Olfactory loss is associated with reduced hippocampal activation in response to emotional pictures.

Emotional processing evolved within brain structures that were originally dedicated to olfactory function. Reduced olfactory function, absence of the olfactory bulb and the experimental removal of the olfactory bulb are associated with depressive behavior. Against this background, we hypothesized that olfactory dysfunction modifies the neural processing of non-olfactory emotion information. Using a functional magnetic resonance imaging design, we therefore tested whether people with and without impaired olfactory function differ in emotional perception and processing. Neural activity of 17 patients with acquired olfactory loss and 23 age- and sex-matched control participants were monitored in the MRI scanner, while they were presented with emotional and neutral pictures. Participants rated the valence and arousal for each picture after scanning. Patients showed reduced right hippocampal brain responses to emotional but not neutral pictures independent of their depressive symptoms. In addition, emotion-dependent activation in the hippocampus and insula was positively associated with the olfactory bulb (OB) volumes in healthy participants. Taken together, these findings suggest a disrupted neural processing of emotional pictures among patients with olfactory loss. This indicates a significant role of the neural olfactory trajectories for general emotion processing. Central emotion processing is reduced in olfactory disorders and relates to the OB volume in normosmic individuals.

Touch aversion in patients with interpersonal traumatization.

BACKGROUND: Interpersonal touch is a key aspect of human interaction and a usually very comforting experience. For patients suffering from posttraumatic stress disorders (PTSD) caused by interpersonal traumatization, such touch is affectively ambiguous. METHODS: In two studies, we investigated the experience and neural processing of various types of interpersonal and impersonal touch in patients as compared with healthy controls. RESULTS: Patients strongly disliked show, interpersonal skin-to-skin stroking, while controls appreciated this kind of touch. No group differences were observed for ratings of impersonal touch. Similarly, the neural activation differed between groups for interpersonal, but not for impersonal touch. The interpersonal touch aversion in patients was accompanied by enhanced blood-oxygen-level-dependent response in the superior temporal gyrus and by a pronounced reduction of response in the hippocampus. This reduction was significantly correlated to symptoms of negative alterations and arousal within the patients. CONCLUSION: We interpret the hippocampal suppression as an attempt to control traumatic memories, evoked by interpersonal touch. This mechanism may maintain the aversion of interpersonal touch in patients with interpersonal trauma-related PTSD.

Neural processing of odor-associated words: an fMRI study in patients with acquired olfactory loss.

Perception of olfactory information is mediated by both bottom-up (from molecules to perception) and top-down (e.g. cross-modal associative learning) processes. Acquired olfactory loss is a frequent disorder which is typically due to alterations in the bottom-up pathway. However, it is unclear how the top-down modulation of olfactory processing is affected by olfactory impairment. Our study aimed to investigate the top-down olfactory processing in patients with acquired olfactory loss and participants with normal olfaction. Using functional MRI, brain responses from 14 patients and 16 healthy controls were assessed during a task of expectation and reading of words with strong olfactory associations (OW) (e.g. "Rose") and control words with little to no olfactory associations (CW) (e.g. "Door"). The expectation but not reading of the OW was associated with stronger neural activation in the angular gyrus and the inferior frontal gyrus extending to insula in the group of patients. During OW reading, the brain activation in the left OFC and right putamen was negatively correlated with odor identification score in patient and control groups, respectively. In addition, the duration of olfactory loss among patients was positively associated with activation in the left putamen during OW expectation. Taken together, these findings suggest an enhanced top-down olfactory modulation in patients with olfactory loss.

Deactivation of default mode network during touch.

