatric condition with significant social and economic impairments and is a major public health issue. However, numerous patients are resistant to currently available pharmacological and psychological interventions. Given that recent animal studies and magnetic resonance spectroscopy research points to glutamate dysfunction in OCD, we investigated the metabotropic glutamate receptor 5 (mGluR5) in patients with OCD and healthy controls. We determined mGluR5 distribution volume ratio (DVR) in the brain of ten patients with OCD and ten healthy controls by using [11C]ABP688 positron-emission tomography. As a clinical measure of OCD severity, the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was employed. We found no significant global difference in mGluR5 DVR between patients with OCD and healthy controls. We did, however, observe significant positive correlations between the Y-BOCS obsession sub-score and mGluR5 DVR in the cortico-striatal-thalamo-cortical brain circuit, including regions of the amygdala, anterior cingulate cortex, and medial orbitofrontal cortex (Spearman's ρ's⩾ = 0.68, p < 0.05). These results suggest that obsessions in particular might have an underlying glutamatergic pathology related to mGluR5. The research indicates that the development of metabotropic glutamate agents would be useful as a new treatment for OCD.

The Frontal Eye Field Is Involved in Visual Vector Inversion in Humans – A Theta Burst Stimulation Study

In the antisaccade task, subjects are requested to suppress a reflexive saccade towards a visual target and to perform a saccade towards the opposite side. In addition, in order to reproduce an accurate saccadic amplitude, the visual saccade vector (i.e., the distance between a central fixation point and the peripheral target) must be exactly inverted from one visual hemifield to the other. Results from recent studies using a correlational approach (i.e., fMRI, MEG) suggest that not only the posterior parietal cortex (PPC) but also the frontal eye field (FEF) might play an important role in such a visual vector inversion process. In order to assess whether the FEF contributes to visual vector inversion, we applied an interference approach with continuous theta burst stimulation (cTBS) during a memory-guided antisaccade task. In 10 healthy subjects, one train of cTBS was applied over the right FEF prior to a memory-guided antisaccade task. In comparison to the performance without stimulation or with sham stimulation, cTBS over the right FEF induced a hypometric gain for rightward but not leftward antisaccades. These results obtained with an interference approach confirm that the FEF is also involved in the process of visual vector inversion.

Prefrontal GABA and glutathione imbalance in posttraumatic stress disorder: Preliminary findings.

Although posttraumatic stress disorder (PTSD) is associated with a variety of structural and functional brain changes, the molecular pathophysiological mechanisms underlying these macroscopic alterations are unknown. Recent studies support the existence of an altered excitation-inhibition balance in PTSD. Further, there is preliminary evidence from blood-sample studies suggesting heightened oxidative stress in PTSD, potentially leading to neural damage through excessive brain levels of free radicals. In this study we investigated PTSD (n=12) and non-PTSD participants (n=17) using single-voxel proton magnetic resonance spectroscopy (MRS) in dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). We found significantly higher levels of γ-amino butyric acid (GABA) (a primary inhibitory neurotransmitter) and glutathione (a marker for neuronal oxidative stress) in PTSD participants. Atypically high prefrontal inhibition as well as oxidative stress may be involved in the pathogenesis of PTSD.

Neural correlates of evaluating hazards of high risk.

In personal and in society related context, people often evaluate the risk of environmental and technological hazards. Previous research addressing neuroscience of risk evaluation assessed particularly the direct personal risk of presented stimuli, which may have comprised for instance aspects of fear. Further, risk evaluation primarily was compared to tasks of other cognitive domains serving as control conditions, thus revealing general risk related brain activity, but not such specifically associated with estimating a higher level of risk. We here investigated the neural basis on which lay-persons individually evaluated the risk of different potential hazards for the society. Twenty healthy subjects underwent functional magnetic resonance imaging while evaluating the risk of fifty more or less risky conditions presented as written terms. Brain activations during the individual estimations of 'high' against 'low' risk, and of negative versus neutral and positive emotional valences were analyzed. Estimating hazards to be of high risk was associated with activation in medial thalamus, anterior insula, caudate nucleus, cingulate cortex and further prefrontal and temporo-occipital areas. These areas were not involved according to an analysis of the emotion ratings. In conclusion, we emphasize a contribution of the mentioned brain areas involved to signal high risk, here not primarily associated with the emotional valence of the risk items. These areas have earlier been reported to be associated with, beside emotional, viscerosensitive and implicit processing. This leads to assumptions of an intuitive contribution, or a "gut-feeling", not necessarily dependent of the subjective emotional valence, when estimating a high risk of environmental hazards.

