Matthias Ruf

Mirrored, imagined and executed movements differentially activate sensorimotor cortex in amputees with and without phantom limb pain

&NA; Extended viewing of movements of the intact hand in a mirror as well as motor imagery has been shown to decrease pain in phantom pain patients. We used functional magnetic resonance imaging to assess the neural correlates of mirrored, imagined and executed hand movements in 14 upper extremity amputees – 7 with phantom limb pain (PLP) and 7 without phantom limb pain (non‐PLP) and 9 healthy controls (HC). Executed movement activated the contralateral sensorimotor area in all three groups but ipsilateral cortex was only activated in the non‐PLP and HC group. Mirrored movements activated the sensorimotor cortex contralateral to the hand seen in the mirror in the non‐PLP and the HC but not in the PLP. Imagined movement activated the supplementary motor area in all groups and the contralateral primary sensorimotor cortex in the non‐PLP and HC but not in the PLP. Mirror‐ and movement‐related activation in the bilateral sensorimotor cortex in the mirror movement condition and activation in the sensorimotor cortex ipsilateral to the moved hand in the executed movement condition were significantly negatively correlated with the magnitude of phantom limb pain in the amputee group. Further research must identify the causal mechanisms related to mirror treatment, imagined movements or movements of the other hand and associated changes in pain perception.

Acute D2 receptor blockade induces rapid, reversible remodeling in human cortical-striatal circuits

Structural remodeling has been observed in the human brain over periods of weeks to months, but the molecular mechanisms governing this process remain incompletely characterized. Using multimodal pharmaco-neuroimaging, we found that acute D2 receptor blockade induced reversible striatal volume changes and structural-functional decoupling in motor circuits within hours; these alterations predicted acute extrapyramidal motor symptoms with high precision. Our findings suggest a role for D2 receptors in short-term neural plasticity and identify a potential biomarker for neuroleptic side effects in humans.

Antipsychotic drug effects on motor activation measured by functional magnetic resonance imaging in schizophrenic patients

Brain function and laterality in schizophrenia were investigated by means of a simple motor task with a self-generated left-hand sequential finger opposition (SFO) using a whole-brain high-speed (100 ms per slice) functional imaging technique. Neuroleptic-naïve, acutely ill schizophrenic patients were compared to schizophrenic patients under stable neuroleptic medication and matched controls. The goal was to evaluate both the motor function in first-episode patients and possible effects of different neuroleptic treatments on functional MRI results. Forty patients satisfying ICD 10 criteria (F20.x) for schizophrenia and sex- and age-matched healthy volunteers participated in this study. All subjects underwent fMRI examinations on a conventional 1.5 T MR unit. The primary sensorimotor cortex and the high-order supplementary motor area (SMA) were evaluated. There was a close similarity in the activation of the primary and high-order (SMA) sensorimotor areas between first-episode schizophrenic patients and controls. In contrast, a significant reduction in the overall blood oxygen level dependent (BOLD) response was seen in sensorimotor cortices (contra- and ipsilateral) in schizophrenic patients under stable medication with typical neuroleptics. This effect was not present in patients treated with atypical antipsychotics. Both antipsychotic treatments, however, led to a significant reduction in activation of the SMA region compared to controls and neuroleptic-naïve subjects. Thus, the present study provides no evidence for the localized involvement of the primary motor cortex or the SMA as a relatively stable vulnerability marker in schizophrenia. There is, however, strong evidence that neuroleptics themselves influence fMRI activation patterns and that there are major differences between typical neuroleptics and atypical antipsychotics.

A simultaneous EEG–fMRI study of painful electric stimulation

Together with a detailed behavioral analysis, simultaneous measurement of functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) permits a better elucidation of cortical pain processing. We applied painful electrical stimulation to 6 healthy subjects and acquired fMRI simultaneously with an EEG measurement. The subjects rated various stimulus properties and the individual affective state. Stimulus-correlated BOLD effects were found in the primary and secondary somatosensory areas (SI and SII), the operculum, the insula, the supplementary motor area (SMA proper), the cerebellum, and posterior parts of the anterior cingulate gyrus (ACC). Perceived pain intensity was positively correlated with activation in these areas. Higher unpleasantness rating was associated with suppression of activity in areas known to be involved in stimulus categorization and representation (ventral premotor cortex, PCC, parietal operculum, insula) and enhanced activation in areas initiating, propagating, and executing motor reactions (ACC, SMA proper, cerebellum, primary motor cortex). Concordant dipole localizations in SI and ACC were modeled. Using the dipole strength in SI, the network was restricted to SI. The BOLD signal change in ACC was positively correlated to the individual dipole strength of the source in ACC thus revealing a close relationship of BOLD signal and possibly underlying neuronal electrical activity in SI and the ACC. The BOLD signal change decreased in SI over time. Dipole strength of the ACC source decreased over the experiment and increased during the stimulation block suggesting sensitization and habituation effects in these areas.

