Aberrant frontostriatal connectivity in Alzheimer's disease with positive palmomental reflex.

BACKGROUND AND PURPOSE: Primitive reflexes may reoccur in various neurodegenerative diseases. However, little is known about their structural and functional correlates in the human brain. Notably, the neural mechanisms underlying a positive palmomental reflex (PMR) are poorly understood. As recent studies link Alzheimer's disease (AD)-related primitive reflexes to a dysfunction of the corticostriatal motor circuit (CMC), we conducted the present study to investigate functional and structural correlates of a positive PMR. We hypothesized an involvement of frontostriatal structures and an impairment of the CMC. METHODS: Using whole-brain resting-state functional connectivity (FC), hypothesis and FC result-based probabilistic tractography, and voxel-based morphometry analyses, we compared two groups of AD patients with either positive (n = 12) or negative PMR (n = 12). RESULTS: No significant differences in grey matter volume or structural connectivity (SC) could be observed between the PMR-positive and PMR-negative groups. In contrast, the PMR-positive group showed a decreased seed-to-voxel FC between the bilateral supplementary motor area and parts of the right-hemispherical caudate nucleus and thalamus and a decreased region of interest (ROI)-to-ROI FC between the left putamen and the left superior frontal gyrus. CONCLUSION: Data suggest that dysfunction of the CMC reflected by decreased FC underlies a positive PMR in patients with AD. The lack of significant grey matter or SC differences might reflect that changes in FC appear before changes in SC in the structures of the CMC and brain atrophy.

Test-retest variability of resting-state networks in healthy aging and prodromal Alzheimer's disease.

In recent years, changes in resting-state networks (RSN), identified by functional magnetic resonance imaging (fMRI), have gained increasing attention as potential biomarkers and trackers of neurological disorders such as Alzheimer's disease (AD). Intersession reliability of RSN is fundamental to this approach. In this study, we investigated the test-retest reliability of three memory related RSN (i.e., the default mode, salience, and executive control network) in 15 young, 15 healthy seniors (HS), and 15 subjects affected by mild cognitive impairment (MCI) with positive biomarkers suggestive of incipient AD (6 females each). FMRI was conducted on three separate occasions. Independent Component Analysis decomposed the resting-state data into RSNs. Comparisons of variation in functional connectivity between groups were made applying different thresholds in an explorative approach. Intersession test-retest reliability was evaluated by intraclass correlation coefficient (ICC) comparisons. To assess the effect of gray matter volume loss, motion, cerebrospinal fluid based biomarkers and the time gap between sessions on intersession variation, the former four were correlated separately with the latter. Data showed that i) young subjects ICCs (relative to HS/MCI-subjects) had higher intersession reliability, ii) stringent statistical thresholds need to be applied to prevent false-positives, iii) both HS and MCI-subjects (relative to young) showed significantly more clusters of intersession variation in all three RSN, iv) while intersession variation was highly correlated with head motion, it was also correlated with biomarkers (especially phospho-tau), the time gap between sessions and local GMV. Results indicate that time gaps between sessions should be kept constant and that head motion must be taken into account when using RSN to assess aging and neurodegeneration. In patients with prodromal AD, re-test reliability may be increased by accouting for overall disease burden by including biomarkers of neuronal injury (especially phospho-tau) in statistical analyses. Local atrophy however, does not seem to play a major role in regards to reliability, but should be used as covariate depending on the research question.

[The Therapeutic Dilemma in Treatment of Intracranial Infectious Aneurysm in Patients with Infective Endocarditis: Proposal for a Patient-Centered, Interdisciplinary Treatment Concept]. / Das infektiöse Pseudoaneurysma - eine seltene Komplikation bei Patienten mit septischem Krankheitsbild: aktuelle Datenlage und Vorschlag eines diagnostischen und therapeutischen Algorithmus.

Intracranial infectious aneurysms are rare but hazardous complications of an infective endocarditis. To date, there are no evidence-based recommendations for the treatment of patients with this condition. Therefore, it remains an interdisciplinary challenge to decide which treatment steps are required and in which order they should be carried out. To illustrate the interdisciplinary dilemma in the treatment of these patients, we here present a case of a 23-year-old, drug-addicted woman with infectious endocarditis. While antibiotic treatment of the streptococcus-mitis-induced endocarditis stabilized the overall status of the patient, rupture of a basilar artery aneurysm caused her sudden death. We discuss the decision-making processes of the treatment, potential difficulties and dilemmas when dealing with patients suffering from infectious endocarditis and infectious intracranial aneurysm. Based upon case reports, studies and reviews, we present the options and risks of conservative, neurosurgical, endovascular, and cardiosurgical treatment of intracranial infectious aneurysms, and propose a patient-centered, interdisciplinary treatment concept.

