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Health-related quality of life is likely associated with the brain via processes relating to physiology, behavior, cognition, emotion and stress. Previous studies with small student or clinical samples have identified associations with gray matter volume in the anterior cingulate cortex, prefrontal cortex, insular cortex, (para)hippocampal area, amygdala, and precuneus. The present study investigated the association of gray matter volume of these brain areas with mental and physical components of health, as well as general health perception, measured with the 12-item Short Form Health Survey, in a large sample of 3027 participants from the Study of Health in Pomerania, using voxel-based morphometry for T1-weighted magnetic resonance imaging. Higher physical, but not mental, health-related quality of life and general health perception were associated with larger gray matter volume of the anterior cingulate cortex, medial prefrontal cortex, insular cortex, and the precuneus with a substantial decrease when controlling for lifestyle, comorbidity and symptoms. Age-stratified analyses revealed significantly higher partial correlations of physical health and left insular gray matter volume in the oldest age group. Our study emphasizes the importance of high medial prefrontal and anterior insula gray matter volume for health-related quality of life on the basis of a large sample size., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The corpus callosum (CC) is the largest white matter structure of the brain and offers the structural basis for an intense interaction between both cerebral hemispheres. Especially with respect to the interaction of both motor cortices it shows a differentiated somatotopic organization. Neuropathological processes are often reflected in structural alterations of the CC and a spatially precise description of structures for the healthy brain is essential for further differentiation of structural damage in patients. We performed a fine-grained parcellation of the CC on 1065 diffusion-weighted data sets of the Human Connectome Project. Interhemispheric tractograms between interhemispherically corresponding functional subdivisions of the primary motor cortex (M1; Brainnetome Atlas) were calculated, transformed into a common space, averaged and thresholded, to be assessed for localization, fractional anisotropy (FA) and mean diffusivity (MD). Spatially distinct CC regions for each functional M1 subdivision (lower and upper limbs, head/face, tongue/larynx) were identified and will be available as anatomical masks. Non-parametrical statistics for the average FA and MD values showed significant differences between all callosal regions. The newly proposed callosal regions allow for a precise differentiation of M1-M1 motor connectivity and the structural integrity of these tracts. Availability of masked regions in a common space will help to better understand inter-hemispherical callosal connectivity in patients or healthy volunteers.

While the significance of auditory cortical regions for the development and maintenance of speech motor coordination is well established, the contribution of somatosensory brain areas to learned vocalizations such as singing is less well understood. To address these mechanisms, we applied intermittent theta burst stimulation (iTBS), a facilitatory repetitive transcranial magnetic stimulation (rTMS) protocol, over right somatosensory larynx cortex (S1) and a nonvocal dorsal S1 control area in participants without singing experience. A pitch-matching singing task was performed before and after iTBS to assess corresponding effects on vocal pitch regulation. When participants could monitor auditory feedback from their own voice during singing (Experiment I), no difference in pitch-matching performance was found between iTBS sessions. However, when auditory feedback was masked with noise (Experiment II), only larynx-S1 iTBS enhanced pitch accuracy (50-250 ms after sound onset) and pitch stability (>250 ms after sound onset until the end). Results indicate that somatosensory feedback plays a dominant role in vocal pitch regulation when acoustic feedback is masked. The acoustic changes moreover suggest that right larynx-S1 stimulation affected the preparation and involuntary regulation of vocal pitch accuracy, and that kinesthetic-proprioceptive processes play a role in the voluntary control of pitch stability in nonsingers. Together, these data provide evidence for a causal involvement of right larynx-S1 in vocal pitch regulation during singing., (© 2019 Wiley Periodicals, Inc.)

Biomarkers indicating characteristic alterations in the brains of pain patients would in comparison to behavioral examinations allow for earlier diagnoses of pain disease development, a more immediate monitoring of pain disease progression, and for the development of interventions to reverse or compensate for the alterations. To reveal causal relations between an observed alteration and the pain disease longitudinal examinations are essential. Resting-state fMRI examinations can readily be included in large longitudinal cohorts allowing to achieve sufficiently large patient samples even for rare diseases. Our literature review on longitudinal resting-state fMRI examinations of pain patients indicates that pain chronicity is predicted by alterations to the brain's reward system and default mode network. A brain wide reorganization of the resting-state networks is associated with the emergence of the chronic pain state. The functional connectivity of the left frontoparietal network predicts the evolution of pain intensity in the chronic state. Further investigations are necessary concerning the generalization of the biomarkers across the phases in pain development especially for the healthy state, across different pain etiologies, and their specificity to chronic pain. The currently acquired representative longitudinal cohorts will allow for clarification of those issues within the next decades., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Neural plasticity is the basis for an adaptation process of functional and structural characteristics of the nervous system in response to a changing environment. However, changes during training in healthy volunteers are only partially comparable to that observed in patients with circumscribed lesions. Pathologies can even be associated with maladaptive plasticity. We first introduce basic processes underlying brain plasticity with respect to the sensorimotor system and outline their limitations. A number of methods showing potential in the evaluation of these processes are compared before literature on postlesional plasticity is reviewed. Approaches in monitoring plasticity processes of the healthy sensorimotor system are partially applicable after brain damage and for the documentation of recovery processes. Some of these techniques can further be used for outcome prediction or therapy selection and optimization. Extreme examples from athletes or professional musicians illustrate the amount of plastic changes the human brain can achieve. Profound understanding of neural plasticity in health and disease will help to modify and individually optimize therapy strategies in neurorehabilitation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

There is still disagreement among studies with respect to the magnitude, location, and direction of sex differences of local gray matter volume (GMV) in the human brain. Here, we applied a state-of-the-art technique examining GMV in a well-powered sample (n = 2,838) validating effects in two independent general-population cohorts, age range 21-90 years, measured using the same MRI scanner. More GMV in women than in men was prominent in medial and lateral prefrontal areas, the superior temporal sulcus, the posterior insula, and orbitofrontal cortex. In contrast, more GMV in men than in women was detected in subcortical temporal structures, such as the amygdala, hippocampus, temporal pole, fusiform gyrus, visual primary cortex, and motor areas (premotor cortex, putamen, anterior cerebellum). The findings in this large-scale study may clarify previous inconsistencies and contribute to the understanding of sex-specific differences in cognition and behavior.

Age-related decline in interhemispheric connectivity between motor areas has been reported with both transcranial magnetic stimulation (TMS) and diffusion tensor imaging (DTI) measurements. However, not all studies were able to confirm these findings, and previous studies did not apply structural (DTI) and functional (TMS) measurements within each individual appropriately. Here, we investigated age dependency of the ipsilateral silent period (ISP) and integrity of fibers in the corpus callosum as operationalized by fractional anisotrophy (FA), using TMS and DTI, respectively, in 20 participants between 19 and 72 years of age. We found age-dependent increase for ISP, and decrease of FA, both indicating a decrease in interhemispheric inhibition, with a negative association between FA and ISP for the dominant hemisphere ( r = -0.39, p = 0.043). Our findings suggest that aging leads to decline of interhemispheric motor connectivity, as evidenced in both structural and functional parameters, which should be taken into account when interpreting disease- or medication-related changes.

