March 2016 - Vol 18 - No. 1
Diseases of the Dorsal and Ventral Striatum
In This issue
Nancy C. Andreasen, MD, PhD; Deborah Morris-Rosendahl, PhD
Diseases of the dorsal and ventral striatum as a journal
theme? Yuck! That would be a typical response from most
people, as they decide to move on to friendlier and easier
topics, such as memory or schizophrenia. Learning the
anatomy and functionality of the dorsal and ventral striatum,
as well as its relationship to a variety of diseases, is a
Instead of putting this issue of Dialogues in Clinical Neuroscience aside, and instead picking up a recent issue of Nature or a wonderful book like All the Light We Cannot See (Winner of the 2015 Pulitzer Prize for Fiction), give this theme issue a chance. You won’t regret it. And you will very likely find yourself turning back to the issue on multiple occasions, when you need to review terminology, connectivity, and functions. The authors of the articles in this issue comprise a “Who’s Who” of experts on the dorsal and ventral striatum. They are people whose work I have turned to over and over as I struggle (yes, struggle) to understand this complex network and its relationship to diseases such as schizophrenia or addictions. It is also relevant to understanding emerging new fields in the study of normal brain function, such as neuroeconomics.
The issue begins with a State of the art article (p 7) by Suzanne Haber, one of the world’s leading experts on the dorsal and ventral striatum and their various connections, which are widespread in the human brain. If you don’t remember them, you will need to tune up your brain to recall the concepts of dorsal/ventral (up vs down, or high vs low) and rostral/caudal (forward vs backward or anterior vs posterior) in order to fully appreciate this wonderful article. Looking at the list of abbreviations on page 8 indicates the level of complexity that we must deal with, and Figure 1 (a classic summary of DS and VS connectivity) shows the numerous interactions that we must grapple with as we try to imagine these regions in action in a living thinkingand- feeling and movement-monitoring human brain. As we progress through the discussion of the various connections in this system, a complex story emerges: Goal-directed behaviors require processing a complex chain of events, beginning with motivation and proceeding through cognitive processing that shapes final motor outcomes…. Information is “channeled from limbic, to cognitive, to motor circuits.” In summary, cognition, emotion, decision-making, and motor responses are appropriately intertwined though the activity of corticostriatal circuitry.
A section describing Basic Research follows Haber’s article. It contains three articles, all of which have used animal models as a stepping stone for understanding human cognition and behavior. A charming article by Wolfram Schultz (p 23) opens the section. He tackles the task of explaining positive and negative reward prediction error (RPE) coding, a key concept in the study of corticostriatal circuitry, brain reward systems, and neuroeconomics. He developed the concept by studying the response of nonhuman primates to variations in rewards some 20 to 30 years ago. Nonhuman primate studies often use juice rewards in order to study behavior. So in the opening paragraphs of the article he makes himself an experimental primate seeking his favorite blackcurrant juice at a juice-dispensing machine in Japan, where he cannot read the labels, and uses this inside joke to provide a lucid description of RPE. He extends his discussion to the role of the dopamine system in responding to rewards and then relates this to disorders such as the addictions. He concludes by taking a very broad philosophical view, pointing out that human striving for ever-greater rewards has evolutionary value, “but also generates frustrations and inequalities that endanger individual well-being and the social fabric.” The two remaining Basic research articles—Smith and Graybiel on habit formation and Sirigu and Duhamel on reward and decision processes in the brains of humans and nonhuman primates—continue the theme of trying to understand the functions of striatal circuitry using animal models. Smith and Graybiel (p 33) propose replacing the classical behaviorist tendency to conceptualize habits within the behavioral model of stimulus-response associations with a model that “reconsiders habits as being formed through multiple, simultaneously signaling processes in the brain.” They support this point of view by relying primarily on rat models and maze tasks and examining “chunking activity,” which may be part of the basis for habit formation. They argue that habit formation is more complex than suggested by older conceptualizations, and that a broader understanding of habit formation may enhance understanding of “disorders of habit” such as addictions or obsessive-compulsive disorder. In a related article, Sirigu and Duhamel (p 45) place studies of reward and decision making within the context of neuroeconomics—a very “hot” field at the moment. The advent of neuroimaging technologies provides a method for understanding economic choice at the neural level as well as the behavioral level. Although not without flaws, neuroimaging paradigms, such as the Iowa Gambling Task, can be used in humans to visualize brain activity when subjects make choices of an economic nature. The task can be used with healthy normal individuals, with patients who have specific brain lesions, and with patients with disorders such as Parkinson disease.