Noradrenergic-glucocorticoid modulation of emotional memory encoding in the human hippocampus.

BACKGROUND: Current rodent models emphasize the joint action of the stress mediators noradrenaline (NE) and cortisol (CORT) in conferring a memory advantage of emotional over neutral stimuli. METHOD: Using a pharmacological strategy of tackling this stress-related mechanism to enhance human episodic (autobiographical) memory, we measured amygdala-hippocampal responses during encoding of emotional and neutral stimuli with functional magnetic resonance imaging in 51 healthy subjects under four pharmacological conditions in a double-blind parallel group design: (i) placebo; (ii) the NE-reuptake inhibitor reboxetine (4 mg); (iii) hydrocortisone (synthetic CORT) (30 mg); or (iv) both agents in combination. RESULTS: Differential drug effects were found in the left hippocampus, whereas hydrocortisone alone selectively decreased hippocampal responses to emotional relative to neutral stimuli, reboxetine potentiated hippocampal responses to these stimuli. Importantly, the inhibitory influence of hydrocortisone was reversed by co-administration of reboxetine. CONCLUSIONS: Our results imply that stress levels of CORT alone attenuate hippocampal responses to emotional stimuli, an effect possibly related to a regulatory negative feedback loop. However, when simultaneously elevated to stress levels, NE and CORT act together to synergistically enhance hippocampal activity during encoding of emotional stimuli, a mechanism that may turn maladaptive under circumstances of traumatic stress.

[Neurobiology of neglect: implications for new therapeutic strategies]. / Neurobiologische Grundlagen des Neglects: Implikationen für neue Therapieansätze.

Neglect is characterised by a clinically relevant impairment of spatial perception and awareness observed after focal brain damage. The neglect-specific deficit in responding to contralesional stimuli in various sensory modalities is most commonly explained by impairments of spatial attention, spatial working memory, impaired spatial reference frames and lateralised movement initiation. Many neglect interventions have been developed in the last decades to alleviate symptoms of neglect in stroke patients. However, hardly any of these methods has been proven to significantly ameliorate the patient's deficits in everyday activities. Thus, the identification of predictors for recovery of function and of the success of rehabilitative measures provides a major challenge for future research on neglect.

Medial temporal lobe dysfunction during encoding and retrieval of episodic memory in non-demented APOE epsilon4 carriers.

Presence of the apolipoprotein E (APOE) epsilon4 allele is linked to an increased risk to develop Alzheimer's dementia (AD). However, there are controversial data concerning the impact of the APOE genotype on cognitive functioning and brain activity in healthy subjects. We used event-related functional magnetic resonance imaging (fMRI) to investigate the effects of APOE genotype on spatial contextual memory encoding and retrieval success in healthy older adults. Eighteen subjects (eight APOE4 heterozygotes (epsilon4+) and 10 non-carriers (epsilon4-), mean age 60.0+/-5.0 years) were included in the present analysis. Behaviorally, epsilon4+ subjects performed significantly worse than epsilon4- subjects in item memory and spatial context retrieval. fMRI data revealed that epsilon4+ subjects, compared to epsilon4-subjects, predominantly showed an increase of neural activity specific to encoding of items and their spatial context in prefrontal, temporal and parietal regions. In contrast, epsilon4+ subjects showed activity decreases in the right amygdala during successful item recognition and in the prefrontal cortex bilaterally during spatial context retrieval when compared to epsilon4- subjects. While the activity increases during encoding may reflect compensatory activity in the attempt to maintain normal performance, the decreases during retrieval indicate incipient neural decline in epsilon4+ subjects. These data highlight that preclinical ApoE-related changes in neural activity are not unidirectional but dissociate depending on the memory phase, i.e., encoding or retrieval.

Human amygdala reactivity is diminished by the ß-noradrenergic antagonist propranolol.