To examine the association between the amount of sports activity performed during leisure time and gray matter volume (GMV) of the brain we investigated differences in GMV in a large cohort study of community-dwelling older adults. 967 individuals indicated their average weekly sports activity via a questionnaire, and underwent high resolution T1-weighted structural imaging of the brain. We used voxel based morphometry (CAT 12) in a region of interest approach for (1) comparing participants with higher versus lower sports activity (median split) and (2) calculating a linear regression on GMV and sports activity. We carefully corrected for other factors known to have an impact on GMV (sex, age, total brain volume, education, cigarettes and alcohol consumption, body mass index) and excluded pathology (history of psychiatric or neurological disease; visual inspection of brain scans). Those participants who spend more time performing sports activity per week (median split with > 1 h/week) showed higher GMV in the dorsomedial frontal lobe, the superior parietal lobe, and the precuneus/cuneus area. When splitting participants by their median (55.5 years) into two groups we found a stronger protective effect of sports against age related GMV decline for the older part of the cohort. Overall, a more active lifestyle was associated with increased GMV in areas associated with self-awareness and working memory. These cohort data support data on the protective role of sports activity for the GMV., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Patients with a complex regional pain syndrome (CRPS) in the upper limb show a sensory and motor impairment of the hand. Decreased intra-cortical-inhibition (ICI) of the motor representation of the affected hand muscle and decreased somatosensory hand representation size were related to maladaptive plasticity., Objective: To achieve new insights about CRPS we examined whether these alterations were present in a single cohort., Methods: We used a multi-modal approach comprising behavioral testing, transcranial magnetic stimulation, and high resolution fMRI combined with a new analysis technique for improved neuronal specificity., Results: We found a decreased pinch-grip performance, two-point discrimination on the fingertips, ICI in the motor cortex, and representation size of the hand in Brodmann Area 3b (BA3b) in the somatosensory cortex. Our analysis further showed that correlations with ICI on the non-affected side were absent on the affected side., Conclusions: This study is the first to gather behavioral, neurophysiologic and imaging measurements for one patient cohort and it therefore enables a comprehensive view of collapsed associations of function and representation focused on the hemisphere contralateral to the affected hand.

Arm Ability Training (AAT) has been specifically designed to promote manual dexterity recovery for stroke patients who have mild to moderate arm paresis. The motor control problems that these patients suffer from relate to a lack of efficiency in terms of the sensorimotor integration needed for dexterity. Various sensorimotor arm and hand abilities such as speed of selective movements, the capacity to make precise goal-directed arm movements, coordinated visually guided movements, steadiness, and finger dexterity all contribute to our "dexterity" in daily life. All these abilities are deficient in stroke patients who have mild to moderate paresis causing focal disability. The AAT explicitly and repetitively trains all these sensorimotor abilities at the individual's performance limit with eight different tasks; it further implements various task difficulty levels and integrates augmented feedback in the form of intermittent knowledge of results. The evidence from two randomized controlled trials indicates the clinical effectiveness of the AAT with regard to the promotion of "dexterity" recovery and the reduction of focal disability in stroke patients with mild to moderate arm paresis. In addition, the effects have been shown to be superior to time-equivalent "best conventional therapy." Further, studies in healthy subjects showed that the AAT induced substantial sensorimotor learning. The observed learning dynamics indicate that different underlying sensorimotor arm and hand abilities are trained. Capacities strengthened by the training can, in part, be used by both arms. Non-invasive brain stimulation experiments and functional magnetic resonance imaging data documented that at an early stage in the training cortical sensorimotor network areas are involved in learning induced by the AAT, yet differentially for the tasks trained. With prolonged training over 2 to 3 weeks, subcortical structures seem to take over. While behavioral similarities in training responses have been observed in healthy volunteers and patients, training-induced functional re-organization in survivors of a subcortical stroke uniquely involved the ipsilesional premotor cortex as an adaptive recruitment of this secondary motor area. Thus, training-induced plasticity in healthy and brain-damaged subjects are not necessarily the same.

Background: Biomarkers for gains of evidence based interventions for upper limb motor training in the subacute stage following stroke have rarely been described. Information about these parameters might help to identify patients who benefit from specific interventions and to determine individually expected behavioral gains for a certain period of therapy. Objective: To evaluate predictors for hand motor outcome after arm ability training in the subacute stage after stroke selected from known potentially relevant parameters (initial motor strength, structural integrity of the pyramidal tract and functional motor cortex integrity). Methods: We applied the arm ability training (AAT) over 3 weeks to a subpopulation of stroke patients with mild arm paresis, i.e., in 14 patients on average 4 weeks after stroke. The following biomarkers were measured before therapy onset: grip strength on the affected hand, transcranial magnetic stimulation recruitment curve steepness over the primary motor hand area [slope ratio between the ipsilesional hemisphere (IH) and contralesional hemisphere (CH)], and diffusion weighted MRI fractional anisotropy (FA) in the posterior limb of the internal capsule (PLIC; determined as a lateralization index between IH and CH). Outcome was assessed as the AATgain (percentage improvement over training). The "Test d'Evaluation des Membres Supérieurs de Personnes Âgées" (TEMPA) was assessed before and after training to test for possible associations of AAT with activity of daily living. Results: A stepwise linear regression identified the lateralization index of PLIC FA as the only significant predictor for AAT-gain ( R 2 = 0.519; P = 0.029). AAT-gain was positively associated ( r = 0.59; P = 0.028) with improvement in arm function during daily activities (TEMPA). Conclusions: While all mildly affected patients achieved a clinically relevant therapeutic effect, pyramidal tract integrity nevertheless had a modifying role for clinical benefit.

Continuous practice modulates those features of brain anatomy specifically associated with requirements of the respective training task. This study aimed to highlight brain structural changes going along with long-term experience in creative writing. To this end, we investigated the grey matter volume of 23 expert writers with voxel-based morphometry and compared it to 28 matched nonexpert controls. Expert writers had higher grey matter volume in the right superior frontal and middle frontal gyri (BA 9,10) as well as left middle frontal gyrus (BA 9, 10, 46), the bilateral medial dorsal nuclei of the thalamus and left posterior cerebellum. A regression analysis confirmed the association of enhanced grey matter volume in the right superior frontal gyrus (BA 10) with practice index of writing. In region-of-interest based regression analyses, we found associations of grey matter volume in the right Broca's analogue (BA 44) and right primary visual cortex (BA 17) with creativity ratings of the texts written during scanning, but not with a standardised verbal creativity test. Creative writing thus seems to be strongly connected to a prefronto-thalamic-cerebellar network that supports the continuous generation, organisation and revision of ideas that is necessary to write literary texts., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Motor imagery (MI) is the mental simulation of action frequently used by professionals in different fields. However, with respect to performance, well-controlled functional imaging studies on MI training are sparse. We investigated changes in fMRI representation going along with performance changes of a finger sequence (error and velocity) after MI training in 48 healthy young volunteers. Before training, we tested the vividness of kinesthetic and visual imagery. During tests, participants were instructed to move or to imagine moving the fingers of the right hand in a specific order. During MI training, participants repeatedly imagined the sequence for 15 min. Imaging analysis was performed using a full-factorial design to assess brain changes due to imagery training. We also used regression analyses to identify those who profited from training (performance outcome and gain) with initial imagery scores (vividness) and fMRI activation magnitude during MI at pre-test (MI pre ). After training, error rate decreased and velocity increased. We combined both parameters into a common performance index. FMRI activation in the left inferior parietal lobe (IPL) was associated with MI and increased over time. In addition, fMRI activation in the right IPL during MI pre was associated with high initial kinesthetic vividness. High kinesthetic imagery vividness predicted a high performance after training. In contrast, occipital activation, associated with visual imagery strategies, showed a negative predictive value for performance. Our data echo the importance of high kinesthetic vividness for MI training outcome and consider IPL as a key area during MI and through MI training., (© 2018 Wiley Periodicals, Inc.)

