Dear Colleagues,

With the progressive aging of the population, the medical community is increasingly focusing on the maintenance of optimal cognitive functioning well into late life.

In this issue of Dialogues in Clinical Neuroscience, we examine neuroplasticity and the part it plays in the development of treatments for the aging brain.

We have invited Prof Gwenn Smith to share her expertise on this subject with us in a Guest Editorial.

We would like to warmly thank Prof Smith and the distinguished panel of authors for their contributions to this issue. We are also grateful to Prof Barry Lebowitz for coordinating this issue, with the assistance of Prof Michael Davidson.

Sincerely yours,

Jean-Paul Macher, MD

We are entering a new era of treatment discovery for the mental illnesses. Theory-based approaches, based on new understanding of the neurocircuitry disruptions underlying the mental illnesses, are moving beyond proof-of-concept to larger-scale testing and broader use. Neuroplasticity provides one of the most promising of these theory-based approaches. 1 In this issue we consider the significance of neuroplasticity in the development of treatments for the mental disorders of late life.

This may seem a somewhat paradoxical focus. After all, neuroplasticity and the aging brain have not been seen as a promising, or even a legitimate area for scientific investigation. Sigmund Freud, for example, wrote that “About the age of fifty, the elasticity of the mental processes on which treatment depends is, as a rule, lacking. Old people are no longer educable.”2 The papers in this issue demonstrate just how wrong this statement was.

Our exploration of the aging brain begins at the molecular and cellular level with a State of the art paper by Profs Jeremy Henley and Kevin Wilkinson (p 9). Their work is directed toward a better understanding of the biochemical “nuts and bolts” of synaptic plasticity. This, in turn, could help us gain insight into some of the pathways that lead to neuronal dysfunction in neurodegenerative disease. This is basic science at its best, in that it forms the basis of the more targeted and disease-specific applications to follow.

The issue continues with a set of Translational research papers that explore different aspects of plasticity. The first, by Profs Kurt Jellinger and Johannes Attems (p 29), examines the bridges to basic science by examining the neuropathological substrate of brain aging and neuroplasticity. They highlight the extreme variability in brain aging, and bring in the processes of adult neurogenesis as a way to account for this heterogeneity. They extend their approach to a consideration of preventive and therapeutic target identification. The next paper, by Prof Francisco Mora (p 45), highlights the fact that the aging brain functions in a complex environment of lifestyle factors that themselves affect brain structure and function. Prof Mora has called this phenomenon “ambionics,” a set of factors that interact with the genome (see paper by Sibille to follow) and can themselves become the targets for intervention (see the paper by Erickson to follow). This section concludes with a paper from Prof Etienne Sibille (p 53) examining changes in gene expression over time and the relationship of these changes to brain aging in both healthy aging and disease. Despite age-associated changes and the interaction of age and disease, the paper suggests that most gene expression remains unchanged throughout the life course. Paradoxically, he observed that life-long progressive changes in expression were seen in only 7.5% of genes studied in his work and that of others. This represents another fruitful direction for target development.

The next set of papers is concerned with Treatment research. As befitting the theory-driven nature of the issue, the authors cast a broad net over pharmacologic, biological, cognitive, and physical exercise-based approaches. Prof François Chollet (p 67) opens the section with a review of his work on stroke and brain plasticity. He concludes that the brain retains the capacity for neuroplasticity even after stroke, and reviews the contributions of pharmacologic agents to rehabilitation in stroke. The paper discusses new data on the beneficial effects of serotonergic agents poststroke and calls for the development of multi-modality studies that would combine medication with cognitive or exercise- based approaches. The section moves on to a pair of papers dealing with different methods of brain stimulation. The first of these, from Profs Bettina Bewernick and Thomas Schlaepfer (p 77), uses a neurogenesis model of depression to provide rationale for a treatment approach based on deep brain stimulation (DBS). Based on a review of human and animal studies, they conclude that DBS has contributed to “a novel view of depression—away from a synaptocentric view to a conceptualization of dysfunctional brain networks for the processing of emotions.” Transcranial magnetic stimulation (TMS) and magnetic seizure therapy (MST) are considered in the paper by Profs Bruce Luber, Shawn M. McClintock, and Sarah H. Lisanby (p 87). The paper underscores the direct relevance of these approaches to neuroplasticity through consideration of long-term potentiation (LTP) and long-term depression (LTD). They show how these approaches can be used as probes of brain function as well as therapeutic interventions in their own right. Additionally, they suggest that these approaches may enhance treatment tolerability. The relationship of physical activity to brain plasticity has been touched upon in many of the papers in this issue. In the next paper, Profs Kirk Erickson, Ariel Gildengers, and Meryl Butters (p 99) directly address the issue. They provide a comprehensive overview of human and animal studies and conclude that “exercise influences the integrity of the hippocampus [and other brain regions] by influencing gene expression, cell proliferation and survival, vascularization, and synaptic plasticity”… Additionally, “there are many different molecular and cellular pathways mediating the effects of exercise on cognitive and behavioral outcomes including increased neurogenesis, angiogenesis, and the production of growth factors important in memory and cognitive function.” After reviewing the results of treatment trials of exercise interventions on cognitive function, mood, and anxiety, they conclude with a set of provocative questions to guide future development. Profs Denise C. Park and Gérard Bischof (p 109) tackle perhaps the most controversial subject in this issue: whether some sort of training may rewire the brain and prevent age-associated deterioration or even dementias. Their careful and dispassionate review of the evidence concludes that nearly all these claims are overly optimistic. Using the Scaffolding Theory of Aging and Cognition (STAC) they provide a comprehensive look at the sort of compensatory mechanisms that are employed in brain aging and the limits of these strategies when it comes to generalizing beyond specifically learned tasks. The need for multidisciplinary perspectives on future studies is underscored.

The issue concludes with a Brief report by Profs Fumihiko Yasuno and Takashi Asada (p 120) on the relationship between plasma lipids and APOE genotype on cognitive function in a community sample of older people followed for 3 years. They document an association between HDL and cognitive function, and posit a mechanism to account for the often-observed relationship between heart and brain health. The issue comes full circle: underlying the issue was the notion that theory would lead us to a number of insights and new directions for treatment development regarding age, disease, brain structure and function, and processes of neuroplasticity. The authors, an international group of senior investigators and those just launching their research careers, have taken on this challenge and have led to a number of interesting and provocative conclusions and directions for the future. And one thing that can be concluded from all this is, that at least in this instance, Sigmund Freud was absolutely wrong. Neuroplasticity in the aging brain is real, important, and necessary for development of new treatments in our field.

REFERENCES

1. Insel T. Next generation treatment for mental disorders. Sci Transl Med. 2012;(4):155ps19.

2. Freud S. On Psychotherapy. Standard edition, Vol 7. London, UK: Hogarth Press; 1905.