ReviewSearching human brain for mechanisms of psychiatric disorders. Implications for studies on schizophrenia
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).
Section snippets
Diagnosis
The debate about diagnostic criteria, highlighted during the recent release of the DSM 5, raises important issues relative to categorical versus dimensional diagnostic approaches (Barch et al., 2013, Heckers et al., 2013). These issues are equally important to clinicians and researchers, as they impact on the conceptual framework and design of group comparisons. Clinical presentations do not often fit into categories and may change over time, raising important questions with regard to the
Comorbidity
Comorbidity of psychiatric disorders with other brain disorders, as well as systemic disorders, is a potential source of variance and deserves careful consideration. Within the realm of psychiatric disorders, several clinical domains and/or categorical diagnoses often coexist, such as psychosis, anxiety and depression (Dernovsek and Sprah, 2009, Simon, 2009, Cerda et al., 2010, Potuzak et al., 2012, Braga et al., 2013, Pallanti et al., 2013). The variety of psychiatric disorders represented in
Substance use disorders
Substance use disorders, a frequent comorbidity in psychiatric disorders, pose a significant challenge to human brain studies. Estimates of lifetime prevalence of substance use disorders in subjects with psychiatric disorders vary broadly from 15 to 50%, largely depending on the disorder, type of substance, age and length of exposure and geographical location (Lasser et al., 2000, Conway et al., 2006, Barnett et al., 2007, Katz et al., 2008, National Collaborating Centre, 2011, Wisdom et al.,
Pharmacological therapy
The large majority of psychiatric patients receive, or have received in the past, pharmacological treatment extending over many years. Without a doubt, such treatment impacts on molecular, cellular and morphological neural features, and thus represents a potential confounding factor in brain imaging and postmortem brain studies of human subjects. It is important to emphasize that exposure to pharmacological agents may either induce or mask differences between diagnosis and control groups. The
Conclusions
Over the past 20 years, postmortem studies of the human brain have benefitted from continued improvement of their design, the availability of increasingly powerful cellular and molecular technologies, and enhanced integration of complementary approaches. Often-quoted limitations in postmortem studies of the human brain obviously exist, which may be qualitatively, but not quantitatively, different from those inherent to other approaches to the study of the brain. It is critical to promote an
Role of funding source
Many of the authors' publications quoted in this perspective paper were made possible by NIH funds.
Contributors
All authors contributed to the preparation of this perspective manuscript.
Conflict of interest
The authors of this manuscript do not have any actual or potential conflict of interest to disclose.
Acknowledgments
Many of the authors' publications quoted in this perspective paper were made possible by NIH funds. The authors are grateful to NIH/NIMH for funding of their respective groups.
References (110)
- et al.
Molecular and cellular mechanisms of altered GAD1/GAD67 expression in schizophrenia and related disorders
Brain Res. Rev.
(2006) - et al.
Logic and justification for dimensional assessment of symptoms and related clinical phenomena in psychosis: relevance to DSM-5
Schizophr. Res.
(2013) Emerging principles of altered neural circuitry in schizophrenia
Brain Res. Brain Res. Rev.
(2000)- et al.
GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder
Neuropsychopharmacology
(2001) - et al.
The density of pyramidal and nonpyramidal neurons in anterior cingulate cortex of schizophrenic and bipolar subjects
Biol. Psychiatry
(2001) - et al.
Neuron numbers and volume of the amygdala in subjects diagnosed with bipolar disorder or schizophrenia
Biol. Psychiatry
(2007) - et al.
Schizophrenia and affective disorders — cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family
Am. J. Hum. Genet.
(2001) - et al.
Anxiety comorbidity in schizophrenia
Psychiatry Res.
(2013) - et al.
Genetic and environmental influences on psychiatric comorbidity: a systematic review
J. Affect. Disord.
(2010) - et al.
Substance use disorders among treatment naive first-episode psychosis patients
Compr. Psychiatry
(2014)
Hippocampal volume and total cell numbers in major depressive disorder
J. Psychiatr. Res.
The density and spatial distribution of GABAergic neurons, labelled using calcium binding proteins, in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia
Biol. Psychiatry
Psychiatric brain banking: three perspectives on current trends and future directions
Biol. Psychiatry
The neuroproteomics of schizophrenia
Biol. Psychiatry
Inflammatory cytokines and neurological and neurocognitive alterations in the course of schizophrenia
Biol. Psychiatry
First episode schizophrenia-related psychosis and substance use disorders: acute response to olanzapine and haloperidol
Schizophr. Res.
Epigenetic GABAergic targets in schizophrenia and bipolar disorder
Neuropharmacology
Increased lactate levels and reduced pH in postmortem brains of schizophrenics: medication confounds
J. Neurosci. Methods
Using our brains: the findings, flaws, and future of postmortem studies of psychiatric disorders
Biol. Psychiatry
Structure of the psychotic disorders classification in DSM-5
Schizophr. Res.