Functional imaging studies on mental rotation of hands have consistently pointed to the importance of the motor network implying the use of motor simulations for task solving. There is some evidence that the putamen may be a critical modulator of processing egocentric spatial orientation in mental rotation of hands and implicit motor imagery strategies have been described involving hand motor areas. This recruitment of resources processing representations of the own body is used in therapeutic mental rotation training. However, studies are lacking that investigate training-induced changes on the neuronal level. We used functional MRI to study the effects of long-term training on the neuro-functional correlates of mental rotation of hands in healthy volunteers and compared the training group to a passive control group. From pre- to post training, we found a transition of activation from the anterior putamen in unskilled performance to the posterior putamen in skilled performance. We also found an increase in activation in motor cortices and the supramarginal gyrus after learning. By contrast, members of the control group showed no improvements in performance and no pre/post-test differences in cortical activity. In conclusion, these findings suggest that increased neural efficiency after training in mental rotation of hands manifests as a decrease in visual imagery in conjunction with increased recruitment of motor-related regions. This is consistent with the obtained behavioral effects depicting motor imagery mediating expertise in mental rotation of hands., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Facial expressions and voice modulations are among the most important communicational signals to convey emotional information. The ability to correctly interpret this information is highly relevant for successful social interaction and represents an integral component of emotional competencies that have been conceptualized under the term emotional intelligence. Here, we investigated the relationship of emotional intelligence as measured with the Salovey-Caruso-Emotional-Intelligence-Test (MSCEIT) with cerebral voice and face processing using functional and structural magnetic resonance imaging. MSCEIT scores were positively correlated with increased voice-sensitivity and gray matter volume of the insula accompanied by voice-sensitivity enhanced connectivity between the insula and the temporal voice area, indicating generally increased salience of voices. Conversely, in the face processing system, higher MSCEIT scores were associated with decreased face-sensitivity and gray matter volume of the fusiform face area. Taken together, these findings point to an alteration in the balance of cerebral voice and face processing systems in the form of an attenuated face-vs-voice bias as one potential factor underpinning emotional intelligence.

Background: Motor rehabilitation after brain damage relies on motor re-learning as induced by specific training. Non-invasive brain stimulation (NIBS) can alter cortical excitability and thereby has a potential to enhance subsequent training-induced learning. Knowledge about any priming effects of NIBS on motor learning in healthy subjects can help to design targeted therapeutic applications in brain-damaged subjects., Objective: To examine whether complex motor learning in healthy subjects can be enhanced by intermittent theta burst stimulation (iTBS) to primary motor or sensory cortical areas., Methods: Eighteen young healthy subjects trained eight different arm motor tasks (arm ability training, AAT) once a day for 5 days using their left non-dominant arm. Except for day 1 (baseline), training was performed after applying an excitatory form of repetitive transcranial magnetic stimulation (iTBS) to either (I) right M1 or (II) S1, or (III) sham stimulation to the right M1. Subjects were randomly assigned to conditions I, II, or III., Results: A principal component analysis of the motor behaviour data suggested eight independent motor abilities corresponding to the 8 trained tasks. AAT induced substantial motor learning across abilities with generalisation to a non-trained test of finger dexterity (Nine-Hole-Peg-Test, NHPT). Participants receiving iTBS (to either M1 or S1) showed better performance with the AAT tasks over the period of training compared to sham stimulation as well as a bigger improvement with the generalisation task (NHPT) for the trained left hand after training completion., Conclusion: Priming with an excitatory repetitive transcranial magnetic stimulation as iTBS of either M1 or S1 can enhance motor learning across different sensorimotor abilities.

Both histological and neuroimaging studies highlight the role of the cerebellum in multiple sclerosis (MS). There is at least some evidence for associations of cerebellar gray matter (GM) loss with motor and cognitive ability. We therefore correlated motor and cognitive ability scores (the multiple sclerosis functional composite MSFC) with regional cerebellar GM volumes. We used voxel-based morphometry (VBM) to assess the regional GM volume loss in a cohort of 45 MS patients. For the regression analysis, we used the clinical subscores of the multiple sclerosis functional composite (25-ft walk test (T25FW), nine-hole peg test (9HPT), paced auditory serial addition task (PASAT)). Decreased GM in distinct cerebellar areas was associated with different subscores of the MSFC in Larsell's lobule VI with the T25FW (t = 5.16), in lobule IX with the 9HPT (t = 3.95), and in lobule IX with the PASAT (t = 4.81). Regional volume decrease in distinct cerebellar areas involved in motor and cognitive domains were associated with clinical impairment in these fields. Our data confirm the relationship between cerebellar GM volume loss and disability, extending the knowledge in the functional neuroanatomical perspective.

Background: Randomized clinical trials (RCT) demonstrated that auricular acupuncture (AA) is effective in treatment of acute and chronic pain, although the mechanisms behind AA are not elucidated., Methods: The data concerning the localization of AA points, which are commonly used to treat pain, were extracted from the meta-analysis of 17 RCTs and evaluated using the anatomical map of auricular afferent nerve supply., Results: Fifteen out of 20 specific AA points, used in the treatment of pain, are situated in areas innervated mostly by the auricular branch of the vagal nerve (ABVN), whereas sham stimulation was applied at the helix of the auricle, innervated by cervical nerves., Conclusion: Considering the clinical data relating to the anatomy of neural pathways and experimental findings of the mechanisms of transcutaneous auricular vagal nerve stimulation, the analgesic effects of AA may be explained by stimulation of ABVN., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background & Aims: Induction of nonapoptotic cell death could be an approach to eliminate apoptosis-resistant tumors. We investigated necroptosis-based therapies in mouse models of pancreatic ductal adenocarcinoma cancer (PDAC)., Methods: We screened 273 commercially available kinase inhibitors for cytotoxicity against a human PDAC cell line (PANC1). We evaluated the ability of the aurora kinase inhibitor CCT137690 to stimulate necroptosis in PDAC cell lines (PANC1, PANC2.03, CFPAC1, MiaPaCa2, BxPc3, and PANC02) and the HEK293 cell line, measuring loss of plasma membrane integrity, gain in cell volume, swollen organelles, and cytoplasmic vacuoles. We tested the effects of CCT137690 in colon formation assays, and the effects of the necroptosis (necrostatin-1 and necrosulfonamide), apoptosis, autophagy, and ferroptosis inhibitors. We derived cells from tumors that developed in Pdx1-Cre;K-Ras G12D/+ ;p53 R172H/+ (KPC) mice. Genes encoding proteins in cell death pathways were knocked out, knocked down, or expressed from transgenes in PDAC cell lines. Athymic nude or B6 mice were given subcutaneous injections of PDAC cells or tail-vein injections of KPC tumor cells. Mice were given CCT137690 (80 mg/kg) or vehicle and tumor growth was monitored; tumor tissues were collected and analyzed by immunohistochemistry. We compared gene expression levels between human pancreatic cancer tissues (n = 130) with patient survival times using the online R2 genomics analysis and visualization platform., Results: CCT137690 induced necrosis-like death in PDAC cell lines and reduced colony formation; these effects required RIPK1, RIPK3, and MLKL, as well as inhibition of aurora kinase A (AURKA). AURKA interacted directly with RIPK1 and RIPK3 to reduce necrosome activation. AURKA-mediated phosphorylation of glycogen synthase kinase 3 beta (GSK3β) at serine 9 inhibited activation of the RIPK3 and MLKL necrosome. Mutations in AURKA (D274A) or GSK3β (S9A), or pharmacologic inhibitors of RIPK1 signaling via RIPK3 and MLKL, reduced the cytotoxic activity of CCT137690 in PDAC cells. Oral administration of CCT137690 induced necroptosis and immunogenic cell death in subcutaneous and orthotopic tumors in mice, and reduced tumor growth and tumor cell phosphorylation of AURKA and GSK3β. CCT137690 increased survival times of mice with orthotopic KPC PDACs and reduced tumor growth, stroma, and metastasis. Increased expression of AURKA and GSK3β mRNAs associated with shorter survival times of patients with pancreatic cancer., Conclusions: We identified the aurora kinase inhibitor CCT137690 as an agent that induces necrosis-like death in PDAC cells, via RIPK1, RIPK3, and MLKL. CCT137690 slowed growth of orthotopic tumors from PDAC cells in mice, and expression of AURKA and GSK3β associate with patient survival times. AURKA might be targeted for treatment of pancreatic cancer., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