Interhemispheric cerebral blood flow balance during recovery of motor hand function after ischemic stroke - a longitudinal MRI study using arterial spin labeling perfusion

BACKGROUND Unilateral ischemic stroke disrupts the well balanced interactions within bilateral cortical networks. Restitution of interhemispheric balance is thought to contribute to post-stroke recovery. Longitudinal measurements of cerebral blood flow (CBF) changes might act as surrogate marker for this process. OBJECTIVE To quantify longitudinal CBF changes using arterial spin labeling MRI (ASL) and interhemispheric balance within the cortical sensorimotor network and to assess their relationship with motor hand function recovery. METHODS Longitudinal CBF data were acquired in 23 patients at 3 and 9 months after cortical sensorimotor stroke and in 20 healthy controls using pulsed ASL. Recovery of grip force and manual dexterity was assessed with tasks requiring power and precision grips. Voxel-based analysis was performed to identify areas of significant CBF change. Region-of-interest analyses were used to quantify the interhemispheric balance across nodes of the cortical sensorimotor network. RESULTS Dexterity was more affected, and recovered at a slower pace than grip force. In patients with successful recovery of dexterous hand function, CBF decreased over time in the contralesional supplementary motor area, paralimbic anterior cingulate cortex and superior precuneus, and interhemispheric balance returned to healthy control levels. In contrast, patients with poor recovery presented with sustained hypoperfusion in the sensorimotor cortices encompassing the ischemic tissue, and CBF remained lateralized to the contralesional hemisphere. CONCLUSIONS Sustained perfusion imbalance within the cortical sensorimotor network, as measured with task-unrelated ASL, is associated with poor recovery of dexterous hand function after stroke. CBF at rest might be used to monitor recovery and gain prognostic information.

Neural patterns underlying social comparisons of personal performance

Humans often evaluate their abilities by comparing their personal performance with that of others. For this process, it is critical whether the comparison turns out in one's favor or against it. Here, we investigate how social comparisons of performance are encoded and integrated on the neural level. We collected functional magnetic resonance images while subjects answered questions in a knowledge quiz that was related to their profession. After each question, subjects received a feedback about their personal performance, followed by a feedback about the performance of a reference group who had been quizzed beforehand. Based on the subjects' personal performance, we divided trials in downward and upward comparisons. We found that upward comparisons correlated with activity in the dorsolateral prefrontal cortex and the anterior insula. Downward comparisons were associated with increased activation in the ventral striatum (VS), the medial orbitofrontal cortex and the ventral anterior cingulate cortex (ACC). The extent to which subjects outperformed the reference group modulated the activity in the VS and in the dorsal ACC. We suggest that the co-activation of the VS and the dorsal ACC contributes to the integration of downward comparisons into the evaluation of personal performance.

Functional lateralization of the anterior insula during feedback processing

Effective adaptive behavior rests on an appropriate understanding of how much responsibility we have over outcomes in the environment. This attribution of agency to ourselves or to an external event influences our behavioral and affective response to the outcomes. Despite its special importance to understanding human motivation and affect, the neural mechanisms involved in self-attributed rewards and punishments remain unclear. Previous evidence implicates the anterior insula (AI) in evaluating the consequences of our own actions. However, it is unclear if the AI has a general role in feedback evaluation (positive and negative) or plays a specific role during error processing. Using functional magnetic resonance imaging and a motion prediction task, we investigate neural responses to self- and externally attributed monetary gains and losses. We found that attribution effects vary according to the valence of feedback: significant valence × attribution interactions in the right AI, the anterior cingulate cortex (ACC), the midbrain, and the right ventral putamen. Self-attributed losses were associated with increased activity in the midbrain, the ACC and the right AI, and negative BOLD response in the ventral putamen. However, higher BOLD activity to self-attributed feedback (losses and gains) was observed in the left AI, the thalamus, and the cerebellar vermis. These results suggest a functional lateralization of the AI. The right AI, together with the midbrain and the ACC, is mainly involved in processing the salience of the outcome, whereas the left is part of a cerebello-thalamic-cortical pathway involved in cognitive control processes important for subsequent behavioral adaptations.

