Polymorphism in the µ-opioid receptor gene (OPRM1) modulates neural processing of physical pain, social rejection and error processing.

Variations of the µ-opioid receptor gene OPRM1 have been shown to modulate pain perception with some evidence pointing towards a modulation of not only physical but also "psychological pain". In line with suggestions of a common neural network involved in the processing of physical pain and negative and distressing stimuli, like social rejection as a psychologically harmful event, we examined the influence of the A118G polymorphism on the neural processing of physical and non-physical pain. Using fMRI, we investigated a sample of 23 females with the more frequent AA genotype, and eight females with the relatively rare but more pain-sensitive AG genotype during electrical stimulation to the dorsum of the non-dominant hand. Non-physical pain was investigated using Cyberball, a virtual ball-tossing game, to induce experiences of non-self-dependent social rejection. A Go/NoGo task with an increased risk of self-dependent erroneous performance was used as a control task to investigate the effects of negative feedback as a more cognitive form of distress. Relative to A118G homozygous A-allele carriers, G-allele carriers showed significantly increased activation of the supplementary motor area/superior frontal gyrus and the precentral gyrus during electrical stimulation. Increased activation of the secondary sensorimotor cortex (SII) was found during social exclusion and during negative feedback. We demonstrate that brain regions particularly related to the somatosensory component of pain processing are modulated by variations in OPRM1. Influences were evident for both physical and psychological pain processing supporting the assumption of shared neural pathways.

The neuroanatomy of subthreshold depressive symptoms in Huntington's disease: a combined diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) study.

BACKGROUND: Depressive symptoms are prominent psychopathological features of Huntington's disease (HD), making a negative impact on social functioning and well-being. METHOD: We compared the frequencies of a history of depression, previous suicide attempts and current subthreshold depression between 61 early-stage HD participants and 40 matched controls. The HD group was then split based on the overall HD group's median Hospital Anxiety and Depression Scale-depression score into a group of 30 non-depressed participants (mean 0.8, s.d. = 0.7) and a group of 31 participants with subthreshold depressive symptoms (mean 7.3, s.d. = 3.5) to explore the neuroanatomy underlying subthreshold depressive symptoms in HD using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). RESULTS: Frequencies of history of depression, previous suicide attempts or current subthreshold depressive symptoms were higher in HD than in controls. The severity of current depressive symptoms was also higher in HD, but not associated with the severity of HD motor signs or disease burden. Compared with the non-depressed HD group DTI revealed lower fractional anisotropy (FA) values in the frontal cortex, anterior cingulate cortex, insula and cerebellum of the HD group with subthreshold depressive symptoms. In contrast, VBM measures were similar in both HD groups. A history of depression, the severity of HD motor signs or disease burden did not correlate with FA values of these regions. CONCLUSIONS: Current subthreshold depressive symptoms in early HD are associated with microstructural changes - without concomitant brain volume loss - in brain regions known to be involved in major depressive disorder, but not those typically associated with HD pathology.

Role of the ventral striatum in developing anorexia nervosa.

Functional imaging data in adult patients with anorexia nervosa (AN) support a dysfunctional signal in the ventral striatum as neural signature of AN. In the present study, development of this signal was investigated with the prediction that a characteristic pattern of ventral-striatal signalling will be shown in response to cues associated with food restriction that reflects the evolvement of starvation dependence over time. The signal was assessed in adolescent patients with AN, whose duration of illness was about five times shorter relative to the adult sample. During functional magnetic resonance imaging subjects were required to estimate weights of body images (underweight, normal weight, overweight) and to process each stimulus in a self-referring way. Relative to age-matched, young healthy controls, underweight stimuli were already associated with greater activity of the ventral striatum, and processing of normal-weight stimuli elicited already reduced signalling. Subjective preferences showed exactly the same pattern of results. Relative to adult AN, the present data reveal a developing dysfunctional signal that, if untreated, will essentially contribute to the maintenance of AN. We discuss putative mechanisms that may play a crucial role in the development of AN, and also deduce new hypotheses about the involvement of the midbrain dopamine system, of which illness-related alterations may contribute to the development of AN.

[Mental practice has influence on limitation of motion and muscle atrophy following immobilisation of the radiocarpal joint - a prospective randomised experimental study]. / Mentales Training beeinflusst Bewegungseinschränkung des ruhiggestellten Handgelenks - eine prospektive Experimentalstudie.