In the present study, we investigated whether inter-individual differences in vagally-mediated cardiac activity (high frequency heart rate variability, HF-HRV) would be associated with inter-individual differences in mind-reading, a specific aspect of social cognition. To this end, we recorded resting state HF-HRV in 49 individuals before they completed the Reading the Mind in the Eyes Test, a test that required the identification of mental states on basis of subtle facial cues. As expected, inter-individual differences in HF-HRV were associated with inter-individual differences in mental state identification: Individuals with high HF-HRV were more accurate in the identification of positive but not negative states than individuals with low HF-HRV. Individuals with high HF-HRV may, thus, be more sensitive to positive states of others, which may increase the likelihood to detect cues that encourage approach and affiliative behavior in social contexts. Inter-individual differences in mental state identification may, thus, explain why individuals with high HF-HRV have been shown to be more successful in initiating and maintaining social relationships than individuals with low HF-HRV.

Defensive behaviors in animals and humans vary dynamically with increasing proximity of a threat and depending upon the behavioral repertoire at hand. The current study investigated physiological and behavioral adjustments and associated brain activation when participants were exposed to dynamically approaching threat that was either inevitable or could be avoided by motor action. When the approaching threat was inevitable, attentive freezing was observed as indicated by fear bradycardia, startle potentiation, and a dynamic increase in activation of the anterior insula and the periaqueductal grey. In preparation for active avoidance a switch in defensive behavior was observed characterized by startle inhibition and heart rate acceleration along with potentiated activation of the amygdala and the periaqueductal grey. Importantly, the modulation of defensive behavior according to threat imminence and the behavioral option at hand was associated with activity changes in the ventromedial prefrontal cortex. These findings improve our understanding of brain mechanisms guiding human behavior during approaching threat depending on available resources., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Functional magnetic resonance imaging (fMRI) is one of the most advanced techniques to analyze the cerebral effects on many behavior aspects of the oral system such as chewing and mastication. Studies on imaging of the cerebral representation of chewing demonstrated differential results with respect to cortical lateralization during unilateral chewing. The aim of our study is to clarify the effects of cerebral responses during unilateral chewing., Material and Methods: We used fMRI to compare brain activities during occlusal function in centric occlusion on natural teeth and chewing on a gum located on the right or the left teeth in 15 healthy subjects. Group data were performed by Talairach normalization and in addition by an assignment of activation maxima to individual anatomical landmarks in order to avoid possible loss of spatial preciseness of activation sites by normalization procedures., Results: Evaluation of group data by Talairach normalization revealed representation sites for occlusal movements in bilateral primary (S1) and secondary (S2) somatosensory cortices, primary motor (M1) and premotor cortices, supplementary motor area (SMA) and medial cingulate gyrus, bilateral anterior cerebellar hemispheres and vermis, insula, orbitofrontal cortex, thalamus, and left pallidum. Right-sided chewing showed no differential activation to left-sided chewing, and both showed activation in areas also involved in bilateral occlusion. Both techniques, the one based on group normalization and the one based on an individual evaluation method, revealed remarkable low differences in activation maximum location in the primary motor, the primary and secondary somatosensory cortices, and the anterior cerebellar lobe. All chewing movements tested involved bilateral sensorimotor activation without a significant lateralization of activation intensities., Conclusion: Overall, a general lateralization of occlusion movements to the dominant side could not be verified in the present study. Chewing on the left or on the right side of teeth makes no difference for brain representation of chewing., Clinical Relevance: The results describe the basic effects of what we can expect by evaluation of cerebral effects of chewing and mastication. Based on these results, clinical fMRI studies can be performed in different patient groups.

Structural alterations in the corpus callosum (CC), the major white matter tract connecting functionally related brain regions in the two hemispheres, have been shown to be associated with emotional instability, impulsivity and suicidality in various mental disorders. To explore whether structural alterations of the CC would be similarly associated with emotional instability, impulsivity and suicidality in borderline personality disorder (BPD), we used diffusion tensor imaging (DTI) to assess the structural integrity of the CC in 21 BPD and 20 healthy control (HC) participants. Our hypothesis-driven analyses revealed a positive correlation between BPD participants' suicidal behavior and fractional anisotropy (FA) in the splenium and genu of the CC and a negative correlation between BPD participants' suicidal behavior and mean diffusivity (MD) in the splenium of CC. Our exploratory analyses suggested that suicidal BPD participants showed less FA and more MD in these regions than HC participants but that non-suicidal BPD participants showed similar FA and MD in these regions as HC participants. Taken together, our findings suggest an association between BPD participants' suicidal behavior and structural alterations in regions of the CC that are connected with brain regions implicated in emotion regulation and impulse control. Structural alterations of the CC may, thus, account for deficits in emotion regulation and impulse control that lead to suicidal behavior in BPD. However, these findings should be considered as preliminary until replicated and extended in future studies that comprise larger samples of suicidal and non-suicidal BPD participants.

Repetitive unilateral upper limb motor training does not only affect behavior but also increases excitability of the contralateral primary motor cortex (M1). The behavioral gain is partially transferred to the non-trained side. Changes in M1 intracortical facilitation (ICF) might as well be observed for both hand sides. We measured ICF of both left and right abductor pollicis brevis muscles (APB) before and after a two-week period of arm ability training (AAT) of the left hand in 13 strongly right handed healthy volunteers. Performance with AAT-tasks improved for both the left trained and right untrained hand. ICF for the untrained hand decreased over training while it remained unchanged for the left trained hand. Decrease of ICF for the right hand was moderately associated with an increase of AAT-performance for the untrained right hand. We conclude that ICF-imbalance between dominant and non-dominant hand is sensitive to long-term motor training: training of the non-dominant hand results in a decrease of ICF of the dominant hand. The ICF-decrease is associated with a transfer of training-induced improvement of performance from the non-dominant to the dominant hand., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Recent population studies suggest an intriguing inverse relationship between several types of cancer and neurodegenerative diseases, including Alzheimer's disease. Understanding the intersection of the underlying biology for these two distinct families of diseases with one another may offer novel approaches to identify new therapeutic approaches and possible opportunities to repurpose existing drug candidates. The Alzheimer's Association and the Alzheimer's Drug Discovery Foundation convened a one-day workshop to delve into this discussion. Workshop participants outlined research focus areas, potential collaborations, and partnerships for future action., (Copyright © 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Transcutaneous vagal nerve stimulation (TVNS) is a promising complementary method of pain relief. However, the neural networks associated with its analgesic effects are still to be elucidated. Therefore, we conducted two functional magnetic resonance imaging (fMRI) sessions, in a randomized order, with twenty healthy subjects who were exposed to experimental heat pain stimulation applied to the right forearm using a Contact Heat-Evoked Potential Stimulator. While in one session TVNS was administered bilaterally to the concha auriculae with maximal, non-painful intensity, the stimulation device was switched off in the other session (placebo condition). Pain thresholds were measured before and after each session. Heat stimulation elicited fMRI activation in cerebral pain processing regions. Activation magnitude in the secondary somatosensory cortex, posterior insula, anterior cingulate and caudate nucleus was associated with heat stimulation without TVNS. During TVNS, this association was only seen for the right anterior insula. TVNS decreased fMRI signals in the anterior cingulate cortex in comparison with the placebo condition; however, there was no relevant pain reducing effect over the group as a whole. In contrast, TVNS compared to the placebo condition showed an increased activation in the primary motor cortex, contralateral to the site of heat stimulation, and in the right amygdala. In conclusion, in the protocol used here, TVNS specifically modulated the cerebral response to heat pain, without having a direct effect on pain thresholds.

