Reduction of Aversive Learning Rates in Pavlovian Conditioning by Angiotensin II Antagonist Losartan: A Randomized Controlled Trial.

BACKGROUND: Angiotensin receptor blockade has been linked to aspects of aversive learning and memory formation and to the prevention of posttraumatic stress disorder symptom development. METHODS: We investigated the influence of the angiotensin receptor blocker losartan on aversive Pavlovian conditioning using a probabilistic learning paradigm. In a double-blind, randomized, placebo-controlled design, we tested 45 (18 female) healthy volunteers during a baseline session, after application of losartan or placebo (drug session), and during a follow-up session. During each session, participants engaged in a task in which they had to predict the probability of an electrical stimulation on every trial while the true shock contingencies switched repeatedly between phases of high and low shock threat. Computational reinforcement learning models were used to investigate learning dynamics. RESULTS: Acute administration of losartan significantly reduced participants' adjustment during both low-to-high and high-to-low threat changes. This was driven by reduced aversive learning rates in the losartan group during the drug session compared with baseline. The 50-mg drug dose did not induce reduction of blood pressure or change in reaction times, ruling out a general reduction in attention and engagement. Decreased adjustment of aversive expectations was maintained at a follow-up session 24 hours later. CONCLUSIONS: This study shows that losartan acutely reduces Pavlovian learning in aversive environments, thereby highlighting a potential role of the renin-angiotensin system in anxiety development.

A single administration of the antibiotic, minocycline, reduces fear processing and improves implicit learning in healthy volunteers: analysis of the serum metabolome.

Minocycline has shown therapeutic promise in pre-clinical animal models and early phase clinical trials for a variety of psychiatric disorders. Previous studies on minocycline have shown its ability to suppress microglia activity and reduce inflammatory cytokine levels, and its amelioration of depressive-like behaviour in animals and humans. However, the underlying mechanisms that lead to minocycline's psychotropic effects are not clear. In this study, we investigated the psychological and biochemical effects of an acute dose of minocycline or placebo in 40 healthy adult volunteers. Psychological changes in emotional processing, implicit learning, and working memory were assessed. Plasma inflammatory markers, measured with enzyme-linked immunosorbent assays, and serum metabolites, measured with proton nuclear magnetic resonance combined with multi-variate analysis techniques, were also studied. Results showed that minocycline administration decreased fear misclassification and increased contextual learning, which suggested that reducing negative biases and improving cognition, respectively, may underlie the antidepressant actions of this agent. An examination of serum metabolites revealed higher levels of lipoproteins, particularly cholesterol, in the minocycline group. Minocycline also decreased circulating concentrations of the inflammatory marker C-Reactive Peptide, which is consistent with previous research. These effects highlight two important psychological mechanisms that may be relevant to the efficacy of minocycline reported in clinical trials, and also suggest a possible largely unexplored lipid-related biochemical pathway for the action of this drug.

Methylphenidate enhances implicit learning in healthy adults.

BACKGROUND AND PURPOSE: One limiting factor in the development of pharmacological interventions to enhance cognition is the absence of biomarkers that can be used in healthy volunteers to screen novel compounds. Drug discovery has tended to rely heavily on explicit measures of cognition, but these are typically insensitive to cognition-enhancing effects in healthy volunteers. This study investigated whether a novel battery of implicit cognition measures is sensitive to the effects of methylphenidate (Ritalin) in healthy volunteers. EXPERIMENTAL APPROACH: Eighty healthy volunteers were randomised to receive either a single (10 mg) dose of methylphenidate or matched placebo. Participants completed a battery of tasks measuring implicit cognition (location priming, contextual cueing, implicit task switching). The effect of methylphenidate on standard, explicit measures of cognition was also assessed. KEY RESULTS: Methylphenidate enhanced implicit learning on the location priming task and the implicit task-switching task. In line with previous work, we found that these effects were greater in male volunteers. There was no evidence for improved learning in any of the explicit measures. CONCLUSION AND IMPLICATIONS: These results demonstrate that implicit measures of cognition are sensitive to pharmacological interventions in healthy volunteers. As such, implicit cognition measures may be a useful way of screening and tracking cognitive effects of novel agents in experimental medicine studies.

A specific role for serotonin in overcoming effort cost.

Serotonin is implicated in many aspects of behavioral regulation. Theoretical attempts to unify the multiple roles assigned to serotonin proposed that it regulates the impact of costs, such as delay or punishment, on action selection. Here, we show that serotonin also regulates other types of action costs such as effort. We compared behavioral performance in 58 healthy humans treated during 8 weeks with either placebo or the selective serotonin reuptake inhibitor escitalopram. The task involved trading handgrip force production against monetary benefits. Participants in the escitalopram group produced more effort and thereby achieved a higher payoff. Crucially, our computational analysis showed that this effect was underpinned by a specific reduction of effort cost, and not by any change in the weight of monetary incentives. This specific computational effect sheds new light on the physiological role of serotonin in behavioral regulation and on the clinical effect of drugs for depression. CLINICAL TRIAL REGISTRATION: ISRCTN75872983.

