Opposing neural effects of naltrexone on food reward and aversion: implications for the treatment of obesity

Rationale: Opioid antagonism reduces the consumption of palatable foods in humans but the neural substrates implicated in these effects are less well understood. Objectives: The aim of the present study was to examine the effects of the opioid antagonist, naltrexone, on neural response to rewarding and aversive sight and taste stimuli. Methods: We used functional magnetic resonance imaging (fMRI) to examine the neural responses to the sight and taste of pleasant (chocolate) and aversive (mouldy strawberry) stimuli in 20 healthy volunteers who received a single oral dose of naltrexone (50 mg) and placebo in a double-blind, repeated-measures cross-over, design. Results: Relative to placebo, naltrexone decreased reward activation to chocolate in the dorsal anterior cingulate cortex and caudate, and increased aversive-related activation to unpleasant strawberry in the amygdala and anterior insula. Conclusions: These findings suggest that modulation of key brain areas involved in reward processing, cognitive control and habit formation such as the dorsal anterior cingulate cortex (dACC) and caudate might underlie reduction in food intake with opioid antagonism. Furthermore we show for the first time that naltrexone can increase activations related to aversive food stimuli. These results support further investigation of opioid treatments in obesity.

Neural responses to emotional faces in women recovered from anorexia nervosa

Impairments in emotional processing have been associated with anorexia nervosa. However, it is unknown whether neural and behavioural differences in the processing of emotional stimuli persist following recovery. The aim of this study was to investigate the neural processing of emotional faces in individuals recovered from anorexia nervosa compared with healthy controls. Thirty-two participants (16 recovered anorexia nervosa, 16 healthy controls) underwent a functional magnetic resonance imaging (fMRI) scan. Participants viewed fearful and happy emotional faces and indicated the gender of the face presented. Whole brain analysis revealed no significant differences between the groups to the contrasts of fear versus happy and vice versa. Region of interest analysis demonstrated no significant differences in the neural response to happy or fearful stimuli between the groups in the amygdala or fusiform gyrus. These results suggest that processing of emotional faces may not be aberrant after recovery from anorexia nervosa.

The D2 antagonist sulpiride modulates the neural processing of both rewarding and aversive stimuli in healthy volunteers.

Rationale: Animal studies indicate that dopamine pathways in the ventral striatum code for the motivational salience of both rewarding and aversive stimuli, but evidence for this mechanism in humans is less established. We have developed a functional magnetic resonance imaging (fMRI) model which permits examination of the neural processing of both rewarding and aversive stimuli. Objectives: The aim of the study was to determine the effect of the dopamine receptor antagonist, sulpiride, on the neural processing of rewarding and aversive stimuli in healthy volunteers. Methods: We studied 30 healthy participants who were randomly allocated to receive a single dose of sulpiride (400 mg) or placebo, in a double-blind, parallel-group design. We used fMRI to measure the neural response to rewarding (taste or sight of chocolate) and aversive stimuli (sight of mouldy strawberries or unpleasant strawberry taste) 4 h after drug treatment. Results: Relative to placebo, sulpiride reduced blood oxygenation level-dependent responses to chocolate stimuli in the striatum (ventral striatum) and anterior cingulate cortex. Sulpiride also reduced lateral orbitofrontal cortex and insula activations to the taste and sight of the aversive condition. Conclusions: These results suggest that acute dopamine receptor blockade modulates mesolimbic and mesocortical neural activations in response to both rewarding and aversive stimuli in healthy volunteers. This effect may be relevant to the effects of dopamine receptor antagonists in the treatment of psychosis and may also have implications for the possible antidepressant properties of sulpiride.

Reduced neural response to reward following 7 days treatment with the cannabinoid CB1 antagonist rimonabant in healthy volunteers