Background: The particular function of the left anterior human insula on emotional arousal has been illustrated with several case studies. Only after left hemispheric insula lesions, patients lose their pleasure in habits such as listening to joyful music. In functional magnetic resonance imaging studies (fMRI) activation in the left anterior insula has been associated with both processing of emotional valence and arousal. Tight interactions with different areas of the prefrontal cortex are involved in bodily response monitoring and cognitive appraisal of a given stimulus. Therefore, a large left hemispheric lesion including the left insula should impair the bodily response of chill experience (objective chill response) but leave the cognitive aspects of chill processing (subjective chill response) unaffected. Methods: We investigated a patient (MC) with a complete left hemispheric media cerebral artery stroke, testing fMRI representation of pleasant (music) and unpleasant (harsh sounds) chill response. Results: Although chill response to both pleasant and unpleasant rated sounds was confirmed verbally at passages also rated as chilling by healthy participants, skin conductance response was almost absent in MC. For a healthy control (HC) objective and subjective chill response was positively associated. Bilateral prefrontal fMRI-response to chill stimuli was sustained in MC whereas insula activation restricted to the right hemisphere. Diffusion imaging together with lesion maps revealed that left lateral tracts were completely damaged but medial prefrontal structures were intact. Conclusion: With this case study we demonstrate how bodily response and cognitive appraisal are differentially participating in the internal monitor of chill response.

Background: Application of repetitive electrical stimulation (rES) of the fingers has been shown to improve tactile perception and sensorimotor performance in healthy individuals., Objective: To increase motor performance by priming the effects of active motor training (arm ability training; AAT) using rES., Methods: We compared the performance gain for the training increase of the averaged AAT tasks of both hands in two groups of strongly right-handed healthy volunteers. Functional Magnetic Resonance Imaging (fMRI) before and after AAT was assessed using three tasks for each hand separately: finger sequence tapping, visually guided grip force modulation, and writing. Performance during fMRI was controlled for preciseness and frequency. A total of 30 participants underwent a two-week unilateral left hand AAT, 15 participants with 20 minutes of rES priming of all fingertips of the trained hand, and 15 participants without rES priming., Results: rES-primed AAT improved the trained left-hand performance across all training tasks on average by 32.9%, non-primed AAT improved by 29.5%. This gain in AAT performance with rES priming was predominantly driven by an increased finger tapping velocity. Functional imaging showed comparable changes for both training groups over time. Across all participants, improved AAT performance was associated with a higher contralateral primary somatosensory cortex (S1) fMRI activation magnitude during the grip force modulation task., Conclusions: This study highlights the importance of S1 for hand motor training gain. In addition, it suggests the usage of rES of the fingertips for priming active hand motor training., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The fingertip somatotopy in BA1 and BA3b of monkeys exhibits characteristic differences with a more discrete separation of the body parts in BA3b and a continuous orientation column-like structure in BA1. We present evidence for similar differences in the human somatotopy using BOLD fMRI for the investigations. Though the variability between the individual maps was large, we found a group-wide somatotopic representation in BA3b and BA1. The variability due to anatomical differences was small in our sample. This was demonstrated by comparing exact shortest distances in the individual brains and after nonlinear normalization to the group space template, for the removal of the individual anatomical variability. Distance mapping along Dijkstra paths was found to be a valid approximation to exact shortest paths only in the individual brains. The degree of fine-scale detail mapping was improved if valid surface distances instead of 3D Euclidean distances were applied. A further improvement was achieved by mapping the distances between all neighboring fingertips instead of only the outer fingertips. Taking into account all optimizations we found mirror symmetry of the somatotopy with respect to the interhemispheric gap., (Copyright © 2016 IBRO. All rights reserved.)

SrGAP3 belongs to the family of Rho GTPase proteins. These proteins are thought to play essential roles in development and in the plasticity of the nervous system. SrGAP3-deficient mice have recently been created and approximately 10 % of these mice developed a hydrocephalus and died shortly after birth. The others survived into adulthood, but displayed neuroanatomical alteration, including increased ventricular size. We now show that SrGAP3-deficient mice display increased brain weight together with increased hippocampal volume. This increase was accompanied by an increase of the thickness of the stratum oriens of area CA1 as well as of the thickness of the molecular layer of the dentate gyrus (DG). Concerning hippocampal adult neurogenesis, we observed no significant change in the number of proliferating cells. The density of doublecortin-positive cells also did not vary between SrGAP3-deficient mice and controls. By analyzing Golgi-impregnated material, we found that, in SrGAP3-deficient mice, the morphology and number of dendritic spines was not altered in the DG. Likewise, a Sholl-analysis revealed no significant changes concerning dendritic complexity as compared to controls. Despite the distinct morphological alterations in the hippocampus, SrGAP3-deficient mice were relatively inconspicuous in their behavior, not only in the open-field, nest building but also in the Morris water-maze. However, the SrGAP3-deficient mice showed little to no interest in burying marbles; a behavior that is seen in some animal models related to autism, supporting the view that SrGAP3 plays a role in neurodevelopmental disorders.