Five papers present Clinical research from the perspective of diseases of the dorsal and ventral striatum. Kennedy, Labbe, and Fecteau (p 55) explore the neural substrates of a variety of disorders in which decision-making skills are impaired: substance use disorders, behavioral addictions such as pathological gambling, and schizophrenia. They discuss the possibility of treating these disorders with a variety of behavioral paradigms, as well as noninvasive brain stimulation, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct-current stimulation (tDCS). Kalivas and Kalivas (p 65) examine corticostriatal circuitry in the context of regulating diseases characterized by intrusive thinking. The intrusion of unwanted thoughts—subjectively a very unpleasant experience—occurs in a variety of disease states: post-traumatic stress disorder, obsessivecompulsive disorder, schizophrenia (particularly in its paranoid form), addictions, and eating disorders, to mention only a few. They point out that an abnormality in a microcircuit in the nucleus accumbens may be the basis of some forms of intrusive thinking and that preclinical and clinical studies show that administering N-acetylcysteine restores uptake of synaptic glutamate by astroglial glutamate transporters and thereby inhibits intrusive thinking. Thus, a new therapeutic approach is potentially available. Deserno, Schlagenhauf, and Heinz (p 77) focus specifically on schizophrenia. They provide an extensive review of the dopamine hypothesis and its support in a variety of imaging studies—varied in both imaging methods (eg, PET, SPECT, fMR) and challenge paradigms. They point out the need for more studies of neuroleptic_na.ve patients, in order to reduce or eliminate medications as a confounding factor, and they also argue for the importance of using longitudinal designs. Nopoulos , Kim, Alberico, Emmons, and Narayanan (p 91) examines another important and scientifically challenging disorder: Huntington disease. It continues to be both remarkable and humbling that, despite the fact that we have now known the genetic basis for this disease since 1993 and can genetically test people to determine if they will develop it, we have not been able to find a preventive measure or a treatment. This article is very clearly written, and it provides an excellent overview of the symptoms and progression of the disease and our current state of knowledge about potential approaches to treatment. The final article in this series is by Parker (p 99), and it introduces readers to optogenetic approaches to evaluate striatal function in animal models of Parkinson disease. This is also a clearly written and informative article that will be very useful for readers unfamiliar with optogenetics.
The final article in the issue, a Pharmacological aspects piece by Georg Juckel (p 109), examines the inhibition of the reward system by antipsychotic treatment. This is a very important topic, because the circuit under discussion (corticostriatal circuitry) relies heavily on dopamine transmission from the nucleus accumbens to “higher” cortical regions. If they are blocked, images obtained using fMR or PET will not be adequate for understanding the role of cortical striatal circuitry using imaging modalities with fMR or PET. It is a depressing thought… but one that we have to face.
Florence Thibaut, MD, PhD - Editor in chief
State of the art
Suzanne N. Haber (USA)
Wolfram Schultz (UK)
Kyle S. Smith; Ann M. Graybiel (USA)
Angela Sirigu; Jean-René Duhamel (France)
Julie Goulet-Kennedy; Sara Labbe; Shirley Fecteau (Canada)
Benjamin C. Kalivas; Peter W. Kalivas (USA)
Lorenz Deserno; Florian Schlagenhauf; Andreas Heinz (Germany)
Peggy C. Nopoulos (USA)
Krystal L. Parker; Youngcho Kim; Stephanie L. Alberico; Eric B. Emmons; Nandakumar S. Narayanan (USA)
Georg Juckel (Germany)