Dysfunction of Cortical Dendritic Integration in Neuropathic Pain Reversed by Serotoninergic Neuromodulation

Neuropathic pain is caused by long-term modifications of neuronal function in the peripheral nervous system, the spinal cord, and supraspinal areas. Although functional changes in the forebrain are thought to contribute to the development of persistent pain, their significance and precise subcellular nature remain unexplored. Using somatic and dendritic whole-cell patch-clamp recordings from neurons in the anterior cingulate cortex, we discovered that sciatic nerve injury caused an activity-dependent dysfunction of hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels in the dendrites of layer 5 pyramidal neurons resulting in enhanced integration of excitatory postsynaptic inputs and increased neuronal firing. Specific activation of the serotonin receptor type 7 (5-HT7R) alleviated the lesion-induced pathology by increasing HCN channel function, restoring normal dendritic integration, and reducing mechanical pain hypersensitivity in nerve-injured animals in vivo. Thus, serotoninergic neuromodulation at the forebrain level can reverse the dendritic dysfunction induced by neuropathic pain and may represent a potential therapeutical target.

Violence-related PTSD and neural activation when seeing emotionally charged male-female interactions.

Post-traumatic stress disorder (PTSD) is a disorder that involves impaired regulation of the fear response to traumatic reminders. This study tested how women with male-perpetrated interpersonal violence-related PTSD (IPV-PTSD) differed in their brain activation from healthy controls (HC) when exposed to scenes of male-female interaction of differing emotional content. Sixteen women with symptoms of IPV-PTSD and 19 HC participated in this study. During magnetic resonance imaging, participants watched a stimulus protocol of 23 different 20 s silent epochs of male-female interactions taken from feature films, which were neutral, menacing or prosocial. IPV-PTSD participants compared with HC showed (i) greater dorsomedial prefrontal cortex (dmPFC) and dorsolateral prefrontal cortex (dlPFC) activation in response to menacing vs prosocial scenes and (ii) greater anterior cingulate cortex (ACC), right hippocampus activation and lower ventromedial prefrontal cortex (vmPFC) activty in response to emotional vs neutral scenes. The fact that IPV-PTSD participants compared with HC showed lower activity of the ventral ACC during emotionally charged scenes regardless of the valence of the scenes suggests that impaired social perception among IPV-PTSD patients transcends menacing contexts and generalizes to a wider variety of emotionally charged male-female interactions.

Visual avoidance in phobia: particularities in neural activity, autonomic responding, and cognitive risk evaluations.

We investigated the neural mechanisms and the autonomic and cognitive responses associated with visual avoidance behavior in spider phobia. Spider phobic and control participants imagined visiting different forest locations with the possibility of encountering spiders, snakes, or birds (neutral reference category). In each experimental trial, participants saw a picture of a forest location followed by a picture of a spider, snake, or bird, and then rated their personal risk of encountering these animals in this context, as well as their fear. The greater the visual avoidance of spiders that a phobic participant demonstrated (as measured by eye tracking), the higher were her autonomic arousal and neural activity in the amygdala, orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and precuneus at picture onset. Visual avoidance of spiders in phobics also went hand in hand with subsequently reduced cognitive risk of encounters. Control participants, in contrast, displayed a positive relationship between gaze duration toward spiders, on the one hand, and autonomic responding, as well as OFC, ACC, and precuneus activity, on the other hand. In addition, they showed reduced encounter risk estimates when they looked longer at the animal pictures. Our data are consistent with the idea that one reason for phobics to avoid phobic information may be grounded in heightened activity in the fear circuit, which signals potential threat. Because of the absence of alternative efficient regulation strategies, visual avoidance may then function to down-regulate cognitive risk evaluations for threatening information about the phobic stimuli. Control participants, in contrast, may be characterized by a different coping style, whereby paying visual attention to potentially threatening information may help them to actively down-regulate cognitive evaluations of risk.

Cortical control of facial expression.

