by Eve Marder, Ph.D.
President, Society for Neuroscience
I bring here perspectives of an unabashed and unapologetic basic scientist looking at a Progress Report that summarizes recent findings of fundamental importance to us and our families as we live our present lives and face our futures.
As a scientist, I have been privileged to work on the most basic of neuroscience problems, such as homeostatic regulation (maintaining stable neuronal function over a lifetime), only to discover that scientists interested in clinical problems such as epilepsy find it relevant to their work.1, 2 At the same time, as a daughter, I watched with amazement as my father recovered from traumatic brain injury suffered as a consequence of a traffic accident. To this day I marvel at the extent to which his then 76-year-old brain rebuilt itself so that, almost seven years later, no one meeting him for the first time would dream that anything untoward had happened.
That said, his recovery is more a testament to the extraordinary ability of the human brain to recover from insult, and to the skill of a surgeon, than it is to our understanding of how and why his recovery was so complete. There is nothing more disconcerting to a neuroscientist than watching a close friend or family member dealing with a brain injury or disease, knowing how little we presently understand, and I welcome all of the advances described in this volume.
As a research scientist working in a liberal arts university, I teach a course titled “Principles of Neuroscience” in which I cover the full range of basic neuroscience and its application to issues of direct clinical and human problems. As an educator, I find extremely satisfying the astonishing numbers of instances in which arcane details addressed by scientists following the most basic of research topics set the stage for understanding clinical conditions. Likewise, cin this collection of essays, I find equally satisfying the numerous instances in which work done over many years by basic scientists has led to important advances that will eventually result in enhanced human outcomes.
One of the great mysteries of our lives is why and how individuals, growing up in families of all kinds, become painters, musicians, or dancers. We all have noticed the degree to which aptitude and practice of the arts “runs in families.” Is that due to genetics, to early exposure and training, or to both? There are urban legends that mathematicians and physicists make good musicians. Is there really a connection with the cortical states that allow individuals to do formal abstract thinking and music? Will educating our children in the arts enhance other kinds of cognitive development? These are the kinds of questions that the Dana Arts and Cognition Consortium has begun to address.
Disorders that affect children, such as autism, attention-deficit/hyperactivity disorder, and mental retardation, are among the most heartbreaking of all neurological problems. Also devastating are neurodegenerative diseases, such as Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease, that affect adults. Recent work shows the power of genetics in understanding the causes of some of these disorders. Indeed, we are seeing today the fruit of decades of work on fundamental genetic mechanisms, as we now have the tools to study the role of interactions of multiple genes in complex human disease. The same message emerges from recent work on brain tumors: Much hope for developing new treatments for gliomas and other brain tumors is coming from studies of the cellular signaling pathways that are controlling the growth and proliferation of cancers of all kinds, including those of the brain.
It was rapid surgical intervention that saved my father’s brain, and recent progress on stroke, highlighted in this volume, shows that timely intervention is also crucial for the protection of the brain in response to stroke and transient ischemic attacks that produce seemingly minor neurological effects. Timely interventions following a transient ischemic attack are now shown to decrease the risk of an additional, more serious, stroke in the weeks following the first evidence of ischemic neurological events.
In many human disorders it can be particularly difficult to translate the intuitions and findings from animal models into clinical practice. Excellent and well-controlled clinical trials are critical for this enterprise, but it can often be difficult to ensure that clinical trialsare done correctly. Toward this end, the International Campaign for Cures of Spinal Cord Paralysis has worked to develop new criteria for patient participation and assessment in clinical trials of potential treatments for spinal cord injury. Equally important are the criteria for clinical trials in all arenas in which evaluation of treatments for any neurological or psychiatric disorder is needed.
The past year has seen a remarkable explosion of interest in a series of issues, grouped together in the young field of neuroethics, to which the American Journal of Bioethics now devotes three issues a year. Four topics garnered significant attention in 2007: commercialization of lie detection, deep brain stimulation for the treatment of depression, genetic studies of addiction, and brain imaging. Here we are seeing unanticipated and thorny consequences of the development of new technologies for the diagnosis and treatment of brain disorders. This comes at the same time as remarkable advances in stem cell biology, which may free us from many of the controversies around the use of stem cells from human embryos.
