SECTION II | NEW METHODS AND NEW TECHNOLOGIES FOR PRECLINICAL AND CLINICAL NEUROBIOLOGY

KARL DEISSEROTH

The mammalian brain is extraordinarily difficult to study. Whether in the clinical or the preclinical realm, investigators focusing on psychiatric disease not only lack fundamental understanding of the key pathophysiological processes but also lack understanding of the normal function of the relevant circuits (or even knowledge of which are the relevant circuits). This challenge is due in large part to technological limitations linked to the complexity and inaccessibility of the circuitry, and for this reason the future of mental illness research depends upon the development and application of new technologies for studying brain function. Collected here in this volume are chapters from leading developers and pioneers of new neuroscience technologies relevant to mental illness.

In Chapter 8 transgenic tools and animal models of mental illness are addressed. Recent exciting progress not only in accelerating mouse genetic targeting, but also in advancing the genetic tractability of rats, has been and will continue to be crucial for delivering causal understanding of the impact of specific genetic modifications or manipulations. Of course, even technologically novel genetic methods do not stand alone but, rather, require smooth integration with physiology, pharmacology, behavior, and more recently, viral engineering and transduction methods. Together these genetic manipulation approaches show great promise for advancing our understanding of the mechanisms and physiology underlying brain function in health and in psychiatric disease-related states.

In Chapter 9 the influence of stem cell technology is discussed in opening up a new landscape for investigating the processes underlying both normal human brain development and developmental pathogenesis of psychiatric disease-related states. It is now possible to generate renewable sources of human neurons from normal or disease-impaired individuals, via (among other methods) cellular reprogramming, thereby defining a novel translational bridge between animal studies and human disease. Such research will not replace but, rather, complement traditional animal models, while at the same time representing a paradigm shift in our investigation of neural substrates of mental disorders.

In Chapter 10 optogenetic technologies are addressed; optogenetics is defined as the combination of genetic and optical methods to achieve gain- or loss-of-function of temporally defined events in specific cells embedded within intact living tissue or organisms, usually via introduction of microbial opsin genes that confer to cells both light detection capability and specific effector function. This approach has now been used to control neuronal activity in a wide range of animals, resulting in insights into fundamental aspects of circuit function, as well as circuit dysfunction and treatment in pathological states. Here we review the current state of optogenetics for neuroscience and psychiatry, and address the rapidly evolving challenges and future opportunities.

In Chapter 11 applications of focused ultrasound are reviewed, which may help address the fact that current treatments of neuropsychiatric disease are limited by the lack of noninvasive, reversible, and regionally selective brain-directed drug delivery methods (in large part because of the blood–brain barrier or BBB). Focused ultrasound (FUS) has been found to provide the capability of noninvasively, locally, and transiently opening the BBB in the context of central nervous system diseases. Remaining challenges that are discussed in the chapter include (1) safety and efficacy tradeoffs, (2) mechanism, (3) quantitative measures of BBB change properties, and (4) practical aspects of application for both small (rodent) and large (nonhuman primate) animals.

Chapter 12 reviews some of the advances made in genetic technologies and their application to large-scale gene-mapping efforts in neuropsychiatric disease. From genome-wide association studies to whole-exome sequencing, the sheer amount of data recently generated is unparalleled. Studies of both common and rare variation in diseases such as schizophrenia, bipolar disorder, and autism are now yielding convergent and robust findings, although the high degree of genetic complexity of these diseases (particularly in terms of the number of genes implicated) has also been made evident.

In Chapter 13 the epigenome is explored—as defined by DNA methylation, posttranslational histone modifications, and other regulators of genome organization and function. In the context of psychiatric disorders, these aspects of genetic control have all become increasingly relevant and widely studied. Related therapeutic options—largely based on preclinical studies in rodents—are also addressed, with linkages forged to human brain biology and the pharmacology of mental illness.

In Chapter 14 novel genetic modeling approaches are reviewed that may enable therapeutic predictions and inform decision making. These approaches will range from deciding on genes to probe experimentally, to defining the best treatment for an individual given detailed molecular, genetic, and other personal data. It will be crucial to infer causality and maintain rigorous quantitative methodology with high-dimensional, large-scale data structures, as large and complex as those encountered by climatology and astrophysics. A new breed of mental health researchers with a new set of tools and styles of thinking are coming to the field, with transformative possibilities emerging.

Chapter 15 reviews neuroimaging modalities that can reflect and inform different aspects of brain anatomy and physiology. Key to the research potential of neuroimaging is noninvasiveness, with clear advantages for global and unperturbative observation as well as speedy clinical translation of applications for insight, diagnosis, and treatment. This chapter focuses on key emerging methodologies that may exert substantive impact on mental illness research in the near future.

Finally, Chapter 16 provides an overview of the ways in which brain imaging modalities may interact with, and guide, brain stimulation. These interactions can arise from structural or functional scans on a subject later used to guide offline treatment planning in terms of stimulation site choice. Key caveats, limitations, and opportunities are reviewed. Additionally, scans can be used to track effects of brain stimulation. In a key distinction, such feedback can be processed and analyzed offline or, alternatively, in real time as the brain is being stimulated, employing modalities such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI). This is an exciting avenue of research that provides potential for insight into the global and individualized causal physiology underlying mental illness.

Together, the chapters in this section endeavor to review the principles and possibilities linked to a range of exciting new methodologies for brain research. While translational approaches are emphasized, it is anticipated that basic scientists will also find this compendium helpful as a resource and guide. Technological limitations and opportunities linked to the complexity of the mammalian central nervous system will continue to define the frontiers of neuroscience research for decades to come.