Lost in translation? The potential psychobiotic Lactobacillus rhamnosus (JB-1) fails to modulate stress or cognitive performance in healthy male subjects

Background: Preclinical studies have identified certain probiotics as psychobiotics a live microorganisms with a potential mental health benefit. Lactobacillus rhamnosus (JB-1) has been shown to reduce stress-related behaviour, corticosterone release and alter central expression of GABA receptors in an anxious mouse strain. However, it is unclear if this single putative psychobiotic strain has psychotropic activity in humans. Consequently, we aimed to examine if these promising preclinical findings could be translated to healthy human volunteers. Objectives: To determine the impact of L. rhamnosus on stress-related behaviours, physiology, inflammatory response, cognitive performance and brain activity patterns in healthy male participants. An 8 week, randomized, placebo-controlled, cross-over design was employed. Twenty-nine healthy male volunteers participated. Participants completed self-report stress measures, cognitive assessments and resting electroencephalography (EEG). Plasma IL10, IL1β, IL6, IL8 and TNFα levels and whole blood Toll-like 4 (TLR-4) agonist-induced cytokine release were determined by multiplex ELISA. Salivary cortisol was determined by ELISA and subjective stress measures were assessed before, during and after a socially evaluated cold pressor test (SECPT). Results: There was no overall effect of probiotic treatment on measures of mood, anxiety, stress or sleep quality and no significant effect of probiotic over placebo on subjective stress measures, or the HPA response to the SECPT. Visuospatial memory performance, attention switching, rapid visual information processing, emotion recognition and associated EEG measures did not show improvement over placebo. No significant anti-inflammatory effects were seen as assessed by basal and stimulated cytokine levels. Conclusions: L. rhamnosus was not superior to placebo in modifying stress-related measures, HPA response, inflammation or cognitive performance in healthy male participants. These findings highlight the challenges associated with moving promising preclinical studies, conducted in an anxious mouse strain, to healthy human participants. Future interventional studies investigating the effect of this psychobiotic in populations with stress-related disorders are required

Neural Correlates of Feedback Processing in Visuo-Tactile Crossmodal Paired-Associate Learning

Previous studies have examined the neural correlates for crossmodal paired-associate (PA) memory and the temporal dynamics of its formation. However, the neural dynamics for feedback processing of crossmodal PA learning remain unclear. To examine this process, we recorded event-related scalp electrical potentials for PA learning of unimodal visual-visual pairs and crossmodal visual-tactile pairs when participants performed unimodal and crossmodal tasks. We examined event-related potentials (ERPs) after the onset of feedback in the tasks for three effects: feedback type (positive feedback vs. negative feedback), learning (as the learning progressed) and the task modality (crossmodal vs. unimodal). The results were as follows: (1) feedback type: the amplitude of P300 decreased with incorrect trials and the P400/N400 complex was only present in incorrect trials; (2) learning: progressive positive voltage shifts in frontal recording sites and negative voltage shifts in central and posterior recording sites were identified as learning proceeded; and (3) task modality: compared with the unimodal PA learning task, positive voltage shifts in frontal sites and negative voltage shifts in posterior sites were found in the crossmodal PA learning task. To sum up, these results shed light on cortical excitability related to feedback processing of crossmodal PA learning

Four-Dimensional Consciousness

Conscious experience is the direct observation of conscious events. Human conscious experience is four-dimensional. Conscious events are linked (associated) by spacetime intervals to produce a coherent conscious experience. This explains why conscious experience appears to us the way it does. Conscious experience is an orientation in space and time, an understanding of the position of the observer in space and time. Causality, past-future relations, learning, memory, cognitive processing, and goal-directed actions all evolve from four-dimensional conscious experience. A neural correlate for four-dimensional conscious experience can be found in the human brain and is modelled by Einstein's special theory of relativity. The relativistic concept of spacetime interval is central for understanding conscious experience and cognition

The gut microbiota in depression

The accruing data linking the gut microbiota to the development and function of the central nervous system has been proposed as a paradigm shift in neuroscience. Neuroimmune, neuroendocrine and neural communication pathways exist between host and microbe. These pathways are components of the brain-gut-microbiota axis and preclinical evidence suggests that the microbiota can recruit this bidirectional communication system to modulate brain development, function and behaviour. Dysfunctional neuro-immune and neuro-endocrine pathways are implicated in stress-related psychiatric disorders. To this end, we proposed that the gut microbiota, by modulating these pathways, plays an influential role in the pathophysiology of depression. We demonstrated that depression is associated with altered gut microbiota composition with decreased richness and diversity. Furthermore, we have shown that transferring the gut microbiota from depressed patients to microbiota-depleted rats can induce behavioural and physiological features characteristic of depression in the recipient animals, including anhedonia and anxiety-like behaviours, as well as alterations in tryptophan metabolism. Although we provide evidence that the gut microbiota is altered in depression and that this alteration could have a role in prominent features of depression, an interventional study based on targeting the gut microbiota in healthy males using Lactobacillus rhamnosus (JB-1) was not superior to placebo in modifying self-reported stress, HPA axis response to an acute stressor, inflammation, cognition or neurophysiological measures. Taken together, these findings have furthered our understanding of the pathophysiology of depression. By incorporating the gut microbiota into existing neurobiological models of depression a more comprehensive model has been developed. The successful translation of this work could lead to stratification based on gut microbiome composition and could deliver further diagnostic accuracy to improve patient phenotyping for treatment selection in future studies in psychiatric populations. Furthermore, our findings advance the possibility of targeting the gut microbiome in the treatment and prevention of stress related disorders and offer an important future strategy in psychiatry