Correlation of Glutamate Levels in the Anterior Cingulate Cortex With Self-reported Impulsivity in Patients With Borderline Personality Disorder and Healthy Controls

CONTEXT Dysfunction and deficits in the structure of the anterior cingulate cortex have been reported in borderline personality disorder (BPD). To our knowledge, there is only 1 published study to date investigating anterior cingulate cortex metabolism in subjects with BPD and co-occurring attention-deficit/hyperactivity disorder using proton magnetic resonance spectroscopy. Impulsivity is a key feature of BPD and can be related to anterior cingulate cortex function. OBJECTIVE To investigate whether anterior cingulate cortex metabolism may be altered in BPD and correlates with BPD pathology. DESIGN Cross-sectional proton magnetic resonance spectroscopy study. SETTING Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health, Mannheim, Germany. PARTICIPANTS AND PATIENTS Thirty unmedicated female subjects meeting DSM-IV criteria for BPD and 31 age-matched healthy female control participants. MAIN OUTCOME MEASURES Neurometabolite concentrations in the anterior cingulate cortex and correlation of glutamate levels with self-reported measures of impulsivity and severity of borderline symptoms. RESULTS Significantly higher levels of glutamate in the anterior cingulate cortex were found in subjects with BPD as compared with healthy controls. A positive correlation between glutamate concentration and the Barratt Impulsiveness Scale total score as well as between glutamate concentration and the subscore for cognitive impulsivity were observed irrespective of diagnosis. We also found a positive correlation between glutamate concentrations and dissociation as well as between glutamate concentration and subscores of the Borderline Symptom List in the patient group. CONCLUSIONS Our results support the hypothesis that higher glutamate concentration in the anterior cingulate cortex is associated with both severity of BPD symptoms and subjective impulsivity ratings, the latter independent of BPD. Further studies should confirm the association between enhanced glutamate concentration in the anterior cingulate cortex and behavioral measures of impulsivity.

Amygdala deactivation as a neural correlate of pain processing in patients with borderline personality disorder and co-occurrent posttraumatic stress disorder

BACKGROUND Previous studies have revealed altered affective pain processing in patients with borderline personality disorder (BPD) as well as in patients with posttraumatic stress disorder (PTSD). Reduced levels of activation in the amygdala might be related to antinociceptive mechanisms pertinent to both disorders. This study aimed at clarifying whether central antinoceptive mechanisms discriminate BPD patients with and without co-occurrent PTSD. METHODS We investigated 29 medication-free female outpatients with BPD, 12 with and 17 without co-occurrent PTSD. Psychophysical characteristics were assessed, and functional magnetic resonance imaging was performed during heat stimulation with stimuli adjusted for equal subjective painfulness. RESULTS No difference in pain sensitivity was found between both groups of patients. Amygdala deactivation, however, was more pronounced in BPD patients with co-occurrent PTSD compared with those without PTSD. Amygdala deactivation was independent of BPD symptom severity and dissociation. CONCLUSIONS Amygdala deactivation seems to differentiate patients who meet criteria for both BPD and PTSD from BPD patients without co-occurrent PTSD. On the basis of these preliminary findings it might be speculated that reduced pain sensitivity or at least the emotional component of it is associated with amygdala deactivation in patients with both disorders, whereas BPD patients without PTSD use different yet unknown antinociceptive mechanisms.

Simultaneous EEG and fMRI Reveals a Causally Connected Subcortical-Cortical Network during Reward Anticipation

Electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) have been used to study the neural correlates of reward anticipation, but the interrelation of EEG and fMRI measures remains unknown. The goal of the present study was to investigate this relationship in response to a well established reward anticipation paradigm using simultaneous EEG-fMRI recording in healthy human subjects. Analysis of causal interactions between the thalamus (THAL), ventral-striatum (VS), and supplementary motor area (SMA), using both mediator analysis and dynamic causal modeling, revealed that (1) THAL fMRI blood oxygenation level-dependent (BOLD) activity is mediating intermodal correlations between the EEG contingent negative variation (CNV) signal and the fMRI BOLD signal in SMA and VS, (2) the underlying causal connectivity network consists of top-down regulation from SMA to VS and SMA to THAL along with an excitatory information flow through a THAL→VS→SMA route during reward anticipation, and (3) the EEG CNV signal is best predicted by a combination of THAL fMRI BOLD response and strength of top-down regulation from SMA to VS and SMA to THAL. Collectively, these findings represent a likely neurobiological mechanism mapping a primarily subcortical process, i.e., reward anticipation, onto a cortical signature.