PURPOSE: Distal radial fracture is the most common bony injury in man. Still there are unsatisfying treatment results, such as limited joint movement, muscle atrophy and pain, resulting from immobilisation while the fracture is healing. During this period, also joint movement seems to be "forgotten". This study experimentally examined if the method of mental practice, meaning the systematic repetition of a consciously imagined movement or action without simultaneous practical execution, can positively influence these findings. MATERIALS AND METHODS: 21 right-handed males had application of a circular forearm plaster for immobilisation of their left radiocarpal joint, simulating a distal radial fracture for three weeks. Following randomisation, half of the study participants learned mental practice for "virtual movement" of their radiocarpal joint and had to perform it, the others were not treated at all. At beginning and end of the experiment, joint movement was measured, and an MRI examination of the forearm muscles was performed. The brain (cortex) areas, responsible for radiocarpal joint movement, were examined concerning their activity with functional MRI at the beginning and also at the end of the three weeks. The experiment was also performed on three "real" patients suffering from a distal radial fracture demanding plaster immobilisation, all of them were mentally treated. RESULTS: Mental practice significantly ameliorated dorsal extension and ulnar abduction after plaster removal in comparison to those not having been mentally trained. Muscle atrophy of forearm muscles, measured via MRI, was significantly less in those having mental training. The cortex areas responsible for radiocarpal joint movements (supplementary motor area, precentral gyrus, putamen, nucleus caudatus, prefrontal cortex, thalamus and cerebellum) showed significant signal changes at the end of the three weeks in those having been mentally trained. There were significant correlations between MRI and functional MRI findings. The findings in the three "real" patients were similiar. CONCLUSIONS: The results of this experimental study show that mental practice can have a positive influence on the outcome of distal radial fractures demanding immobilisation. A study with a larger number of "real patients" should follow.

Texture segmentation in human perception: a combined modeling and fMRI study.

The human visual system uses texture information to segment visual scenes into figure and ground. We developed a computational model of human texture processing [Thielscher A, Neumann H (2003) Neural mechanisms of cortico-cortical interaction in texture boundary detection: a modeling approach. Neuroscience 122:921-939] which allows us to examine the functional roles of early and intermediate stages of the ventral visual pathway in figure-ground segmentation. In particular, the model highlights the central role of cells in mid-level areas (such as V4) with larger receptive fields in the robust identification of texture boundaries and pop-out stimuli even under noisy conditions. A straightforward prediction of the model is that the activity of cells in mid-level, but not early visual areas directly co-varies with the saliency of the texture borders in the visual scene. Consequently, their activity should directly correlate with the saliency of pop-out texture regions as accessed in psychophysical studies [Nothdurft HC (1991) Texture segmentation and pop-out from orientation contrast. Vision Res 31:1073-1078]. This prediction explicitly derived from the model was tested using functional magnetic resonance imaging. The saliency of texture bars composed of oriented line items was varied by parametrically changing the defining orientation contrast between fore- and background lines. Consistent with the model, increasing contrast at texture boundaries resulted in a monotonic increase of blood oxygen level dependent responses in mid-level, but not early visual areas. Our modeling and imaging results indicate that mid-level visual areas form a key stage in figure-ground segregation by gradually signaling the salience of region boundaries defined by orientation contrast.

Inhibition of hippocampal function in mild cognitive impairment: targeting the cholinergic hypothesis.

Mild cognitive impairment (MCI) is a condition with an increased risk of developing Alzheimer's disease. Chief complaint and diagnostic criterion in subjects with mild cognitive impairment is memory failure. We hypothesized that cholinergic malfunction may underlie memory impairment in these subjects and applied a low dosage of an acetylcholinesterase inhibitor and modulator of nicotinic acetylcholine receptors, galantamine (4 mg bid), for 7 days. We used neuropsychological tests to investigate attention, cognitive flexibility, verbal and visual short-term and working memory, susceptibility to interference and episodic memory and functional magnetic resonance imaging to assess spatial navigation both prior to and after treatment. Late episodic learning and delayed recall improved on treatment as did recruitment of the hippocampal region during spatial navigation. Performance in all other neuropsychological measures remained unchanged. We show that an increase of cholinergic neurotransmission in subjects with MCI specifically improves hippocampal function and thus that a cholinergic deficit is functionally relevant in subjects with MCI. Malfunction of the cholinergic system may be tackled pharmacologically via the inhibition of acetylcholinesterase even when the impairment is slight.

[18F]FDG-PET in patients with Alzheimer's disease: marker of disease spread.