Exploring aspects of memory in healthy ageing and following stroke

Memory is critical for everyday functioning. Remembering an event with rich detail requires the ability to remember the temporal order of occurrences within the event and spatial locations associated with it. But it remains unclear whether it also requires memory for the perspective from which we encoded the event, whether these three aspects of memory are affected following stroke, and which are the key brain regions upon which they rely. These questions are explored in this thesis. In the first study presented here, I examined young and elderly healthy subjects with an autobiographical memory interview and a 2D spatial memory task assessing self-perspective, and found no correlation between performance on these tasks. In the second experimental study, by assessing stroke patients on a 3D spatio-temporal memory task, I found that damage to the right intraparietal sulcus was associated with poorer memory for temporal order. However, voxelwise analyses detected no association between parietal lobe regions and accuracy in the egocentric condition of this task, or between medial temporal lobe regions and accuracy in the allocentric condition, one possible reason being that performance was near ceiling. In the third experimental study, by assessing a considerably larger group of stroke patients on a spatial memory task, I found that, as a group, patients performed worse than healthy controls, and performance was correlated with an activities of daily living scale. A spatial memory network was identified in right (but not left) hemisphere stroke patients. These findings provide evidence that spatial memory impairment is common after stroke, highlight its potential functional relevance, and increase our understanding of which regions are critical for remembering temporal order and spatial information. Furthermore, they suggest a dissociation between the mechanisms underpinning recall of 2D scenes over relatively short intervals versus remembering of real-life events across periods of many years.Open Acces

Associative memory in ageing: Changes in anticipatory brain activity

Older adults are impaired in the ability to remember, especially for the associations across different elements of an event. It has been shown that during both memory encoding and retrieval, brain activities in anticipation to an upcoming event can influence memory for that event. To explore the role of the anticipatory brain activity in associative memory processing and how it may be affected by ageing, three electroencephalography (EEG) experiments were performed with both younger and older participants. Analyses were conducted in both ERP and time-frequency domains. Experiment 1 demonstrated that unlike older adults, younger adults were able to engage encoding-related anticipatory neural mechanisms before encountering any to-be-remembered information. During retrieval, however, older adults showed a pronounced ERP anticipatory effect for associative retrieval that was not seen in younger adults. Experiment 2 provided evidence suggesting that age-related differences in anticipatory associative memory effects were due, at least partly, to inefficient encoding as a consequence of diminished processing resources in older adults. Experiment 3 further revealed that when participants switched between words and pictures in an associative recognition task, only younger adults engaged anticipatory encoding-related activity, and they were more likely to recruit material-selective anticipatory mechanisms. Older adults were able to recruit anticipatory mechanisms during retrieval but not during encoding. In conclusion, older adults are impaired in anticipatory activity for associative encoding, but they are able to recruit anticipatory neural mechanisms at retrieval possibly to compensate for poor associative encoding. Compared to younger adults, however, they are less able to recruit these mechanisms flexibly in a goal-directed manner. The present findings advance the understanding of neural mechanisms of associative memory deficits in ageing, which may open new doors for cognitive training in ageing by targeting these mechanisms

The effects of resveratrol on cognition, cerebral blood flow, gastrointestinal microbiota and systemic inflammation in healthy weight, overweight and obese adults

The stilbene polyphenol resveratrol has been shown to interact with several health-promoting mechanisms, which might impact cognitive performance. However previous research has indicated that resveratrol supplementation is not able to impact cognitive performance in young, healthy adults; despite consistent ability to modulate cerebral blood flow. Recent work suggests that resveratrol supplementation may be more beneficial in individuals who are compromised by age, disease, or overweight status. Specifically, obese individuals are characterised by a multitude of health issues including sustained inflammation, elevated cholesterol levels; excessive fat accumulation and neuroinflammation; here resveratrol supplementation offers a therapeutic option. Moreover, a recent shift in literature focus indicates the importance of gut microbial composition on host-health; and specifically, how this can be modified by dietary intervention. Obesity is associated with dysbiosis of the microbiota, disruption to the intestinal barrier and exacerbated pro-inflammatory response; where it is hypothesised that polyphenol intervention may have the capability to modulate microbial composition and exert health-promoting effects. With said health promoting effects of polyphenolic-gut-modulation potentially also extending to cognitive function, via the gutbrain-axis. Therefore, the two randomised, placebo-controlled, double-blind intervention trials included in this thesis aimed to investigate the effects of resveratrol supplementation on cognitive function, cerebral blood flow, inflammation and gastrointestinal microbiota in healthy adults of varying weight status. The key findings here indicate that as in young, healthy adults, resveratrol supplementation results in clear modulation of CBF in healthy overweight-obese adults. Furthermore, it confirms that within this population, resveratrol is unable to exert cognitive enhancing effects, with limited evidence of a detrimental effect observed. Limited changes in microbial composition indicate that this is likely a promising avenue for future investigations of either resveratrol or other polyphenolic or dietary intervention