Analyzing schizophrenia by DNA microarrays
Biol. Psychiatry
Th1, Th2 and Th3 cytokine alteration in schizophrenia
Prog. Neuropsychopharmacol. Biol. Psychiatry
Altered GABA neurotransmission and prefrontal cortical dysfunction in schizophrenia
Biol. Psychiatry
The neurobiology and genetics of suicide and attempted suicide: a focus on the serotonergic system
Neuropsychopharmacology
Novel approaches to the study of postmortem brain in psychiatric illness: old limitations and new challenges
Biol. Psychiatry
Deficits in docosahexaenoic acid and associated elevations in the metabolism of arachidonic acid and saturated fatty acids in the postmortem orbitofrontal cortex of patients with bipolar disorder
Psychiatry Res.
Chromosomal location and genomic structure of the human translin-associated factor X gene (TRAX; TSNAX) revealed by intergenic splicing to DISC1, a gene disrupted by a translocation segregating with schizophrenia
Genomics
The genome in three dimensions: a new frontier in human brain research
Biol. Psychiatry
Altered microRNA expression profiles in postmortem brain samples from individuals with schizophrenia and bipolar disorder
Biol. Psychiatry
Parvalbumin neurons in the entorhinal cortex of subjects diagnosed with bipolar disorder or schizophrenia
Biol. Psychiatry
Epigenetic studies of psychosis: current findings, methodological approaches, and implications for postmortem research
Biol. Psychiatry
Categorical vs dimensional classifications of psychotic disorders
Compr. Psychiatry
Inflamed moods: a review of the interactions between inflammation and mood disorders
Prog. Neuropsychopharmacol. Biol. Psychiatry
Abnormal partitioning of hexokinase 1 suggests disruption of a glutamate transport protein complex in schizophrenia
Schizophr. Res.
Human postmortem tissue: what quality markers matter?
Brain Res.
Neurochemical markers for schizophrenia, bipolar disorder, and major depression in postmortem brains
Biol. Psychiatry
GABAA receptor subunit gene expression in human prefrontal cortex: comparison of schizophrenics and controls
Cereb. Cortex
Chemotherapy in Psychiatry: Pharmacologic Basis of Treatments for Major Mental Illness
Pharmacotherapy of psychosis and mania
The immunology of bipolar disorder
Neuroimmunomodulation
Substance use in a population-based clinic sample of people with first-episode psychosis
Br. J. Psychiatry
Control of synaptic strength by glial TNFalpha
Science
Relationship of GAD(67) regulation to cell cycle and DNA repair in GABA neurons in the adult hippocampus: bipolar disorder versus schizophrenia
Cell Cycle
Nicotinic receptors and functional regulation of GABA cell microcircuitry in bipolar disorder and schizophrenia
Handb. Exp. Pharmacol.
Increased GABAA receptor binding in superficial layers of cingulate cortex in schizophrenics
J. Neurosci.
DNA fragmentation decreased in schizophrenia but not bipolar disorder
Arch. Gen. Psychiatry
Alterations in GABAergic biomarkers in the autism brain: research findings and clinical implications
Anat. Rec. (Hoboken)
The GABAergic system in schizophrenia
Int. J. Neuropsychopharmacol.
Diagnostic shifts during the decade following first admission for psychosis
Am. J. Psychiatry
Schizophrenia: medical illness, mortality, and aging
Int. J. Psychiatry Med.
Cited by (9)
Mapping pathologic circuitry in schizophrenia
2018, Handbook of Clinical NeurologyCitation Excerpt :Information about the disease state can then properly inform the production of animal models which are required for cause-and-effect testing to determine what upstream factors could lead to the pathology identified in the primary disease tissue. As described below, using postmortem human tissue comes with a unique set of considerations and potential confounds (Lewis, 2002; Beneyto et al., 2009; Berretta et al., 2015a). Unlike diagnosing many somatic illnesses, psychiatric diagnoses depend solely upon clinical features, oftentimes which have to be self-reported by the patient.
Distribution and function of hyaluronan binding protein involved in hyaluronan depolymerization (HYBID, KIAA1199) in the mouse central nervous system
2017, NeuroscienceCitation Excerpt :The latter is due to increased lateral diffusion of α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors in postsynaptic neurons (Frischknecht et al., 2009). Abnormality of PNs is reported to be involved in schizophrenia (Berretta et al., 2015). Although HA is a critical component of PNs, some reports have indicated that HA affects synaptic plasticity directly in the hippocampus.
Dimensional clinical phenotyping using post-mortem brain donor medical records: post-mortem RDoC profiling is associated with Alzheimer's disease neuropathology
2023, Alzheimer's and Dementia: Diagnosis, Assessment and Disease MonitoringProteins and Transcriptional Dysregulation of the Brain Extracellular Matrix in Parkinson’s Disease: A Systematic Review
2023, International Journal of Molecular SciencesA glycomics and proteomics study of aging and Parkinson’s disease in human brain
2020, Scientific Reports