Meanwhile, interactions between the immune system and the nervous system are becoming more tangible. In no case is this more evident than with multiple sclerosis, a disorder in which genetic and environmental factors influence the immune system’s attack on the myelin sheath surrounding many nerve cells. Recent studies have demonstrated a link between several immune-system genes and risk for multiple sclerosis. Fascinating recent findings suggest an important link between vitamin D, sun exposure (which increases vitamin D), the immune system, and multiple sclerosis. The immune system may also be important in understanding some chronic pain syndromes.
The mechanisms that produce chronic pain syndromes are mysterious, and they may include maladaptive responses to injury that outlast the initial insult. Because significant chronic pain is so debilitating and often difficult to treat effectively, new insights into the organization and function of pain pathways are required, and new kinds of treatments particularly welcome. This is especially the case as researchers try to provide alternatives to long-term use of opioid drugs, with their potential for becoming addictive. Among the most promising new treatments now under study are neurostimulation, with electrodes implanted either near the spinal cord or peripherally. These methods are intended to use direct stimulation to block the pain signals before they reach the brain. Elsewhere, fascinating new studies provide insight into how the brain produces fever in response to infection,3 again drawing on our new understanding of basic cellular signaling mechanisms and our ability to genetically manipulate these in animal models.
Sadly, the major psychiatric disorders, such as schizophrenia, depression, and addiction, first manifest in many individuals when they are adolescents and young adults, at a time when they should be ready and able to enter and contribute to society creatively and independently. Research in 2007 is contributing to a paradigm shift in the understanding of these disorders.
For a long time scientists had focused on the search for single biochemical and molecular causes. Now we understand that thought and mood disorders could be a consequence of faulty connectivity in brain circuits, even if each neuron is functioning correctly. New imaging techniques and genetic manipulations are enhancing the search for genes that play a role in the establishment and maintenance of appropriate circuit structure under a variety of environmental conditions. Moreover, this change in paradigm should support investigation into a variety of new ways of treating these disorders. It will also help us understand the kinds of cognitive disorders that result from loss of specific components of circuits as neurons die in neurodegenerative diseases, such as Alzheimer’s disease.
One of the biggest difficulties in treating psychiatric disorders is the extreme heterogeneity of the population, and one of the biggest hopes for the future is that the choice of drug or other treatment will be made with knowledge of the likelihood that the treatment will be effective for that individual, on the basis of his or her genetic makeup.
Many young scientists are drawn to the field of neuroscience by fascination with its really “big” questions, such as the nature of consciousness, the structure of human thought, and the relationship between specific brain structures and our ability to use language, appreciate music, and relate to others. Work in 2007 brings us closer to understanding how the brain, composed of circuits of neurons, actually functions during complex cognitive acts.
Despite the extraordinary insights into brain function in health and disease, each new finding only makes it clearer how much remains to be understood. For example, we all experience mental fatigue, but we haven’t a clue what the biological correlates of mental fatigue are. We all know that each person’s brain is different, that each of us has stored different memories and uses those to respond uniquely to each other and to the world. At the same time, we believe that the essential rules by which our brains operate are conserved, most of them not only in the human population but across the animal kingdom. How we understand our individual human attributes in the context of our shared sets of biochemical, molecular, and genetic mechanisms is the major challenge for future work.
1. Echegoyen J, Neu A, Graber KD, and Soltesz I. Homeostatic plasticity studied using in vivo hippocampal activity-blockade: Synaptic scaling, intrinsic plasticity, and age-dependence. Public Library of Science 1 2007 2:e700.
2. Howard AL, Neu A, Morgan RJ, Echegoyen JC, and Soltesz I. Opposing modifications in intrinsic currents and synaptic inputs in post-traumatic mossy cells: Evidence for single-cell homeostasis in a hyperexcitable network. Journal of Neurophysiology 2007 97:2394–2409.
3. Lazarus M, Yoshida K, Coppari R, Bass CE, Mochizuki T, Lowell BB, and Saper CB. EP3 prostaglandin receptors in the median preoptic nucleus are critical for fever responses. Nature Neuroscience 2007 10:1131–1133.