BACKGROUND: Animal models of anxiety disorders emphasize the crucial role of locus ceruleus-noradrenergic (norepinephrine, NE) signaling, the basolateral amygdala (BLA) and their interactions in the expression of anxiety-like behavioral responses to stress. Despite clinical evidence for the efficacy of a ß-noradrenergic receptor blockade with propranolol in the alleviation of anxiety symptoms and the secondary prevention of post traumatic stress disorder, preclinical evidence for a ß-noradrenergic modulation of BLA activity in humans is missing. METHOD: We combined functional magnetic resonance imaging in healthy volunteers with probabilistic mapping of intra-amygdalar responses to fearful, neutral and happy facial expressions to test the hypothesis that a ß-noradrenergic receptor blockade with propranolol would inactivate the BLA. RESULTS: Consistent with our a priori hypothesis, propranolol diminished BLA responses to facial expressions, independent of their emotional valence. The absence of activity changes in probabilistically defined visual control regions underscores the specific action of propranolol in the BLA. CONCLUSIONS: Our findings provide the missing link between the anxiolytic potential of propranolol and the biological basis of ß-noradrenergic activation in the human BLA as a key target for the pharmacological inhibition of anxiety neurocircuitry. Moreover, our findings add to emerging evidence that NE modulates both the reactivity (sensitivity) and the operating characteristics (specificity) of the BLA via ß-noradrenergic receptors.

The effect of nicotine on visuospatial attention in chronic spatial neglect depends upon lesion location.

The deficit to reorient attention from ipsilesional to contralesional space is one key feature of the spatial neglect syndrome. As previous studies suggest that reorienting of visuospatial attention is modulated by cholinergic neurotransmission, we investigated whether cholinergic stimulation with nicotine (Nicorette 2 mg, Pharmacia/Pfizer, Helsingborg, Sweden) facilitates attentional reorienting in spatial neglect patients. Nine nonsmoking patients with stable neglect symptoms were investigated in a within-subject cross-over design. We used a location-cueing paradigm and analysed reaction time (RT) differences between validly and invalidly cued, as well as between neutrally cued and uncued targets as a function of hemifield and drug. Moreover, since the nicotine effect is mediated by parietal brain areas in healthy subjects, we tested whether lesion location influences the pharmacological effect. Nicotine speeded RTs in valid and invalid trials nonspecifically, without modulating the validity effect in the location-cueing task in the whole group of patients. Lesion-symptom mapping revealed a relationship between lesion site and the pharmacological effect on reorienting to contralesional space in right parietal and temporal brain regions. We conclude that in patients with chronic spatial neglect the performance in the location-cueing paradigm can be modulated by a cholinergic stimulant provided that the lesion spares right parietal and temporal cortex.

Modulation of K+-evoked [3H]-noradrenaline release from rat and human brain slices by gabapentin: involvement of KATP channels.

To elucidate the mechanism of action of the anticonvulsant gabapentin (GBP), we compared its effects on K+-evoked [3H]-noradrenaline ([3H]-NA) release from rat hippocampal and human neocortical slices with those of the KATP channel opener pinacidil and the Na+ channel blockers phenytoin, carbamazepine and lamotrigine. Rat hippocampal and human neocortical slices were loaded with [3H]-NA and superfused. [3H]-NA release was evoked by increasing the extracellular [K+] from 3 to 15 mM. GBP decreased [3H]-NA release from rat hippocampal with a pIC50 of 5.59 and a maximum inhibition of 44%. Concentration-dependent inhibition was also seen in human neocortical slices (39% inhibition with 100 microM GBP). These inhibitory effects were antagonized by the KATP channel antagonist glibenclamide, yielding a pA2 of 7.50 in the rat. The KATP channel opener pinacidil (10 microM), like GBP, decreased [3H]-NA release from rat hippocampal slices by 27% and this effect was also antagonized by glibenclamide. In human neocortical slices the inhibition by pinacidil (10 microM) was 31%. Although phenytoin (10 microM), carbamazepine (100 microM) and lamotrigine (10 microM) also decreased [3H]-NA release (by 25%, 57% and 22%, respectively), glibenclamide did not antagonize the effects of these classical Na+ channel blockers. These findings suggest that GBP inhibits K+-evoked [3H]-NA release through activation of KATP channels. To establish whether the KATP channels under investigation were located on noradrenergic nerve terminals or on other neuronal elements, the effects of GBP were compared in the absence and in the presence of tetrodotoxin (TTX 0.32 microM) throughout superfusion. Since the functional elimination of the perikarya of interneurons by TTX reduced the inhibitory effect of GBP, the KATP channels mediating the effect of GBP may be located on nerve terminals, probably on both noradrenergic and glutamatergic nerve endings.