Background: Diffuse gliomas are poorly immunogenic, fatal brain tumors. The basis for insufficient antitumor immunity in diffuse gliomas is unknown. Gain-of-function mutations in isocitrate dehydrogenases (IDH1 and IDH2) promote diffuse glioma formation through epigenetic reprogramming of a number of genes, including immune-related genes. Here, we identify epigenetic dysregulation of natural killer (NK) cell ligand genes as significant contributors to immune escape in glioma., Methods: We analyzed the database of The Cancer Genome Atlas for immune gene expression patterns in IDH mutant or wild-type gliomas and identified differentially expressed immune genes. NKG2D ligand expression levels and NK cell-mediated lysis were measured in IDH mutant and wild-type patient-derived glioma stem cells and genetically engineered astrocytes. Finally, we assessed the impact of hypomethylating agent 5-aza-2'deoxycytodine (decitabine) as a potential NK cell sensitizing agent in IDH mutant cells., Results: IDH mutant glioma stemlike cell lines exhibited significantly lower expression of NKG2D ligands compared with IDH wild-type cells. Consistent with these findings, IDH mutant glioma cells and astrocytes are resistant to NK cell-mediated lysis. Decitabine increases NKG2D ligand expression and restores NK-mediated lysis of IDH mutant cells in an NKG2D-dependent manner., Conclusions: IDH mutant glioma cells acquire resistance to NK cells through epigenetic silencing of NKG2D ligands ULBP1 and ULBP3. Decitabine-mediated hypomethylation restores ULBP1 and ULBP3 expression in IDH mutant glioma cells and may provide a clinically useful method to sensitize IDH mutant gliomas to NK cell-mediated immune surveillance in patients with IDH mutated diffuse gliomas., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: Recent evidence demonstrated that complex regional pain syndrome (CRPS) is associated with a larger than normal somatosensory (S1) representation of the healthy hand. The most intuitive mechanism for this apparent enlargement is increased, i.e. compensatory, use of the healthy hand. We investigated whether enlargement of the S1 representation of the healthy hand is associated with compensatory use in response to CRPS. Specifically, we were interested in whether the size of the S1 representation of the healthy hand is associated with the severity of functional impairment of the CRPS-affected hand. We were also interested in whether CRPS duration might be positively associated with the size of the representation of the healthy hand in S1., Methods: Using functional magnetic resonance imaging (fMRI) data from our previous investigation, the size of the S1 representation of the healthy hand in CRPS patients (n=12) was standardised to that of a healthy control sample (n=10), according to hand dominance. Responses to questionnaires on hand function, overall function and self-efficacy were used to gather information on hand use in participants. Multiple regression analyses investigated whether the S1 representation was associated with compensatory use. We inferred compensatory use with the interaction between reported use of the CRPS-affected hand and (a) reported overall function, and (b) self-efficacy. We tested the correlation between pain duration and the size of the S1 representation of the healthy hand with Spearman's rho., Results: The relationship between the size of the S1 representation of the healthy hand and the interaction between use of the affected hand and overall function was small and non-significant (β=-5.488×10 -5 , 95% C.I. -0.001, 0.001). The relationship between the size of the S1 representation of the healthy hand and the interaction between use of the affected hand and self-efficacy was also small and non-significant (β=-6.027×10 -6 , 95% C.I. -0.001, 0.001). The S1 enlargement of the healthy hand was not associated with pain duration (Spearman's rho=-0.14, p=0.67)., Conclusion: Our exploration did not yield evidence of any relationship between the size of the healthy hand representation in S1 and the severity of functional impairment of the CRPS-affected hand, relative to overall hand use or to self-efficacy. There was also no evidence of an association between the size of the healthy hand representation in S1 and pain duration. The enlarged S1 representation of the healthy hand does not relate to self-reported function and impairment in CRPS., Implications: While this study had a hypothesis-generating nature and the sample was small, there were no trends to suggest compensatory use as the mechanism underlying the apparent enlargement of the healthy hand in S1. Further studies are needed to investigate the possibility that inter-hemispheric differences seen in S1 in CRPS may be present prior to the development of the disorder., (Copyright © 2016 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Individuals with high anxiety sensitivity (AS) have an increased risk of developing anxiety disorders and are more biased in how they process fear-related stimuli. This study investigates the neural correlates of fear-related words and word associations in high- and low-AS individuals. We used a semantic priming paradigm during functional magnetic resonance imaging in which three types of target words (fear symptoms, e.g. 'dizziness'; neutral, e.g. 'drink'; and pseudowords, e.g. 'salkom') were preceded by two types of prime words (fear-triggers, e.g. 'elevator'; and neutral, e.g. 'bottle'). Subjects with high AS rated fear-symptom words (vs neutral words) as more unpleasant than low-AS individuals; they also related these words more strongly to fear-triggers and showed prolonged reaction times. During the processing of fear-symptom words, greater activation in the left anterior insula was observed in high-AS subjects than in low-AS subjects. Lower activation in the left inferior frontal gyrus, angular gyrus, fusiform gyrus and bilateral amygdalae was found in high-AS subjects when fear-symptom words were preceded by fear-trigger words. The findings suggest that cognitive biases and the anterior insula play a crucial role in high-AS individuals. Furthermore, semantic processes may contribute to high AS and the risk of developing anxiety disorders., (© The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

To investigate therapy associated changes in the cerebral representation of movement after stroke, we used functional magnetic resonance imaging (fMRI) during an active and a passive motor task for the affected and unaffected hand before and after a three week comprehensive hand motor training. Twelve patients in the subacute phase from 2 to 9 weeks after mild to moderate motor stroke were recruited. During fMRI, the active task comprised fist clenching, which was precisely controlled for motor performance by visual feedback of force and frequency. The passive task consisted of wrist flexion-extension of 1Hz frequency by means of a pneumatic driven splint. Arm Ability Training (AAT) was conducted one hour per day over 3 weeks in addition to inward rehabilitative therapy. Performance gain was tested using movements trained with AAT, but also with conventional hand motor tests (Nine-Hole-Peg Test, Box-and-Block Test). Rehabilitation therapy and AAT resulted in considerable improvement of performance in trained tasks and other hand motor functions (e.g., Nine-Hole-Peg Test). FMRI activation in the ventral premotor cortex (vPMC) of the lesioned hemisphere increased over time for the active task only for the affected hand. No such change was present for the passive wrist extension task or the active task with the unaffected hand. In addition, only for the post measurement of the active task performed with the affected hand, bilateral vPMC shows a more pronounced activation than in healthy controls. This finding contradicts the simple "near to normal is good recovery" opinion., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Disability in multiple sclerosis (MS) patients is associated with white matter (WM) and gray matter (GM) pathology, and both processes contribute differently over the disease course. Total and regional GM volume loss can be imaged via voxel-based morphometry (VBM). Here, we retrospectively analyzed a group of 213 MS patients [163 relapsing remitting (RR) and 50 secondary progressive (SP)] using semi-automated white matter (WM) lesion mapping and voxel-based morphometry (VBM). Our aim was to assess the association of increasing disability with decreasing total and regional GM volume. As expected, total GM volume and WM lesion load were associated with patients disability, measured with the Expanded Disability Status Scale (EDSS). The more impaired the patients, the greater the statistical association to the total GM volume. Regional volume loss in the cerebellar gray matter was associated with increasing EDSS and WM lesion volume. Furthermore, SPMS patients had significantly more gray matter volume loss in the cerebellum and the hippocampus compared to RRMS patients. Our results confirm histopathological studies emphasizing the important role of the cerebellum and the hippocampus in MS patients' disability.

The insular cortex is fundamentally involved in the processing of interoceptive information. It has been postulated that the integrative monitoring of the bodily responses to environmental stimuli is crucial for the recognition and experience of emotions. Because emotional arousal is known to be closely coupled to functions of the anterior insula, we suspected laughter to be associated primarily with neuronal activity in this region. An anatomically constrained re-analysis of our imaging data pertaining to ticklish laughter, to inhibited ticklish laughter, and to voluntary laughter revealed regional differences in the levels of neuronal activity in the posterior and mid-/anterior portions of the insula. Ticklish laughter was associated specifically with right ventral anterior insular activity, which was not detected under the other two conditions. Hence, apparently, only laughter that is evoked as an emotional response bears the signature of autonomic arousal in the insular cortex., (© 2015 Wiley Periodicals, Inc.)

In contrast to instrumental musicians, professional singers do not train on a specific instrument but perfect a motor system that has already been extensively trained during speech motor development. Previous functional imaging studies suggest that experience with singing is associated with enhanced somatosensory-based vocal motor control. However, experience-dependent structural plasticity in vocal musicians has rarely been studied. We investigated voxel-based morphometry (VBM) in 27 professional classical singers and compared gray matter volume in regions of the "singing-network" to an age-matched group of 28 healthy volunteers with no special singing experience. We found right hemispheric volume increases in professional singers in ventral primary somatosensory cortex (larynx S1) and adjacent rostral supramarginal gyrus (BA40), as well as in secondary somatosensory (S2) and primary auditory cortices (A1). Moreover, we found that earlier commencement with vocal training correlated with increased gray-matter volume in S1. However, in contrast to studies with instrumental musicians, this correlation only emerged in singers who began their formal training after the age of 14years, when speech motor development has reached its first plateau. Structural data thus confirm and extend previous functional reports suggesting a pivotal role of somatosensation in vocal motor control with increased experience in singing. Results furthermore indicate a sensitive period for developing additional vocal skills after speech motor coordination has matured., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Neurogenic dysphagia frequently occurs after stroke and deglutitive aspiration is one of the main reasons for subacute death after stroke. Although promising therapeutic interventions for neurogenic dysphagia are being developed, the functional neuroanatomy of recovered swallowing in this population remains uncertain. Here, we investigated 18 patients post-stroke who recovered from dysphagia using an event related functional magnetic resonance imaging (fMRI) study of swallowing. Patients were characterized by initial dysphagia score (mild to severe), lesion mapping, white matter fractional anisotropy (FA) of the pyramidal tracts, and swallowing performance measurement during fMRI scanning. Eighteen age matched healthy participants served as a control group. Overall, patients showed decreased fMRI-activation in the entire swallowing network apart from an increase of activation in the contralesional primary somatosensory cortex (S1). Moreover, fMRI activation in contralesional S1 correlated with initial dysphagia score. Finally, when lesions of the pyramidal tract were more severe, recovered swallowing appeared to be associated with asymmetric activation of the ipsilesional anterior cerebellum. Taken together, our data support a role for increased contralesional somatosensory resources and ipsilesional anterior cerebellum feed forward loops for recovered swallowing after dysphagia following stroke.