BACKGROUND: It is not known yet whether temporoparietal glucose hypometabolism in patients with probable Alzheimer's disease (AD) reflects disease severity or different subtypes of patients. METHODS: Twenty-five subjects with mild probable AD [NINCDS-ADRDA criteria; age 65.8 +/- 9.3 years (mean +/- SD); Mini-Mental State Examination (MMSE) 26.0 +/- 3.3] were investigated. [(18)F]FDG-PET data were analyzed visually with raters blinded to the diagnosis and with a quantitative analysis in the region of interest on individual anatomically normalized PET scans. RESULTS: Thirteen of 25 patients showed temporoparietal hypometabolism on visual inspection (PET+; age 65.7 +/- 10.7), 12 patients had normal FDG-PET results (PET-; age 65.9 +/- 8.0; n.s.). The MMSE and immediate reproduction of the Wechsler Memory Scale (WMS-R-I) were 27.7 +/- 1.9 and 31.1 +/- 6.1 in the PET- vs. 24.5 +/- 3.6 (p = 0.012) and 22.0 +/- 7.4 (p = 0.006) in the PET+ group. Immediate and delayed recall in the California Verbal Learning Test and delayed reproduction in the Wechsler Memory Scale were alike. Regression analysis revealed a significant correlation of temporoparietal glucose metabolism with the block span (r = 0.60; p < 0.01) and the WMS-R-I (r = 0.68; p < 0.01) but not with measures of hippocampal function. CONCLUSIONS: Temporoparietal glucose metabolism in patients with very mild AD is a sign of disease spread beyond the temporal lobe. This may aid in establishing objective parameters for future therapeutic studies.

Manipulation of working memory information is impaired in Parkinson's disease and related to working memory capacity.

It has been suggested that in patients with Parkinson's disease (PD), difficulties in the manipulation of information, which result in problems in executive tasks, are related to a reduction of working memory capacity (J. D. E. Gabrieli, J. Singh, G. T. Stebbins, & C. G. Goetz, 1996). The present study selectively varied the manipulation demand irrespective of the maintenance requirement. In a group of 14 PD patients, performance declined overproportionally with the increasing task demand and was significantly correlated with a measure of working memory capacity. These results suggest that the complexity of working memory processing may decisively contribute to the exhaustion of resources in PD patients. Increasing complexity may either affect their manipulation ability directly or impede the management of inhibitory control requirements inherent to the task.

Enantio-selective cognitive and brain activation effects of N-ethyl-3,4-methylenedioxyamphetamine in humans.

In a randomised double-blind trial the subjective, neuropsychological and brain activation effects of the two enantiomers of the MDMA (ecstasy-) like drug N-ethyl-3,4-methylenedioxyamphetamine (MDE) were studied in five normal subjects using functional magnetic resonance imaging (fMRI). (S)-MDE produced elevated mood, impairments in conceptually driven cognition and marked right frontal activation. In contrast, (R)-MDE produced increased depression, enhanced visual feature processing, and activation of visual cortical and left frontal areas. Plasma concentrations were higher for the (R)-enantiomer. The so-called entactogenic effects of MDE are likely to be caused by the (S)-enantiomer, whereas (R)-MDE appears to be responsible for neurotoxic effects.

Hippocampal activations during repetitive learning and recall of geometric patterns.

Hippocampal activation is required for episodic memory. Encoding and retrieval of novel and memorable items have been related to different locations in the hippocampus; however, the data remain ambiguous. The application of a newly designed keyboard allowed investigation of brain activation during encoding and free immediate and delayed recall with functional magnetic resonance imaging (fMRI) in young healthy controls (n = 12). Because of the repetitive learning and recall conditions, an individual learning gradient was used to contrast neural activity at different individual levels of novelty. During learning, subjects were asked to memorize 10 geometric patterns requiring the establishment of intra-item associations for memorization. After learning, subjects were asked to recall the items actively via the keyboard. Learning and recall were alternated five times. Delayed recall was scanned about 15 min after the fifth immediate recall condition without subjects having seen the items again. Left-sided anterior hippocampal activity was observed during conditions of initial learning as well as maximum recall. Neural activity during delayed recall did not reveal hippocampal responses and was characterized by a transition of neural activity from occipitoparietal regions to bilateral temporal cortices. We conclude that both lateralization and segregation depend on the specific relational characteristics of the stimuli requiring establishment of intra-item associations for encoding as well as retrieval. The absence of hippocampal activation during delayed recall together with the increase of lateral temporal involvement possibly corresponds with an emerging transition from episodic to long-term memory.

Brain activation during human navigation: gender-different neural networks as substrate of performance.

Visuospatial navigation in animals and human subjects is generally studied using maze exploration. We used functional MRI to observe brain activation in male and female subjects as they searched for the way out of a complex, three-dimensional, virtual-reality maze. Navigation activated the medial occipital gyri, lateral and medial parietal regions, posterior cingulate and parahippocampal gyri as well as the right hippocampus proper. Gender-specific group analysis revealed distinct activation of the left hippocampus in males, whereas females consistently recruited right parietal and right prefrontal cortex. Thus we demonstrate a neural substrate of well established human gender differences in spatial-cognition performance.

The RNA of the glutamate transporter EAAT2 is variably spliced in amyotrophic lateral sclerosis and normal individuals.