Interpersonal touch possesses a strong affective component, which immediately evokes attention. The neural processing of such touch is moderated by specialized C-tactile nerve fibers in the periphery and results in central activation of somatosensory areas as well as regions involved in social processing, such as the superior temporal gyrus (STG). In the present functional neuroimaging investigation, we tested the hypothesis that the attention grasping effect of interpersonal touch as compared to impersonal touch is reflected in a more-pronounced deactivation of the default mode network (DMN). Using functional magnetic resonance imaging, we investigated the neural processing of interpersonal relative to impersonal touch conditions that were furthermore modulated by stroking velocity in order to target c-tactile nerve fibers to a different extent. A sample of 30 healthy participants (19 women, mean age 40.5 years) was investigated. In the impersonal touch, participants were stroked with a brush on the forearm. In the interpersonal touch condition, the experimenter performed the stroking with the palm of his hand. Interpersonal touch was rated as more pleasant and intense than impersonal touch and led to a stronger blood oxygen level dependent (BOLD) signal increase in the somatosensory cortex SII extending to the superior temporal cortex. Over all touch conditions, this activation was coupled in time to the deactivation of prominent nodes of the DMN. Although deactivation of the DMN was most pronounced for interpersonal touch conditions, the direct comparison did not show significant differences in DMN deactivation between interpersonal and impersonal touch or between different stroking velocities. We therefore conclude that all applied touch conditions deactivate the DMN and the strong connection to areas which code the contextual and social characteristics of affective touch may explain the attention grasping effect of touch.

Pepper with and without a sting: Brain processing of intranasal trigeminal and olfactory stimuli from the same source.

Humans have distinct and overlapping brain regions for the processing of intranasal olfactory or trigeminal stimuli. It may be assumed that trigeminal stimulants and "trigeminal-free" odorous stimuli from the same source are processed differently in the human brain. Using functional magnetic resonance imaging (fMRI), this study investigated the question whether the black pepper (Piper nigrum) derived trigeminal active compound piperine and the trigeminal-free pepper essential oil (pepperEO) are processed in relation to their degree of trigeminal stimulation. Twenty-one young healthy adults underwent a fMRI scan where piperine and pepperEO were delivered orthonasally using an olfactometer. Ratings for intensity, irritability, and pleasantness of each stimulus were obtained at the end of the scanning session. Results showed brain activation of the trigeminal network in response to piperine, and olfactory-related areas in response to pepperEO. PepperEO induced larger activations in the trigeminal network as compared to piperine. This was possibly due to the associative learning for the pungent sensations of pepperEO. In addition, conjunction analyses showed that the secondary somatosensory area, insula, and thalamus were involved in the processing of both piperine and pepperEO. In conclusion, the results strongly suggest that the cerebral representations of trigeminal irritants can be evoked by learned associations.

Brain volume changes in hyposmic patients before and after olfactory training.

OBJECTIVES/HYPOTHESIS: Olfactory dysfunction is thought to be associated with reduced gray matter (GM) volume in olfactory-related brain areas. The aim of this study was to determine GM structural changes within olfactory-related regions of the brain in patients with smell loss due to upper respiratory tract infection (URTI) before and after olfactory rehabilitation. STUDY DESIGN: Prospective intervention case-control study. METHODS: Magnetic resonance imaging structural brain images were collected from 30 patients with smell loss due to URTI and 31 controls. Patients exposed themselves to odors (olfactory training [OT]) over 12 weeks and then were rescanned. Olfactory testing was performed using the validated Sniffin' Sticks test. GM was investigated with voxel-based morphometry. RESULTS: GM volumes were found to be reduced in the limbic system and thalamus among pretraining patients compared to controls; in patients, OT was associated with a significant increase of GM volume in these two regions. The GM volume within other olfactory-related regions was not different between patients and controls. In addition, no relevant difference between the GM volume pre- and post-OT was observed in primary olfactory-related regions. CONCLUSIONS: OT was associated with an increase in GM volume of the hippocampus and the thalamus, possibly pointing toward a strategy for more effective exploitation of olfactory signals based on a higher degree of attention toward odors and association of memories with olfactory input. LEVEL OF EVIDENCE: 3b. Laryngoscope, 128:1531-1536, 2018.

Carbamazepine-resistance in the epileptic dentate gyrus of human hippocampal slices.

