The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders

Understanding the neurochemical basis for cognitive function is one of the major goals of neuroscience, with a potential impact on the diagnosis, prevention and treatment of a range of psychiatric and neurological disorders. In this review, the focus will be on a biochemical pathway that remains under-recognised in its implications for brain function, even though it can be responsible for moderating the activity of two neurotransmitters fundamentally involved in cognition – glutamate and acetylcholine. Since this pathway – the kynurenine pathway of tryptophan metabolism - is induced by immunological activation and stress it also stands in an unique position to mediate the effects of environmental factors on cognition and behaviour. Targetting the pathway for new drug development could, therefore, be of value not only for the treatment of existing psychiatric conditions, but also for preventing the development of cognitive disorders in response to environmental pressures

Exercise Training and Functional Connectivity Changes in Mild Cognitive Empairment and Healthy Elders

Background: Effective interventions are needed to improve brain function in mild cognitive impairment (MCI), an early stage of Alzheimer’s disease (AD). The posterior cingulate cortex (PCC)/precuneus is a hub of the default mode network (DMN) and is preferentially vulnerable to disruption of functional connectivity in MCI and AD. Objective: We investigated whether 12 weeks of aerobic exercise could enhance functional connectivity of the PCC/precuneus in MCI and healthy elders. Methods: Sixteen MCI and 16 healthy elders (age range = 60–88) engaged in a supervised 12-week walking exercise intervention. Functional MRI was acquired at rest; the PCC/precuneus was used as a seed for correlated brain activity maps. Results: A linear mixed effects model revealed a significant interaction in the right parietal lobe: the MCI group showed increased connectivity while the healthy elders showed decreased connectivity. In addition, both groups showed increased connectivity with the left postcentral gyrus. Comparing pre to post intervention changes within each group, the MCI group showed increased connectivity in 10 regions spanning frontal, parietal, temporal and insular lobes, and the cerebellum. Healthy elders did not demonstrate any significant connectivity changes. Conclusion: The observed results show increased functional connectivity of the PCC/precuneus in individuals with MCI after 12 weeks of moderate intensity walking exercise training. The protective effects of exercise training on cognition may be realized through the enhancement of neural recruitment mechanisms, which may possibly increase cognitive reserve. Whether these effects of exercise training may delay further cognitive decline in patients diagnosed with MCI remains to be demonstrated

Working memory revived in older adults by synchronizing rhythmic brain circuits

Published in final edited form as: Nat Neurosci. 2019 May ; 22(5): 820–827. doi:10.1038/s41593-019-0371-x.Understanding normal brain aging and developing methods to maintain or improve cognition in older adults are major goals of fundamental and translational neuroscience. Here we show a core feature of cognitive decline—working-memory deficits—emerges from disconnected local and long-range circuits instantiated by theta–gamma phase–amplitude coupling in temporal cortex and theta phase synchronization across frontotemporal cortex. We developed a noninvasive stimulation procedure for modulating long-range theta interactions in adults aged 60–76 years. After 25 min of stimulation, frequency-tuned to individual brain network dynamics, we observed a preferential increase in neural synchronization patterns and the return of sender–receiver relationships of information flow within and between frontotemporal regions. The end result was rapid improvement in working-memory performance that outlasted a 50 min post-stimulation period. The results provide insight into the physiological foundations of age-related cognitive impairment and contribute to groundwork for future non-pharmacological interventions targeting aspects of cognitive decline.Accepted manuscrip

Smell's puzzling discrepancy: Gifted discrimination, yet pitiful identification

Mind &Language, Volume 35, Issue 1, Page 90-114, February 2020

Identifying animal complex cognition requires natural complexity

The search for human cognitive uniqueness often relied on low ecological tests with subjects experiencing unnatural ontogeny. Recently, neuroscience demonstrated the significance of a rich environment on the development of brain structures and cognitive abilities. This stresses the importance to consider the prior knowledge that subjects bring in any experiment. Second, recent developments in multivariate statistics control precisely for a number of factors and their interactions. Making controls in natural observations equivalent and sometimes superior to captive experimental studies without the drawbacks of the latter methods. Thus, we can now investigate complex cognition by accounting for many different factors, as required when solving tasks in nature. Combining both progresses allow us to move towards an “experience-specific cognition”, recognizing that cognition vary extensively in nature as individuals adapt to the precise challenges they experience in life. Such cognitive specialization makes cross-species comparisons more complex, while potentially identifying human cognitive uniqueness

Bodily crises in skilled performance: Considering the need for artistic habits

Empirical evidence demonstrates that performing artists are confronted by a variety of ‘bodily crises’ (e.g., injury, attrition of habits induced by ageing) over the course of their careers (Wainwright, Williams, & Turner, 2005). Such crises may present a serious threat to the embodied subject. Unfortunately, many prominent theories of skill acquisition (e.g., Fitts & Posner, 1967) appear to evacuate the body from performance by suggesting that any form of conscious processing (i.e., paying conscious attention to one's action during motor skill execution) will disrupt habitual behaviour. As a result, few researchers have considered how performers might tackle bodily anomalies. In the current paper, we seek to address this issue by discussing a variety of the ‘crises’ that confront the performing body. We start by discussing a number of disciplinary practices that may contribute to these crises. Next, we argue that habitual movements must be open to ‘acts of creativity’ in order to maintain a productive relationship between the performing body and the environment. Then we consider what this ‘creative action’ might involve and discuss a number of approaches (e.g., mindfulness, somaesthetic awareness) that could maintain and improve one's movement proficiency. Here, our argument draws on Dewey's (1922) pragmatist philosophy and his belief that ‘intelligent habit’ was required to help people to improve their movement functioning. Finally, we consider the implications of our argument for current conceptualisations of ‘habitual’ movement and recommend that researchers explore the adaptive and flexible capacity of the performing body

Cerebellar atrophy in Parkinson's disease and its implication for network connectivity.

Pathophysiological and atrophic changes in the cerebellum are documented in Parkinson's disease. Without compensatory activity, such abnormalities could potentially have more widespread effects on both motor and non-motor symptoms. We examined how atrophic change in the cerebellum impacts functional connectivity patterns within the cerebellum and between cerebellar-cortical networks in 42 patients with Parkinson's disease and 29 control subjects. Voxel-based morphometry confirmed grey matter loss across the motor and cognitive cerebellar territories in the patient cohort. The extent of cerebellar atrophy correlated with decreased resting-state connectivity between the cerebellum and large-scale cortical networks, including the sensorimotor, dorsal attention and default networks, but with increased connectivity between the cerebellum and frontoparietal networks. The severity of patients' motor impairment was predicted by a combination of cerebellar atrophy and decreased cerebellar-sensorimotor connectivity. These findings demonstrate that cerebellar atrophy is related to both increases and decreases in cerebellar-cortical connectivity in Parkinson's disease, identifying potential cerebellar driven functional changes associated with sensorimotor deficits. A post hoc analysis exploring the effect of atrophy in the subthalamic nucleus, a cerebellar input source, confirmed that a significant negative relationship between grey matter volume and intrinsic cerebellar connectivity seen in controls was absent in the patients. This suggests that the modulatory relationship of the subthalamic nucleus on intracerebellar connectivity is lost in Parkinson's disease, which may contribute to pathological activation within the cerebellum. The results confirm significant changes in cerebellar network activity in Parkinson's disease and reveal that such changes occur in association with atrophy of the cerebellum