Better sexual acceptability of agomelatine (25 and 50 mg) compared to escitalopram (20 mg) in healthy volunteers. A 9-week, placebo-controlled study using the PRSexDQ scale.

The present double-blind, placebo-controlled study evaluates the effects of agomelatine and the selective serotonin reuptake inhibitor escitalopram on sexual dysfunction in healthy men and women. METHODS: A total of 133 healthy volunteers (67 men, 66 women) were randomly assigned to agomelatine (25 or 50 mg) or escitalopram (20 mg) or placebo for nine weeks. Sexual acceptability was evaluated by using the psychotropic-related sexual dysfunction questionnaire 5-items total score and sexual dysfunction relative to each sub-score (in 110 volunteers with sexual activity). Sexual dysfunction was evaluated at baseline and after two, five and eight weeks of treatment and one week after drug discontinuation. RESULTS: The psychotropic-related sexual dysfunction questionnaire 5-items total score was significantly lower in both agomelatine groups versus escitalopram at all visits (p < 0.01 to p < 0.0001) with no difference between agomelatine and placebo nor between both agomelatine doses. Similar results were observed after drug discontinuation. The total score was significantly higher in the escitalopram group than in the placebo group at each post-baseline visit (p < 0.01 to p < 0.001). Similar results were observed regardless of volunteers' gender. Compared to placebo, only escitalopram significantly impaired dysfunction relative to "delayed orgasm or ejaculation" (p < 0.01) and "absence of orgasm or ejaculation" (p < 0.05 to p < 0.01). The percentage of participants with a sexual dysfunction was higher in the escitalopram group than in agomelatine groups (p < 0.01 to p < 0.05) and placebo (p < 0.01). CONCLUSION: The study confirms the better sexual acceptability profile of agomelatine (25 or 50 mg) in healthy men and women, compared to escitalopram. TRIAL REGISTRATION NAME: Evaluation of the effect of agomelatine and escitalopram on emotions and motivation in healthy male and female volunteers. TRIAL REGISTRATION NUMBER: ISRCTN75872983.

Short-term plasticity of visuo-haptic object recognition.

Functional magnetic resonance imaging (fMRI) studies have provided ample evidence for the involvement of the lateral occipital cortex (LO), fusiform gyrus (FG), and intraparietal sulcus (IPS) in visuo-haptic object integration. Here we applied 30 min of sham (non-effective) or real offline 1 Hz repetitive transcranial magnetic stimulation (rTMS) to perturb neural processing in left LO immediately before subjects performed a visuo-haptic delayed-match-to-sample task during fMRI. In this task, subjects had to match sample (S1) and target (S2) objects presented sequentially within or across vision and/or haptics in both directions (visual-haptic or haptic-visual) and decide whether or not S1 and S2 were the same objects. Real rTMS transiently decreased activity at the site of stimulation and remote regions such as the right LO and bilateral FG during haptic S1 processing. Without affecting behavior, the same stimulation gave rise to relative increases in activation during S2 processing in the right LO, left FG, bilateral IPS, and other regions previously associated with object recognition. Critically, the modality of S2 determined which regions were recruited after rTMS. Relative to sham rTMS, real rTMS induced increased activations during crossmodal congruent matching in the left FG for haptic S2 and the temporal pole for visual S2. In addition, we found stronger activations for incongruent than congruent matching in the right anterior parahippocampus and middle frontal gyrus for crossmodal matching of haptic S2 and in the left FG and bilateral IPS for unimodal matching of visual S2, only after real but not sham rTMS. The results imply that a focal perturbation of the left LO triggers modality-specific interactions between the stimulated left LO and other key regions of object processing possibly to maintain unimpaired object recognition. This suggests that visual and haptic processing engage partially distinct brain networks during visuo-haptic object matching.

Vision holds a greater share in visuo-haptic object recognition than touch.

The integration of visual and haptic input can facilitate object recognition. Yet, vision might dominate visuo-haptic interactions as it is more effective than haptics in processing several object features in parallel and recognizing objects outside of reaching space. The maximum likelihood approach of multisensory integration would predict that haptics as the less efficient sense for object recognition gains more from integrating additional visual information than vice versa. To test for asymmetries between vision and touch in visuo-haptic interactions, we measured regional changes in brain activity using functional magnetic resonance imaging while healthy individuals performed a delayed-match-to-sample task. We manipulated identity matching of sample and target objects: We hypothesized that only coherent visual and haptic object features would activate unified object representations. The bilateral object-specific lateral occipital cortex, fusiform gyrus, and intraparietal sulcus showed increased activation to crossmodal compared to unimodal matching but only for congruent object pairs. Critically, the visuo-haptic interaction effects in these regions depended on the sensory modality which processed the target object, being more pronounced for haptic than visual targets. This preferential response of visuo-haptic regions indicates a modality-specific asymmetry in crossmodal matching of visual and haptic object features, suggesting a functional primacy of vision over touch in visuo-haptic object recognition.

Does training or deprivation modulate amygdala activation?