The present topical review deals with the motor control of facial expressions in humans. Facial expressions are a central part of human communication. Emotional face expressions have a crucial role in human non-verbal behavior, allowing a rapid transfer of information between individuals. Facial expressions can be both voluntarily or emotionally controlled. Recent studies in non-human primates and humans revealed that the motor control of facial expressions has a distributed neural representation. At least 5 cortical regions on the medial and lateral aspects of each hemisphere are involved: the primary motor cortex, the ventral lateral premotor cortex, the supplementary motor area on the medial wall, and, finally, the rostral and caudal cingulate cortex. The results of studies in humans and non-human primates suggest that the innervation of the face is bilaterally controlled for the upper part, and mainly contralaterally controlled for the lower part. Furthermore, the primary motor cortex, the ventral lateral premotor cortex, and the supplementary motor area are essential for the voluntary control of facial expressions. In contrast, the cingulate cortical areas are important for emotional expression, since they receive input from different structures of the limbic system. This article is protected by copyright. All rights reserved.

Exploring the emotional brain: Neural correlates of homeostatic and sensory-evoked emotions and their interaction in emotional rivalry

Human emotions are essential for survival. They are vital for the satisfaction of basic needs, the regulation of personal life and successful integration into social structures. Depending on which aspect of an emotion is used in its definition, many different theories offer possible answers to the questions of what emotions are and how they can be distinguished. The systematic investigation of emotions in cognitive neuroscience is relatively new, and neuroimaging studies specifically focussing on the neural correlates of different categories of emotions are still lacking. Therefore, the current thesis aimed at investigating the behavioural and neurophysiological correlates of different human emotional levels and their interaction in healthy subjects. We differentiated between emotions according to their cerebral entry site and neural processing pathways: homeostatic emotions, which are elicited by metabolic changes and processed by the interoceptive system (such as thirst, hunger, and need for air), and sensory-evoked emotions, which are evoked by external inputs via the eyes, ears or nose, or their corresponding mental representations and processed in the brain as sensory perception (e.g. fear, disgust, or pride). Using functional magnetic resonance imaging (fMRI) and behavioural parameters, we examined both the specific neural underpinnings of a homeostatic emotion (thirst) and a sensory-evoked emotion (disgust), and their interaction in a situation of emotional rivalry when both emotions were perceived simultaneously. This thesis comprises three research articles reporting the results of this research. The first paper presents disgust-related brain imaging data in a thirsty and a satiated condition. We found that disgust mainly activated the anterior insular cortex. In the thirsty condition, however, we observed an interaction effect between disgust and thirst: when thirsty, the subjects rated the disgusting stimulus as less repulsive. On the neurobiological level, this reduction of subjective disgust was accompanied by significantly reduced neural activity in the insular cortex. These results provide new neurophysiological evidence for a hierarchical organization among homeostatic and sensory-evoked emotions, revealing that in a situation of emotional conflict, homeostatic emotions are prioritized over sensory-evoked emotions. In the second paper, findings on brain perfusion over four different thirst stages are reported, with a special focus on the parametric progression of thirst. Cerebral perfusion differences over all thirst stages were found in the posterior insular cortex. Taking this result together with the findings of the first paper, the insular cortex seems to be a key player in human emotional processing, since it comprises specific representations of homeostatic and sensory-evoked emotions and also represents the site of cortical interaction between the two levels of emotions. Finally, although this thesis focussed on the homeostatic modulation of disgust, we were also interested in whether dehydration modulates taste perception. The results of this behavioural experiment are described in the third paper, where we show that dehydration alters the perception of neutral taste stimuli.

Percutaneous screw fixation of the iliosacral joint: optimal screw pathways are frequently not completely intraosseous

