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The pharmacology of executive functioning

Jack, Bergman; Louk, Vanderschuren; Bart, Ellenbroek; Paul, Willner

doi: 10.1097/FBP.0000000000000444

Welcome to Behavioural Pharmacology’s Special Issue on the Pharmacology of Executive Functioning. This Special Issue is in two parts, with a series of eight review papers comprising the current issue, and a second part to follow in the next issue comprising empirical studies.

Before briefly introducing the reviews contained in the current issue, a few words are to describe how this Special Issue came about. At first sight, the intent and title of the Special Issue may seem ambitious. After all, what shall we consider executive functioning? One can presume that executive functioning reflects a cognitive, ‘higher order’ decision-making process and might exclude the consideration of sensory, motor or even affectual mechanisms. But, with a moment’s reflection, it seems clear that executive functioning probably is not a ‘free-floating’ process but, rather, incorporates all of these various mechanisms to differing extents at differing times. A perhaps more advantageous approach is to consider executive functioning as contextually controlled complex behaviour that inescapably involves central nervous system (CNS) sensorimotor and motivational, as well as cognitive, processes. From this perspective, it is the integrated output of these processes that directly drives decision-making, that is, executive functioning. This perspective informs this Special Issue and provides an empirical framework for understanding the contribution of multiple CNS processes to executive functioning.

But, if executive functioning encompasses such a wide range of CNS processes and, most likely, pharmacology, then what to include in this Special Issue? The answer to this question is actually simple: in keeping with the wide range of relevant CNS processes, a variety of research can be included that informs the interested reader with useful information with new perspectives on our current understanding of executive functioning. The current selection of reviews proves this point, spanning topics ranging from methodology and circuitry to differing pharmacological and pathological conditions with impact on cognitive processes and proper executive functioning.

For example, the first review by Carr and colleagues discusses the application of recently developed state-of-the-art methodological approaches to the study of cognitive processes in rodents. The authors carefully point out the advantages of optogenetic and chemogenetic methodologies for circuit-level neural manipulations, discuss how such manipulations can be used in behavioural paradigms to investigate cognitive control, and then detail their own work using these methods to study various aspects of choice behaviour in serial reaction time tasks. The second review by Chau and colleagues also focuses on decision-making behaviour, addressing the gaps in our understanding of the role of dopamine-related circuitry in reward-based decision-making processes. The authors summarize our current understanding of the circuitry on the basis of midbrain dopaminergic projections, and draw attention to the need for a similarly informed understanding of the role of dopamine in the prefrontal cortex and how information processing across the various nodes of the reward/decision-making networks is reconciled. In the next review, Bahari and colleagues address another aspect of the role of cortical dopamine in the complex control of executive function. They review the well-described relationship between stress and dopaminergic activity, and emphasize its impact on memorial processing and executive function. The authors provide an informative summary of the neuronal circuitry involved in this relationship, including a discussion of the role of glucocorticoids in stress-related cognitive impairment. The fourth review by Sun also addresses memorial processes and discusses the relationship between memory and attention, highlighting the latter as a key ingredient of successful executive functioning. Sun further argues provocatively that targeting signalling pathways, for example, by increasing brain expression of brain-derived neurotrophic factor, may be a medicinal approach to improving degraded attention and, consequently, memorial and other cognitive processes. This suggestion fits well with the current focus on potential positive effects of brain-derived neurotrophic factor on cognition and affect, for example, for improving long-term memory or providing relief from depression.

The remaining four reviews address factors that may compromise executive functioning. The first of these, by Oomen and colleagues, discusses the effects of cannabis, a widely discussed topic in view of the increasing legitimacy of cannabis use in the USA. These authors focus on several important elements of executive processes – response inhibition, working memory and reasoning/association. They undertake the unenviable task of reviewing a highly variable literature, and they do an excellent job of identifying the sources of such variability – a constant challenge in cannabis research. The next pair of reviews addresses starkly more dramatic challenges to executive functioning, those of traumatic brain injury and stroke. In the first, Ozga and colleagues review the disruptions in monoaminergic signalling that are produced by traumatic brain injury and that lead thereafter to a range of deficits in the broad domain of executive function. They conclude their excellent overview with considerations for pharmacotherapy that may be uniquely suited for managing the cognitive sequelae of traumatic brain injury. The second of this pair of reviews, by Povroznik and colleagues, is very much a parallel treatment of aspects of executive functioning that are damaged by stroke. An especially illuminating aspect of this review is the discussion of secondary behavioural sequelae of stroke, for example, poststroke depression and drug addiction, that compound the difficulty in rehabilitation and treatment. The authors very nicely also cover cellular and molecular mechanisms that are uncoupled by stroke, again with emphasis on monoaminergic systems and how understanding the particular damage to these systems may, in turn, direct the development of pharmacotherapeutics.

In the final review in this Special Issue, Roman and colleagues continue the theme of interplay between pathology and executive functioning in discussing the relationship between autism spectrum disorder and executive processes. But, here, deficits in cognition or executive processing are not secondary sequelae of the pathology but, rather, define its clinical presentation. The authors offer a provocative perspective on autism spectrum disorder, focusing directly on the possible role of gastrointestinal microbiota in pathogenesis. There has been a longstanding appreciation of common physiological and pharmacological elements in gut and brain, and the emergence of autism spectrum disorder as a main public health concern has spurred research into better understanding the gut–brain axis and its role in both health and disease. In these pages, the authors capably discuss the role of microbiota in triggering autism spectrum disorder, common gut–brain symptomology in individuals suffering the disorder, and the possible use of microbiota in devising effective strategies for treating it.

We hope that readers will appreciate the wealth of information complied in these eight review papers, and will look forward to the empirical studies of executive functioning that will follow in the next issue of Behavioural Pharmacology.

Jack Bergman

Louk Vanderschuren

Bart Ellenbroek

Paul Willner

September 2018

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