Searching human brain for mechanisms of psychiatric disorders. Implications for studies on schizophrenia

Abstract

In the past 25 years, research on the human brain has been providing a clear path toward understanding the pathophysiology of psychiatric illnesses. The successes that have been accrued are matched by significant difficulties identifying and controlling a large number of potential confounding variables. By systematically and effectively accounting for unwanted variance in data from imaging and postmortem human brain studies, meaningful and reliable information regarding the pathophysiology of human brain disorders can be obtained. This perspective paper focuses on postmortem investigations to discuss some of the most challenging sources of variance, including diagnosis, comorbidity, substance abuse and pharmacological treatment, which confound investigations of the human brain.

Introduction

There is no controversy regarding the fundamental role of human brain studies in investigations of the pathophysiology of psychiatric disorders. These illnesses do after all involve changes in cognitive and emotional behaviors, and there is no other organ of the body where such functions receive their primary mediation. Because these disorders are only diagnosable in patients, the human brain becomes by necessity the primary object of investigation. A clear example of the success of this strategy is the involvement of GABAergic interneurons in the pathophysiology of disorders such as schizophrenia, bipolar disorder and autism (Benes et al., 1992, Akbarian et al., 1995, Woo et al., 1998, Lewis et al., 1999, Benes, 2000, Volk et al., 2000, Benes and Berretta, 2001, Cotter et al., 2002, Heckers et al., 2002, Costa et al., 2004, Guidotti et al., 2005, Lewis et al., 2005, Torrey et al., 2005, Akbarian and Huang, 2006, Fatemi et al., 2009, Lawrence et al., 2010, Blatt and Fatemi, 2011, Fatemi et al., 2011, Guidotti et al., 2011) (see also articles included in this Special Issue). The postulated role of the GABA system in schizophrenia, the main focus of this Special Issue, has originated from a variety of technological approaches to the study of the human brain that include both in vivo brain imaging and postmortem investigations of the human brain.

While studies of this type led important breakthroughs in our knowledge and offer great promise for the future, they also present daunting difficulties related in great part to the inherent complexity of psychiatric disorders and the many potential confounding factors. While it is inconceivable for studies on the pathophysiology of schizophrenia and other psychiatric disorders to be undertaken without investigations on the human brain, the challenges these disorders pose can only be met by a highly diverse and complementary array of methodological approaches, ones capable of integrating human studies with investigations of non-human mammalian species and in vitro cell systems. This integration makes it possible for studies of cognition and emotion to be understood within the context of detailed cellular and molecular mechanisms related to neural circuitry. Our understanding of psychiatric disorders critically depends upon the inherent synergy between brain imaging and postmortem studies of the human brain, human genetic investigations, experimental animals and in vitro models, and their ability to reciprocally complement one another with their respective strengths and weaknesses. In this context, it is essential to maintain an open and constructive dialogue regarding the strengths and weaknesses of each of these respective methodologies. The intent of this perspective paper is to stimulate a dialogue that will help to highlight some of the main challenges that studies of the human brain, and postmortem in particular, in psychiatric disorders present to the field of translational neuroscience.

Methodological innovations applied to postmortem investigations on the human brain have in recent years rapidly amplified their potential and usefulness. Increasingly more sophisticated methodological approaches, such as studies of microarray-based genomic integrity, gene expression and methylation, cell level gene and microRNA expression profiling, as well as epigenetics, proteomics, and quantitative high resolution microscopy, hold important promises for progress (English et al., 2011, Horváth et al., 2011, Moreau et al., 2011, Pidsley and Mill, 2011, Benes, 2012, Mitchell et al., 2014). In parallel, attention to a growing number of potential confounding variables, and advances in our understanding of the effects on the brain of systemic physiological and pathological conditions, has contributed to elevate accepted standards. This process is leading toward increasingly more rigorous approaches with regard to diagnostic criteria, comorbidity, effects of pharmacological treatment and drugs of abuse, among many. Far from wishing to push forth one specific approach over others, a discussion of commonly used strategies is intended to encourage an ongoing conversation about valid approaches to the study of postmortem human brain.

Although we focus on human postmortem investigations, it is important to remember that several of the aspects discussed below are also critical to in vivo imaging studies. Both in vivo and postmortem human studies bring to the fore issues related to reliable psychiatric diagnosis, comorbidity, substance abuse, current and past pharmacological treatment and compliance. Each of these issues presents a distinct challenge to both postmortem and brain imaging studies of the brain in relation to psychiatric disorders. For both, it is critical to emphasize the importance of gathering extensive, detailed, information on study subjects. While this task can be particularly challenging for postmortem studies, which rely heavily on medical records and family interviews/questionnaires, the availability of toxicological and neuropathological assessments represents a significant advantage, as discussed in more detail below. The reliance of human postmortem studies on the availability of subject information underlies the importance of modern approaches to brain banking and thoughtful screening of available information. Other important aspects related to human brain studies have been elegantly discussed by other authors (Deep-Soboslay et al., 2011, Harrison, 2011, Horváth et al., 2011, McCullumsmith and Meador-Woodruff, 2011, Tunbridge et al., 2011).