INTRODUCTION In iliosacral screw fixation, the dimensions of solely intraosseous (secure) pathways, perpendicular to the ilio-sacral articulation (optimal) with corresponding entry (EP) and aiming points (AP) on lateral fluoroscopic projections, and the factors (demographic, anatomic) influencing these have not yet been described. METHODS In 100 CTs of normal pelvises, the height and width of the secure and optimal pathways were measured on axial and coronal views bilaterally (total measurements: n=200). Corresponding EP and AP were defined as either the location of the screw head or tip at the crossing of lateral innominate bones' cortices (EP) and sacral midlines (AP) within the centre of the pathway, respectively. EP and AP were transferred to the sagittal pelvic view using a coordinate system with the zero-point in the centre of the posterior cortex of the S1 vertebral body (x-axis parallel to upper S1 endplate). Distances are expressed in relation to the anteroposterior distance of the S1 upper endplate (in %). The influence of demographic (age, gender, side) and/or anatomic (PIA=pelvic incidence angle; TCA=transversal curvature angle, PID-Index=pelvic incidence distance-index; USW=unilateral sacral width-index) parameters on pathway dimensions and positions of EP and AP were assessed (multivariate analysis). RESULTS The width, height or both factors of the pathways were at least 7mm or more in 32% and 53% or 20%, respectively. The EP was on average 14±24% behind the centre of the posterior S1 cortex and 41±14% below it. The AP was on average 53±7% in the front of the centre of the posterior S1 cortex and 11±7% above it. PIA influenced the width, TCA, PID-Index the height of the pathways. PIA, PID-Index, and USW-Index significantly influenced EP and AP. Age, gender, and TCA significantly influenced EP. CONCLUSION Secure and optimal placement of screws of at least 7mm in diameter will be unfeasible in the majority of patients. Thoughtful preoperative planning of screw placement on CT scans is advisable to identify secure pathways with an optimal direction. For this purpose, the presented methodology of determining and transferring EPs and APs of corresponding pathways to the sagittal pelvic view using a coordinate system may be useful.

Theta burst stimulation improves overt visual search in spatial neglect independently of attentional load

Visual neglect is considerably exacerbated by increases in visual attentional load. These detrimental effects of attentional load are hypothesised to be dependent on an interplay between dysfunctional inter-hemispheric inhibitory dynamics and load-related modulation of activity in cortical areas such as the posterior parietal cortex (PPC). Continuous Theta Burst Stimulation (cTBS) over the contralesional PPC reduces neglect severity. It is unknown, however, whether such positive effects also operate in the presence of the detrimental effects of heightened attentional load. Here, we examined the effects of cTBS on neglect severity in overt visual search (i.e., with eye movements), as a function of high and low visual attentional load conditions. Performance was assessed on the basis of target detection rates and eye movements, in a computerised visual search task and in two paper-pencil tasks. cTBS significantly ameliorated target detection performance, independently of attentional load. These ameliorative effects were significantly larger in the high than the low load condition, thereby equating target detection across both conditions. Eye movement analyses revealed that the improvements were mediated by a redeployment of visual fixations to the contralesional visual field. These findings represent a substantive advance, because cTBS led to an unprecedented amelioration of overt search efficiency that was independent of visual attentional load.

Structural Organization of the Corpus Callosum Predicts Attentional Shifts after Continuous Theta Burst Stimulation

Repetitive transcranial magnetic stimulation (rTMS) applied over the right posterior parietal cortex (PPC) in healthy participants has been shown to trigger a significant rightward shift in the spatial allocation of visual attention, temporarily mimicking spatial deficits observed in neglect. In contrast, rTMS applied over the left PPC triggers a weaker or null attentional shift. However, large interindividual differences in responses to rTMS have been reported. Studies measuring changes in brain activation suggest that the effects of rTMS may depend on both interhemispheric and intrahemispheric interactions between cortical loci controlling visual attention. Here, we investigated whether variability in the structural organization of human white matter pathways subserving visual attention, as assessed by diffusion magnetic resonance imaging and tractography, could explain interindividual differences in the effects of rTMS. Most participants showed a rightward shift in the allocation of spatial attention after rTMS over the right intraparietal sulcus (IPS), but the size of this effect varied largely across participants. Conversely, rTMS over the left IPS resulted in strikingly opposed individual responses, with some participants responding with rightward and some with leftward attentional shifts. We demonstrate that microstructural and macrostructural variability within the corpus callosum, consistent with differential effects on cross-hemispheric interactions, predicts both the extent and the direction of the response to rTMS. Together, our findings suggest that the corpus callosum may have a dual inhibitory and excitatory function in maintaining the interhemispheric dynamics that underlie the allocation of spatial attention. SIGNIFICANCE STATEMENT: The posterior parietal cortex (PPC) controls allocation of attention across left versus right visual fields. Damage to this area results in neglect, characterized by a lack of spatial awareness of the side of space contralateral to the brain injury. Transcranial magnetic stimulation over the PPC is used to study cognitive mechanisms of spatial attention and to examine the potential of this technique to treat neglect. However, large individual differences in behavioral responses to stimulation have been reported. We demonstrate that the variability in the structural organization of the corpus callosum accounts for these differences. Our findings suggest novel dual mechanism of the corpus callosum function in spatial attention and have broader implications for the use of stimulation in neglect rehabilitation.