Reduced subjective experience of reward (anhedonia) is a key symptom of major depression. The anti-obesity drug and cannabinoid type 1 receptor (CB(1)) antagonist, rimonabant, is associated with significant rates of depression and anxiety in clinical use and was recently withdrawn from the market because of these adverse effects. Using a functional magnetic resonance imaging (fMRI) model of reward we hypothesized that rimonabant would impair reward processing. Twenty-two healthy participants were randomly allocated to receive rimonabant (20 mg), or placebo, for 7 d in a double-blind, parallel group design. We used fMRI to measure the neural response to rewarding (sight and/or flavour of chocolate) and aversive (sight of mouldy strawberries and/or an unpleasant strawberry taste) stimuli on the final day of drug treatment. Rimonabant reduced the neural response to chocolate stimuli in key reward areas such as the ventral striatum and the orbitofrontal cortex. Rimonabant also decreased neural responses to the aversive stimulus condition in the caudate nucleus and ventral striatum, but increased lateral orbitofrontal activations to the aversive sight and taste of strawberry condition. Our findings are the first to show that the anti-obesity drug rimonabant inhibits the neural processing of rewarding food stimuli in humans. This plausibly underlies its ability to promote weight loss, but may also indicate a mechanism for inducing anhedonia which could lead to the increased risk of depressive symptomatology seen in clinical use. fMRI may be a useful method of screening novel agents for unwanted effects on reward and associated clinical adverse reactions.

NK1 receptor antagonism and the neural processing of emotional information in healthy volunteers

The neuropeptide substance P and its receptor NK1 have been implicated in emotion, anxiety and stress in preclinical studies. However, the role of NK1 receptors in human brain function is less clear and there have been inconsistent reports of the value of NK1 receptor antagonists in the treatment of clinical depression. The present study therefore aimed to investigate effects of NK1 antagonism on the neural processing of emotional information in healthy volunteers. Twenty-four participants were randomized to receive a single dose of aprepitant (125 mg) or placebo. Approximately 4 h later, neural responses during facial expression processing and an emotional counting Stroop word task were assessed using fMRI. Mood and subjective experience were also measured using self-report scales. As expected a single dose of aprepitant did not affect mood and subjective state in the healthy volunteers. However, NK1 antagonism increased responses specifically during the presentation of happy facial expressions in both the rostral anterior cingulate and the right amygdala. In the emotional counting Stroop task the aprepitant group had increased activation in both the medial orbitofrontal cortex and the precuneus cortex to positive vs. neutral words. These results suggest consistent effects of NK1 antagonism on neural responses to positive affective information in two different paradigms. Such findings confirm animal studies which support a role for NK1 receptors in emotion. Such an approach may be useful in understanding the effects of novel drug treatments prior to full-scale clinical trials.

Neural representation of reward in recovered depressed patients

These findings support the view that abnormal neural responses to reward may be an endophenotype for depression and a potential target for intervention and prevention strategies.

Towards optimizing the selection of neurons in affordable neural networks

This paper considers variations of a neuron pool selection method known as Affordable Neural Network (AfNN). A saliency measure, based on the second derivative of the objective function is proposed to assess the ability of a trained AfNN to provide neuronal redundancy. The discrepancies between the various affordability variants are explained by correlating unique sub group selections with relevant saliency variations. Overall this study shows that the method in which neurons are selected from a pool is more relevant to how salient individual neurons are, than how often a particular neuron is used during training. The findings herein are relevant to not only providing an analogy to brain function but, also, in optimizing the way a neural network using the affordability method is trained.

Single-carrier frequency domain equalisation for hammerstein communication systems using complex-valued neural networks

Single-carrier (SC) block transmission with frequency-domain equalisation (FDE) offers a viable transmission technology for combating the adverse effects of long dispersive channels encountered in high-rate broadband wireless communication systems. However, for high bandwidthefficiency and high power-efficiency systems, the channel can generally be modelled by the Hammerstein system that includes the nonlinear distortion effects of the high power amplifier (HPA) at transmitter. For such nonlinear Hammerstein channels, the standard SC-FDE scheme no longer works. This paper advocates a complex-valued (CV) B-spline neural network based nonlinear SC-FDE scheme for Hammerstein channels. Specifically, We model the nonlinear HPA, which represents the CV static nonlinearity of the Hammerstein channel, by a CV B-spline neural network, and we develop two efficient alternating least squares schemes for estimating the parameters of the Hammerstein channel, including both the channel impulse response coefficients and the parameters of the CV B-spline model. We also use another CV B-spline neural network to model the inversion of the nonlinear HPA, and the parameters of this inverting B-spline model can easily be estimated using the standard least squares algorithm based on the pseudo training data obtained as a natural byproduct of the Hammerstein channel identification. Equalisation of the SC Hammerstein channel can then be accomplished by the usual one-tap linear equalisation in frequency domain as well as the inverse B-spline neural network model obtained in time domain. Extensive simulation results are included to demonstrate the effectiveness of our nonlinear SC-FDE scheme for Hammerstein channels.