Background: Connectivity-based predictions of hand motor outcome have been proposed to be useful in stroke patients. We intended to assess the prognostic value of different imaging methods on short-term (3 months) and long-term (6 months) motor outcome after stroke., Methods: We measured resting state functional connectivity (rsFC), diffusion weighted imaging (DWI) and grip strength in 19 stroke patients within the first days (5-9 days) after stroke. Outcome measurements for short-term (3 months) and long-term (6 months) motor function was assessed by the Motricity Index (MI) of the upper limb and the box and block test (BB). Patients were predominantly mildly affected since signed consent was necessary at inclusion. We performed a multiple stepwise regression analysis to compare the predictive value of rsFC, DWI and clinical measurements., Results: Patients showed relevant improvement in both motor outcome tests. As expected grip strength at inclusion was a predictor for short- and long-term motor outcome as assessed by MI. Diffusion-based tract volume (DTV) of the tracts between ipsilesional primary motor cortex and contralesional anterior cerebellar hemisphere showed a strong trend (p = 0.05) for a predictive power for long-term motor outcome as measured by MI. DTV of the interhemispheric tracts between both primary motor cortices was predictive for both short- and long-term motor outcome in BB. rsFC was not associated with motor outcome., Conclusions: Grip strength is a good predictor of hand motor outcome concerning strength-related measurements (MI) for mildly affected subacute patients. Therefore additional connectivity measurements seem to be redundant in this group. Using more complex movement recruiting bilateral motor areas as an outcome parameter, DTV and in particular interhemispheric pathways might enhance predictive value of hand motor outcome.

Background: To introduce a standardized and automatized method for functional MRI (fMRI) examinations of the cortical sensory somatotopy in large samples for investigations of the fingertip somatotopy in the primary somatosensory cortex., Methods: At 3 Tesla, T2* (spin-spin relaxation time) weighted images (gradient-echo echo planar imaging, voxel size 1.5 × 1.5 × 2 mm3) were acquired during stimulation of the finger tips for thumb, index and middle finger on both hands, in a group of 18 healthy participants. In addition, structural T1 weighted (magnetization prepared rapid gradient echo, isotropic voxel size 1 mm) and MR-angiography (time of flight, voxel size 0.26 × 0.26 × 0.5 mm3) images were recorded. Boundary based register served to combine movement correction and registration in FreeSurfer Functional analysis stream (FS-Fast), resulting in fine scale corrections, as revealed with FSL Possum (FSL FMRIB Software Library Physics-Oriented Simulated Scanner for Understanding MRI) simulations. Automated data analysis was achieved by inclusion of cytoarchitectonic probability maps for calculation of functional activation in Brodmann area 3b. Draining vessel artifacts were identified using the peak value approach and the MR-angiography. Distances were computed as the shortest connection within the gray matter., Results: The fMRI somatotopic maps agreed with the expected fingertip somatotopy in 63% of the investigated subjects, an improvement of 34% compared with FS-Fast. Artifacts have been removed completely. Adjacent fingertips showed average distances of 8 ± 4.3 mm, and between thumb and middle finger 13.4 ± 4.8 mm was found. Distances for both hands were similar as expected from the characteristics of the fingertip spatial tactile resolution., Conclusion: The introduced evaluation procedure allowed automated analysis of the fingertip representation in excellent agreement with preceding results., (© 2015 Wiley Periodicals, Inc.)

Purpose and Methods: The study sought to alter visual spatial attention in young healthy subjects by a neuronavigated inhibitory rTMS protocol (cTBS-600) to right brain areas thought to be involved in visual attentional processes, i.e. the temporoparietal junction (TPJ) and the posterior middle frontal gyrus (pMFG), and to test the reversibility of effects by an additional consecutive cTBS to the homologue left brain cortical areas., Results: Healthy subjects showed a leftward bias of the egocentric perspective for both visual-perceptive and visual-exploratory tasks specifically for items presented in the left hemifield. cTBS to the right TPJ, and less systematically to the right pMFG reduced this bias for visuo-spatial and exploratory visuo-motor behaviour. Further, a consecutive cTBS to the left TPJ changed the bias again towards the left for a visual-perceptive task., Conclusions: The evidence supports the notion of an involvement of the right TPJ (and pMFG) in spatial visual attention. The observations further indicate that inhibitory non-invasive brain stimulation (cTBS) to the left TPJ has a potential for reversing a rightward bias of spatial attention when the right TPJ is dysfunctional. Accordingly, the findings could have implications for therapeutic rTMS development for right brain damaged patients with visual neglect.

Unlabelled: Chronic back pain (CBP) is associated with circumscribed atrophy in gray matter (GM) predominantly localized in areas of the so-called pain matrix and the prefrontal cortex (PFC). Previous studies applying voxel-based morphometry (VBM) for identifying structural brain alterations related to CBP have reported inconsistent results, were limited to small sample sizes, and often did not control for medication. We therefore used VBM for high-resolution magnetic resonance images to investigate the association of CBP and regional GM volume in 111 individuals with CBP and 432 pain-free controls derived from the representative Study of Health in Pomerania, controlling for effects of medication. CBP was associated with decreased regional GM in the ventrolateral PFC and dorsolateral PFC, both the ventral and dorsal medial PFC, and the anterior insula. Pain intensity showed a weak negative correlation with GM volume in the left dorsolateral PFC, ventrolateral PFC, and anterior cingulate cortex. The CBP sample showed alterations in regions commonly associated with pain processing and emotional demands. To our knowledge, this is the first VBM study reporting decreased regional GM volume in the medial PFC in a CBP sample. We were unable to confirm alterations in regions other than the dorsolateral PFC and the insula., Perspective: Previous studies reported inconsistent results for brain areas altered in chronic pain conditions, which may be in part attributable to small sample sizes, medication use, or emotional comorbidities. This study in a large and representative cohort helps to clarify these issues., (Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Expert performance constitutes the endpoint of skill acquisition and is accompanied by widespread neuroplastic changes. To reveal common mechanisms of reorganization associated with long-term expertise in a cognitive domain (mental calculation, chess, language, memory, music without motor involvement), we used activation likelihood estimation meta-analysis and compared brain activation of experts to nonexperts. Twenty-six studies matched inclusion criteria, most of which reported an increase and not a decrease of activation foci in experts. Increased activation occurred in the left rolandic operculum (OP 4) and left primary auditory cortex and in bilateral premotor cortex in studies that used auditory stimulation. In studies with visual stimulation, experts showed enhanced activation in the right inferior parietal cortex (area PGp) and the right lingual gyrus. Experts' brain activation patterns seem to be characterized by enhanced or additional activity in domain-specific primary, association, and motor structures, confirming that learning is localized and very specialized., (© 2015 Wiley Periodicals, Inc.)