Overexpression of drug efflux pumps at the blood brain barrier (BBB) has been suggested to be one important factor contributing to drug resistance in epilepsy. This would imply that resected brain tissue of drug-resistant patients is drug-sensitive in absence of the BBB. Here we studied the effects of carbamazepine (CBZ) at therapeutically relevant concentration on epileptiform activity electrophysiologically recorded in acute hippocampal slices of patients with mesial temporal lobe epilepsy (MTLE; 28 patients, 49 slices) or extra-hippocampal tumours (tumour; 6 patients, 11 slices). Epileptiform activity was induced by hilar stimulation (0.067 Hz) during elevation of extracellular potassium concentration ([K(+)](o)) and remained self-sustained in presence of 10-12 mM [K(+)](o). Quantitative analysis of data revealed that epileptiform activity in tissue of tumour-patients was predominantly suppressed by CBZ, indicating that the 'epilepsy model' used is CBZ-sensitive. In contrast, epileptiform activity in tissue of drug-resistant MTLE patients was resistant to CBZ in 82% of patients, partially suppressed in 11% and completely suppressed in 7%. The effects of CBZ in tissue of MTLE patients did not depend on the type of activity, hippocampal pathology, excitability of the tissue, or equilibration time of the drug. Considering that CBZ has direct access to all compartments of the slice, our results suggest that CBZ-resistance mechanisms are located within the parenchyma of the dentate gyrus and contribute to drug resistance in the majority of MTLE patients. BBB-located drug-resistance mechanisms per se may play a minor role in this region, because CBZ-sensitivity was only observed in 7% of CBZ-resistant patients.

Drug resistance in cortical and hippocampal slices from resected tissue of epilepsy patients: no significant impact of p-glycoprotein and multidrug resistance-associated proteins.

Drug resistant patients undergoing epilepsy surgery have a good chance to become sensitive to anticonvulsant medication, suggesting that the resected brain tissue is responsible for drug resistance. Here, we address the question whether P-glycoprotein (Pgp) and multidrug resistance-associated proteins (MRPs) expressed in the resected tissue contribute to drug resistance in vitro. Effects of anti-epileptic drugs [carbamazepine (CBZ), sodium valproate, phenytoin] and two unspecific inhibitors of Pgp and MRPs [verapamil (VPM) and probenecid (PBN)] on seizure-like events (SLEs) induced in slices from 35 hippocampal and 35 temporal cortex specimens of altogether 51 patients (161 slices) were studied. Although in slice preparations the blood brain barrier is not functional, we found that SLEs predominantly persisted in the presence of anticonvulsant drugs (90%) and also in the presence of VPM and PBN (86%). Following subsequent co-administration of anti-epileptic drugs and drug transport inhibitors, SLEs continued in 63% of 143 slices. Drug sensitivity in slices was recognized either as transition to recurrent epileptiform transients (30%) or as suppression (7%), particularly by perfusion with CBZ in PBN containing solutions (43, 9%). Summarizing responses to co-administration from more than one slice per patient revealed that suppression of seizure-like activity in all slices was only observed in 7% of patients. Patients whose tissue was completely or partially sensitive (65%) presented with higher seizure frequencies than those with resistant tissue (35%). However, corresponding subgroups of patients do not differ with respect to expression rates of drug transporters. Our results imply that parenchymal MRPs and Pgp are not responsible for drug resistance in resected tissue.

Functional test of multidrug transporter activity in hippocampal-neocortical brain slices from epileptic patients.

About 70% of the patients suffering from temporal lobe epilepsy (TLE) are resistant to currently available antiepileptic drugs (AEDs). For them one therapeutic option to achieve seizure control is to undergo epilepsy surgery. Expression of multidrug transporters is upregulated in resected tissue specimens from TLE patients, as well as in animal models of chronic epilepsy, which might lead to altered tissue availability of AEDs and therefore contribute to drug refractoriness. Here we describe a functional test of multidrug transporter activity in brain slices from TLE patients based on intracellular accumulation of the fluorescent multidrug transporter substrate calcein and compare functional data to the expression pattern of multidrug transporters. The rate of cytosolic calcein fluorescence increase was altered by inhibitors of multidrug transport such as probenecid (400 µM) and verapamil (40 µM) in a subset of slices, indicating the presence of functional multidrug transport proteins in human epileptic tissue. Interestingly, there were differences between the expression pattern of multidrug transporters and their ability to remove calcein-AM. Consequently, in vitro studies on multidrug transporters should always include functional tests of their activity as expression alone is not necessarily conclusive.