The anterior temporal lobes support residual comprehension in Wernicke’s aphasia

Wernicke’s aphasia occurs following a stroke to classical language comprehension regions in the left temporoparietal cortex. Consequently, auditory-verbal comprehension is significantly impaired in Wernicke’s aphasia but the capacity to comprehend visually presented materials (written words and pictures) is partially spared. This study used fMRI to investigate the neural basis of written word and picture semantic processing in Wernicke’s aphasia, with the wider aim of examining how the semantic system is altered following damage to the classical comprehension regions. Twelve participants with Wernicke’s aphasia and twelve control participants performed semantic animate-inanimate judgements and a visual height judgement baseline task. Whole brain and ROI analysis in Wernicke’s aphasia and control participants found that semantic judgements were underpinned by activation in the ventral and anterior temporal lobes bilaterally. The Wernicke’s aphasia group displayed an “over-activation” in comparison to control participants, indicating that anterior temporal lobe regions become increasingly influential following reduction in posterior semantic resources. Semantic processing of written words in Wernicke’s aphasia was additionally supported by recruitment of the right anterior superior temporal lobe, a region previously associated with recovery from auditory-verbal comprehension impairments. Overall, the results concord with models which indicate that the anterior temporal lobes are crucial for multimodal semantic processing and that these regions may be accessed without support from classic posterior comprehension regions.

Smart-phone based electrocardiogram wavelet decomposition and neural network classification

This paper discusses ECG classification after parametrizing the ECG waveforms in the wavelet domain. The aim of the work is to develop an accurate classification algorithm that can be used to diagnose cardiac beat abnormalities detected using a mobile platform such as smart-phones. Continuous time recurrent neural network classifiers are considered for this task. Records from the European ST-T Database are decomposed in the wavelet domain using discrete wavelet transform (DWT) filter banks and the resulting DWT coefficients are filtered and used as inputs for training the neural network classifier. Advantages of the proposed methodology are the reduced memory requirement for the signals which is of relevance to mobile applications as well as an improvement in the ability of the neural network in its generalization ability due to the more parsimonious representation of the signal to its inputs.

Coordinated Cluster, ground-based instrumentation and low-altitude satellite observations of transient poleward-moving events in the ionosphere and in the tail lobe

During the interval between 8:00-9:30 on 14 January 2001, the four Cluster spacecraft were moving from the central magnetospheric lobe, through the dusk sector mantle, on their way towards intersecting the magnetopause near 15:00 MLT and 15:00 UT. Throughout this interval, the EIS-CAT Svalbard Radar (ESR) at Longyearbyen observed a series of poleward-moving transient events of enhanced F-region plasma concentration ("polar cap patches"), with a repetition period of the order of 10 min. Allowing for the estimated solar wind propagation delay of 75 ( 5) min, the interplanetary magnetic field (IMF) had a southward component during most of the interval. The magnetic footprint of the Cluster spacecraft, mapped to the ionosphere using the Tsyganenko T96 model (with input conditions prevailing during this event), was to the east of the ESR beams. Around 09:05 UT, the DMSP-F12 satellite flew over the ESR and showed a sawtooth cusp ion dispersion signature that also extended into the electrons on the equatorward edge of the cusp, revealing a pulsed magnetopause reconnection. The consequent enhanced ionospheric flow events were imaged by the SuperDARN HF backscatter radars. The average convection patterns (derived using the AMIE technique on data from the magnetometers, the EISCAT and SuperDARN radars, and the DMSP satellites) show that the associated poleward-moving events also convected over the predicted footprint of the Cluster spacecraft. Cluster observed enhancements in the fluxes of both electrons and ions. These events were found to be essentially identical at all four spacecraft, indicating that they had a much larger spatial scale than the satellite separation of the order of 600 km. Some of the events show a correspondence between the lowest energy magnetosheath electrons detected by the PEACE instrument on Cluster (10-20 eV) and the topside ionospheric enhancements seen by the ESR (at 400-700 km). We suggest that a potential barrier at the magnetopause, which prevents the lowest energy electrons from entering the magnetosphere, is reduced when and where the boundary-normal magnetic field is enhanced and that the observed polar cap patches are produced by the consequent enhanced precipitation of the lowest energy electrons, making them and the low energy electron precipitation fossil remnants of the magnetopause reconnection rate pulses.