Impaired re-uptake of synaptic glutamate, and a reduced expression of the glutamate transporter EAAT2 have been found in the motor cortex of patients with amyotrophic lateral sclerosis (ALS). Two splice forms of the EAAT2 RNA resulting from retention of intronic sequences (EAAT2/Int) and deletion of one protein coding exon (EAAT2/C1) have been reported to account for the EAAT2 protein loss in ALS. In this study we investigated the presence of two known (EAAT2/C1; EAAT2/Int) and three novel (EAAT2/C2-4) EAAT2 RNA in motor cortex of 17 ALS cases and 11 controls. Reverse transcription and PCR were carried out to amplify the complementary DNA of the complete and variably spliced EAAT2 transcripts. Nested PCR was followed to generate amplicons specific for EAAT2/C1-4 and EAAT2/Int. EAAT2/Int was detected in 59% of ALS specimens as compared to 36% of controls showing a trend but no statistical significance of a more frequent expression in ALS (Type I error 24.6%). EAAT2/C1-4 were found to be equally expressed in ALS patients and controls. Our results indicate that the involvement of EAAT2 transcripts in ALS is unlikely to be primary, and more complex than previously recognized. Alterations of quantitative expression of distinct EAAT2 splice forms in ALS cannot be excluded from this study and remain to be investigated.

Auditory and visual working memory performance in patients with frontal lobe damage and in schizophrenic patients with low scores on the Wisconsin Card Sorting Test.

Impaired performance in the Wisconsin Card Sorting Test (WCST) has frequently been postulated to be one typical feature indicating frontal dysfunction in patients with schizophrenia. From a functional point of view, impairments were attributed to a dysfunction of working memory. The present study compares the performance of groups of schizophrenic patients, groups of patients with acquired brain damage as well as normal controls on tasks involving visual and auditory working memory. Modified versions of Sternberg tasks were used varying the physical attributes of the material to be rehearsed in order to force a different involvement of both the 'visuo-spatial sketch-pad' and the 'phonological loop'. Within a group of frontal-lobe-damaged patients (n=6), processing was markedly prolonged for both kinds of material, an observation attributed to a dysfunction of the central executive component of the working memory model. On the other hand, results for schizophrenic patients with poor WCST performance (n=6) suggest a more discrete dysfunction of the phonological loop, but not the visuo-spatial sketch-pad. There were no significant differences between normal controls (n=6) and clinical control groups [patients with non-frontal lesions (n=6) and schizophrenic patients with normal scores on the WCST (n=6)]. Comparisons of the various group data rule out an unspecified frontal dysfunction of schizophrenic patients with low scores on the WCST.

Cognitive deficits in schizophrenia and affective disorders: evidence for a final common pathway disorder.

This study was designed to determine whether patients with schizophrenia and those with affective disorders display a common pattern of cognitive deficits. Cognitive performance was assessed with a neuropsychological test battery in consecutively admitted in-patients with schizophrenia (n=100) and affective disorders (n=100). The two groups of patients showed a similar pattern of cognitive deficits, especially in tests focusing on attentional capacities. The groups only differed significantly in their performance on the Wisconsin Card Sorting Test (WCST), with the schizophrenic patients performing less well. These results suggest that, with the exception of the deficit as measured by the WCST, similar cognitive impairments exist in schizophrenia and affective disorders, even at very early stages of the illness. Therefore, patients with schizophrenia and those with affective disorders cannot be qualitatively distinguished with sufficient reliability. We postulate that the cognitive deficit pattern represents a final common pathway disorder in the two groups of patients.

Assessment of cognitive performance after progesterone administration in healthy male volunteers.

Administration of progesterone produces sleep EEG patterns that resemble those of agonistic modulators at the GABAA receptor. Previous studies evaluating the effects of an oral progesterone administration on attention performance in females pointed to putative sedative effects of progesterone at high dosages. However, no data are available whether progesterone dosages that influence sleep produce sedative hangover effects on the following morning. Therefore, we assessed the effects of a single oral dose of 300 mg micronized progesterone administered in the evening on cognitive performance parameters in male healthy volunteers on the following morning using a placebo-controlled double-blind crossover design. There was a great variability in bioavailability following progesterone intake. The administration of progesterone produced no consistent effects on attention performance. Thus, dosages of progesterone that are sufficient to modulate sleep are not likely to exert sedative hangover effects.

Cognitive slowing in patients with acquired brain damage: an experimental approach.

Nine brain-damaged patients (19-54 years old) with "cognitive slowing", and 10 healthy subjects (26-56 years old) were tested with a slightly modified version of a Sternberg memory task (varied-set procedure). Cognitive slowing in the sense of reduced information-processing speed is reflected by mean RTs and slopes and intercepts derived from the RTs as a function of memory set size. Patients showed a marked increase of these parameters. While the results obtained from the control subjects are in accordance with typical Sternberg findings, patients showed no parallel regression lines for positive and negative responses. As an alternative explanation for this result an extended "self-terminating" process is proposed that also appears to be helpful in explaining the overall cognitive slowing in the patients.