Studying neural networks and behavioral indices such as potentiated startle responses during fear conditioning has a long tradition in both animal and human research. However, most of the studies in humans do not link startle potentiation and neural activity during fear acquisition and extinction. Therefore, we examined startle blink responses measured with electromyography (EMG) and brain activity measured with functional MRI simultaneously during differential conditioning. Furthermore, we combined these behavioral fear indices with brain network activity by analyzing the brain activity evoked by the startle probe stimulus presented during conditioned visual threat and safety cues as well as in the absence of visual stimulation. In line with previous research, we found a fear-induced potentiation of the startle blink responses when elicited during a conditioned threat stimulus and a rapid decline of amygdala activity after an initial differentiation of threat and safety cues in early acquisition trials. Increased activation during processing of threat cues was also found in the anterior insula, the anterior cingulate cortex (ACC), and the periaqueductal gray (PAG). More importantly, our results depict an increase of brain activity to probes presented during threatening in comparison to safety cues indicating an involvement of the anterior insula, the ACC, the thalamus, and the PAG in fear-potentiated startle processing during early extinction trials. Our study underlines that parallel assessment of fear-potentiated startle in fMRI paradigms can provide a helpful method to investigate common and distinct processing pathways in humans and animals and, thus, contributes to translational research., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Complex regional pain syndrome (CRPS) type I is characterized by somatosensory and motor deficits, and abnormalities have been reported for primary somatosensory (S1) and motor cortex (M1) excitability. For the latter, reduced short-latency intracortical inhibition (SICI) has been demonstrated in the somatotopic representation of the affected side. Recently, an intervention of applying anesthetic cream to the forearm has been shown to modulate both somatosensory deficits (eg, spatial tactile resolution [STR]) and SICI measured in hand muscles. We examined the efficacy of this intervention in patients with CRPS I. Cutaneous anesthesia of the forearm of the affected side was used to increase SICI of hand muscles and decrease impaired STR of the affected limb. In a double-blinded placebo-controlled study, we enrolled 12 patients with unilateral CRPS I of the hand in the chronic state. Before and after intervention, we measured motor evoked potentials of the first dorsal interosseus to obtain SICI and STR of both hand sides. Patients showed decreased STR on the tip of the thumb of their affected side, which improved after anesthetic cream but not after placebo application. Hand motor function of the affected side improved after anesthetic cream but not after placebo. Pain intensity was not modulated after intervention. At both hemispheres, SICI was decreased compared with reference values but selectively increased at the intervention side only after analgesic cream and not after placebo. Temporary deafferentation of an area neighbouring the CRPS-affected region can modulate neuropathological characteristics of CRPS and might be a promising strategy for therapeutic interventions.

Background: A dysfunctional network of prefrontal and (para-)limbic brain region has been suggested to underlie emotional dysregulation in borderline personality disorder (BPD). Abnormal activity in this network may be due to structural alterations in white-matter tracts connecting prefrontal and (para-)limbic brain regions. To test this hypothesis, we investigated the structural integrity of major white-matter tracts connecting these regions in BPD., Method: Using diffusion tensor imaging, we investigated fractional anisotropy (FA), axonal anisotropy (AD) and radial diffusivity (RD) in the uncinate fasciculus, the major white-matter tract connecting (para-)limbic and prefrontal brain regions, in 26 healthy controls (HC) and 26 BPD participants. To clarify the specificity of possible white-matter alterations among HC and BPD participants, FA, AD and RD were also investigated in the cingulum., Results: We found distinct structural alterations in the uncinate fasciculus but not in the cingulum of BPD participants. Compared to HC participants, BPD participants showed lower FA and higher RD in the uncinate fasciculus. By contrast, AD did not differ in the uncinate fasciculus of HC and BPD participants., Conclusions: Our finding of abnormal FA and RD in the uncinate fasciculus indicates distinct white-matter alterations in BPD, presumably due to stress-induced myelin degeneration in the aftermath of stressful life events. Although these alterations may account for abnormal activity in brain regions implicated in emotion dysregulation, such as the amygdala, anterior cingulate cortex and prefrontal cortex, it remains to be determined whether these alterations are specific for BPD.

Conventional rehabilitation of patients with chronic pain is often not successful and is frustrating for the treatment team. However, theoretical developments and substantial advances in our understanding of the neurological aspects of chronic pain are changing these experiences. Modern theoretical models of pain consider pain to be a perceptual inference that reflects a "best guess" that protective action is required. This article argues that keen observation and open and respectful clinician-patient and scientist-clinician relationships have been critical for the emergence of effective rehabilitation approaches and will be critical for further improvements. The role in modern pain rehabilitation of reconceptualizing the pain itself-by "Explaining Pain," careful and intentional observation of the person in pain, and the strategic and constant communication of safety-is emphasized. It also is suggested that better understanding of the neural mechanisms underpinning chronic pain has directly informed the development of new therapeutic approaches, which are being further refined and tested. Conventional pain treatment (where the clinician strives to find the pain-relieving medication or exercise) or pain management (where the clinician helps the patient to manage life despite unabating pain) is being replaced by pain rehabilitation, where a truly biopsychosocial approach allows clinicians to provide patients with the knowledge, understanding, and skills to reduce both their pain and disability. A brief overview is provided of the key aspects of modern pain rehabilitation and the considerations that should lead our interaction with patients with chronic pain., (© 2015 American Physical Therapy Association.)

In several mouse models of mental retardation, ventricular enlargements have been observed. Mutation in the SrGAP3 gene residing on chromosome 3p25 has previously been associated with intellectual disability in humans. In addition, SrGAP3 is related to Rho-GAPs signaling pathways, which play essential roles in the development and plasticity of the nervous system. About 10 % of postnatal homozygous SrGAP3-deficient mice die due to hydrocephalus, whereas the remaining mice survive into adulthood but display enlarged ventricles. We analyze the ventricular enlargement of these mice by performing a post-mortem MRI approach. We found a more than 15-fold enlargement of the lateral ventricles of homozygous SrGAP3-deficient mice. Moreover, we demonstrate that this phenotype was not accompanied by a stenosis of the aqueduct. Instead, SrGAP3 knockout mice displayed reduced densities of cilia of ependymal cells in These third ventricle compared to age-matched controls. This results indicate that the ventricular enlargement may be due to ciliopathy.

Background & Aims: The mechanisms of hypoxia-induced tumor growth remain unclear. Hypoxia induces intracellular translocation and release of a variety of damage associated molecular patterns (DAMPs) such as nuclear HMGB1 and mitochondrial DNA (mtDNA). In inflammation, Toll-like receptor (TLR)-9 activation by DNA-containing immune complexes has been shown to be mediated by HMGB1. We thus hypothesize that HMGB1 binds mtDNA in the cytoplasm of hypoxic tumor cells and promotes tumor growth through activating TLR9 signaling pathways., Methods: C57BL6 mice were injected with Hepa1-6 cancer cells. TLR9 and HMGB1 were inhibited using shRNA or direct antagonists. HuH7 and Hepa1-6 cancer cells were investigated in vitro to determine how the interaction of HMGB1 and mtDNA activates TLR9 signaling pathways., Results: During hypoxia, HMGB1 translocates from the nucleus to the cytosol and binds to mtDNA released from damaged mitochondria. This complex subsequently activates TLR9 signaling pathways to promote tumor cell proliferation. Loss of HMGB1 or mtDNA leads to a defect in TLR9 signaling pathways in response to hypoxia, resulting in decreased tumor cell proliferation. Also, the addition of HMGB1 and mtDNA leads to the activation of TLR9 and subsequent tumor cell proliferation. Moreover, TLR9 is overexpressed in both hypoxic tumor cells in vitro and in human hepatocellular cancer (HCC) specimens; and, injection in mice to knockdown either HMGB1 or TLR9 from HCC cells suppressed tumor growth in vivo., Conclusions: Our data reveals a novel mechanism by which the interactions of HMGB1 and mtDNA activate TLR9 signaling during hypoxia to induce tumor growth., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)