Pathological amygdala activation during working memory performance: Evidence for a pathophysiological trait marker in bipolar affective disorder

Recent evidence suggests that deficits of working memory may be a promising neurocognitive endophenotype of bipolar affective disorder. However, little is known about the neurobiological correlates of these deficits. The aim of this study was to determine possible pathophysiological trait markers of bipolar disorder in neural circuits involved in working memory. Functional magnetic resonance imaging was performed in 18 euthymic bipolar patients and 18 matched healthy volunteers using two circuit‐specific experimental tasks established by prior systematic neuroimaging studies of working memory. Both euthymic bipolar patients and healthy controls showed working memory‐related brain activations that were highly consistent with findings from previous comparable neuroimaging studies in healthy subjects. While these patterns of brain activation were completely preserved in the bipolar patients, only the patients exhibited activation of the right amygdala during the articulatory rehearsal task. In the same task, functional activation in right frontal and intraparietal cortex and in the right cerebellum was significantly enhanced in the patients. These findings indicate that the right amygdala is pathologically activated in euthymic bipolar patients during performance of a circuit‐specific working memory task (articulatory rehearsal). This pathophysiological abnormality appears to be a trait marker in bipolar disorders that can be observed even in the euthymic state and that seems to be largely independent of task performance and medication. Hum Brain Mapp, 2010.

Abnormal amygdala activation profile in pedophilia

Despite considerable public interest research in neurobiological correlates of pedophilia is scarce. Since amygdala activation is central for emotional valuation, arousal, and salience, we investigated the activation profile of this structure in 10 male subjects with pedophilia (exclusively attracted to boys), all convicted sex-offenders and sentenced to forensic psychiatric treatment along with ten male heterosexual matched controls. We used a sexually non-explicit functional Magnetic Resonance Imaging (fMRI) paradigm with images of men, women, boys or girls randomly embedded in neutral target/non-target geometrical symbols. We applied statistical parametric mapping (SPM2) and SPSS 14 for image processing and analysis. While controls activated significantly less to pictures of children compared to adults, the activation profile was reversed in subjects with pedophilia, who exhibited significantly more activation to children than adults. The highest activation was observed for boys in the patient group, and for women in control participants. Our data show enhanced activation to children’s pictures even in an incidental context and suggest the provocative hypothesis that a normally present mechanism for reduced emotional arousal for children relative to adults is reversed in pedophilia, suggesting a neural substrate associated with deviant sexual preference in this condition. More extensive research in this field would be of benefit for both the victims and the offenders.Despite considerable public interest research in neurobiological correlates of pedophilia is scarce. Since amygdala activation is central for emotional valuation, arousal, and salience, we investigated the activation profile of this structure in 10 male subjects with pedophilia (exclusively attracted to boys), all convicted sex-offenders and sentenced to forensic psychiatric treatment along with ten male heterosexual matched controls. We used a sexually non-explicit functional Magnetic Resonance Imaging (fMRI) paradigm with images of men, women, boys or girls randomly embedded in neutral target/non-target geometrical symbols. We applied statistical parametric mapping (SPM2) and SPSS 14 for image processing and analysis. While controls activated significantly less to pictures of children compared to adults, the activation profile was reversed in subjects with pedophilia, who exhibited significantly more activation to children than adults. The highest activation was observed for boys in the patient group, and for women in control participants. Our data show enhanced activation to children’s pictures even in an incidental context and suggest the provocative hypothesis that a normally present mechanism for reduced emotional arousal for children relative to adults is reversed in pedophilia, suggesting a neural substrate associated with deviant sexual preference in this condition. More extensive research in this field would be of benefit for both the victims and the offenders.

Prefrontal-temporal gray matter deficits in bipolar disorder patients with persecutory delusions

OBJECTIVES Although brain structural deficits have been repeatedly associated with bipolar disorder (BD), inconsistency in morphometric results has been a feature of neuroimaging studies. We hypothesize that this discrepancy is related to the heterogeneity of BD, and examine the question of whether or not more homogeneous clinical subgroups display a more coherent pattern of morphometric abnormalities. METHODS In a case-control design, we examined differences in gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) concentration in 42 BD patients and 42 healthy matched controls using optimized voxel-based morphometry (VBM). Subgroup analyses of patients with a lifetime history of psychotic symptoms (BDP, n=30) and patients with mood-incongruent psychotic symptoms in the form of persecutory delusions (BDPD, n=15) were performed to accord with previous genetic findings. RESULTS Analysis of the total BD sample was largely inconclusive, but the BDPD patient subgroup displayed a widespread pattern of significant decreases in GM concentration in the dorsolateral prefrontal (DLPFC), temporal and cingulate cortices, and a significant CSF increase in the adjacent outer ventricular sulci. Comparison of BDPD patients versus BD and BDP patients without persecutory delusions revealed a significant GM decrease in the left DLPFC for the former group. CONCLUSIONS BDPD show pronounced structural abnormalities of the prefrontal and temporal lobes which are similar to the deficits previously reported for schizophrenia (SCZ). Our findings suggest that stratification based solely on psychotic symptoms is insufficient for the differentiation of BD into biologically meaningful subgroups, but also question the pathophysiological validity of the dichotomy in classification between schizophrenia and BD.