Reconfiguration and closure of lobe flux by reconnection during northward IMF: possible evidence for signatures in cusp/cleft auroral emissions

Observations are presented of the response of the dayside cusp/cleft aurora to changes in both the clock and elevation angles of the interplanetary magnetic field (IMF) vector, as monitored by the WIND spacecraft. The auroral observations are made in 630 nm light at the winter solstice near magnetic noon, using an all-sky camera and a meridian-scanning photometer on the island of Spitsbergen. The dominant change was the response to a northward turning of the IMF which caused a poleward retreat of the dayside aurora. A second, higher-latitude band of aurora was seen to form following the northward turning, which is interpreted as the effect of lobe reconnection which reconfigures open flux. We suggest that this was made possible in the winter hemisphere, despite the effect of the Earth's dipole tilt, by a relatively large negative X component of the IMF. A series of five events then formed in the poleward band and these propagated in a southwestward direction and faded at the equatorward edge of the lower-latitude band as it migrated poleward. It is shown that the auroral observations are consistent with overdraped lobe flux being generated by lobe reconnection in the winter hemisphere and subsequently being re-closed by lobe reconnection in the summer hemisphere. We propose that the balance between the reconnection rates at these two sites is modulated by the IMF elevation angle, such that when the IMF points more directly northward, the summer lobe reconnection site dominates, re-closing all overdraped lobe flux and eventually becoming disconnected from the Northern Hemisphere.

Neural effects of cannabinoid CB1 neutral antagonist tetrahydrocannabivarin (THCv) on food reward and aversion in healthy volunteers

Disturbances in the regulation of reward and aversion in the brain may underlie disorders such as obesity and eating disorders. We previously showed that the cannabis receptor subtype (CB1) inverse agonist rimonabant, an antiobesity drug withdrawn due to depressogenic side effects, diminished neural reward responses yet increased aversive responses (Horder et al., 2010). Unlike rimonabant, tetrahydrocannabivarin is a neutral CB1 receptor antagonist (Pertwee, 2005) and may therefore produce different modulations of the neural reward system. We hypothesized that tetrahydrocannabivarin would, unlike rimonabant, leave intact neural reward responses but augment aversive responses. Methods: We used a within-subject, double-blind design. Twenty healthy volunteers received a single dose of tetrahydrocannabivarin (10mg) and placebo in randomized order on 2 separate occasions. We measured the neural response to rewarding (sight and/or flavor of chocolate) and aversive stimuli (picture of moldy strawberries and/or a less pleasant strawberry taste) using functional magnetic resonance imaging. Volunteers rated pleasantness, intensity, and wanting for each stimulus. Results: There were no significant differences between groups in subjective ratings. However, tetrahydrocannabivarin increased responses to chocolate stimuli in the midbrain, anterior cingulate cortex, caudate, and putamen. Tetrahydrocannabivarin also increased responses to aversive stimuli in the amygdala, insula, mid orbitofrontal cortex, caudate, and putamen. Conclusions: Our findings are the first to show that treatment with the CB1 neutral antagonist tetrahydrocannabivarin increases neural responding to rewarding and aversive stimuli. This effect profile suggests therapeutic activity in obesity, perhaps with a lowered risk of depressive side effects. Keywords: reward, THCv, obesity, fMRI, cannabinoid

MCP-1 induces migration of adult neural stem cells

As a model for brain inflammation we previously studied transcriptional profiles of tumor necrosis factor-alpha (TNF)treated U373 astroglioma cells. In previous work we were able to demonstrate that the chemokine monocyte chemoattractant protein-1 (MCP-1, SCYA2, CCL2, MCAF) expression in U373 cells was inducible by TNF-alpha treatment. Demonstrably MCP-1 mRNA and protein expression in U373 cells was sustainable over time and at the highest level of all genes analyzed (Schwamborn et al., BMC Genomics 4, 46, 2003). In the hematopoietic system MCP-1 is a CC chemokine that attracts monocytes, memory T lymphocytes, and natural killer cells. In search of further functions in brain inflammation we tested the hypothesis that MCP-1 acts as a chemokine on neural stem cells. Here we report that MCP-1 activates the migration capacity of rat-derived neural stem cells. The migration of stem cells in a Boyden chamber analysis was elevated after stimulation with MCP-1. Time-lapse video microscopy visualized the migration of single stem cells from neurospheres in MCP-1-treated cultures, whereas untreated cultures depicted no migration at all, but showed signs of sprouting. Expression of the MCP-1 receptor CCR2 in neurosphere cultures was verified by RT-PCR and immunofluorescence microscopy. Supernatants from TNF-treated U373 cells also induced migration of neural stem cells.