Amygdala involvement in visual emotional processing has been unequivocally established, but the amygdala's participation in auditory emotional processing is less clear. In a previous functional magnetic resonance imaging study (Klinge et al., 2010) we investigated the amygdala's role in auditory emotional processing in blind and sighted humans. We observed stronger amygdala responses to auditory emotional stimuli in the blind who were also better at discriminating emotional stimuli. Importantly, inter-individual differences in this skill correlated with amygdala activation. While these data suggested that the amygdala serves the dominant sensory modality for emotional perception, we could not rule out possible influences of use-dependent training effects. To disambiguate between plastic changes due to deprivation or training we now studied professional actors who have undergone extensive perceptual and expressive auditory emotional trainings but no sensory deprivation. Actors showed emotion discrimination skills comparable to those of blind individuals. However, in contrast to blind volunteers they lacked increased amygdala activations. Surprisingly, actors selectively rated angry stimuli as less intense than control participants, paralleled by a down-regulation of amygdala responses via the anterior cingulate cortex. Taken together, the data from our two studies suggest that enhanced amygdala responses in the blind are mainly due to deprivation-induced plasticity, as highly trained actors who possess the same excellent emotion discrimination skills as the blind did not show these responses. It is also conceivable that the actors' training requires a more professional and controlled dealing with the emotional stimuli, resulting in a down-regulation of affective experience and accompanying amygdala responses.

The left fusiform gyrus hosts trisensory representations of manipulable objects.

During object manipulation the brain integrates the visual, auditory, and haptic experience of an object into a unified percept. Previous brain imaging studies have implicated for instance the dorsal part of the lateral occipital complex in visuo-tactile and the posterior superior temporal sulcus in audio-visual integration of object-related inputs (Amedi et al., 2005). Yet it is still unclear which brain regions represent object-specific information of all three sensory modalities. To address this question, we performed two complementary functional magnetic resonance imaging experiments. In the first experiment, we identified brain regions which were consistently activated by unimodal visual, auditory, and haptic processing of manipulable objects relative to non-object control stimuli presented in the same modality. In the second experiment, we assessed regional brain activations when participants had to match object-related information that was presented simultaneously in two or all three modalities. Only a well-defined region in left fusiform gyrus (FG) showed an object-specific activation during unisensory processing in the visual, auditory, and tactile modalities. The same region was also consistently activated during multisensory matching of object-related information across all three senses. Taken together, our results suggest that this region is central to the recognition of manipulable objects. A putative role of this FG region is to unify object-specific information provided by the visual, auditory, and tactile modalities into trisensory object representations.

Corticocortical connections mediate primary visual cortex responses to auditory stimulation in the blind.

Blind individuals have to rely on nonvisual information to a greater extent than sighted to efficiently interact with the environment, and consequently exhibit superior skills in their spared modalities. These performance advantages are often paralleled by responses in the occipital cortex, which have been suggested to be essential for nonvisual processing in the blind. However, it is currently unclear through which pathways (i.e., thalamocortical or corticocortical connections) nonvisual information reaches the occipital cortex of the blind. Here, we used functional magnetic resonance imaging to study blind and matched sighted humans with an auditory discrimination paradigm and used dynamic causal modeling to investigate the effective connectivity underlying auditory activations in the primary visual cortex of blind volunteers. Model comparison revealed that a model connecting the medial geniculate nucleus (MGN), primary auditory cortex (A1), and primary visual cortex (V1) in a bidirectional manner outperformed all other models in both groups. Regarding inference on model parameters, we observed that basic auditory mechanisms (i.e., sensory input to MGN and connections from MGN to A1) did not differ significantly between the two groups. In contrast, we found clear evidence for stronger corticocortical connections from A1 to V1 in the blind, whereas results with regard to thalamocortical enhancement (from MGN to V1 and, in a control analysis, from the lateral geniculate nucleus to V1) were not consistent. These results suggest that plastic changes especially in corticocortical connectivity allow auditory information to evoke responses in the primary visual cortex of blind individuals.

Increased amygdala activation to emotional auditory stimuli in the blind.

Emotional signals are of pivotal relevance in social interactions. Neuroimaging and lesion studies have established an important role of the amygdala for the processing of these signals. While the human amygdala receives input from all sensory modalities, it is the visual modality that is most important for emotional aspects in social interactions. Consequently, amygdala involvement in visual emotional processing has been unequivocally established, whereas its role in auditory emotional processing is less clear. To investigate amygdala involvement in auditory emotional processing, we used functional magnetic resonance imaging in sighted and connatally blind volunteers, the latter of which lack visual experience during development but have outstanding capabilities to process auditory signals, which are their dominant source of information in social interactions. First, we observed a performance advantage of the connatally blind in auditory discrimination tasks that was paralleled by occipital cortex activation, which was not present in the sighted. More importantly, the blind not only showed robust selective activation in the amygdala to fearful and angry compared to neutral voices but also showed stronger activation to those stimuli than sighted participants. Higher amygdala activity for fearful items was further associated with individual performance in the blind, indicating that amygdala activation in the blind is not only driven by blindness per se but also by inter-individual differences in auditory capabilities. Our results indicate that the responsivity of the amygdala to emotional signals develops even in the absence of visual emotional experience and serves the sensory modality which is the most reliable source of emotional information.