Here is a new review of my book by Brian Miller in Brain Behavior and Immunity:
I read Paul Patterson’s book Infectious Behavior: Brain–Immune Connections in Autism, Schizophrenia, and Depression “cover-to-cover” in one sitting. Did the mild stress of the impending due date of this review alter cytokine production by my immune system, which then interacted with my neurons, resulting in behavioral changes (e.g., increased attention)? Did I enjoy the balance of fascinating historical anecdotes, clear explanations of basic concepts, breadth of topics, dry humor, a willingness to broach controversial topics, including prodromal psychosis and vaccinations, and occasional references to popular culture (e.g., neurons in humans that only fire electrical impulses in response to pictures of Jennifer Aniston)? Or perhaps both? Such are the kind of provocative questions that Dr. Patterson asks about neuroimmune interactions in his book.
A developmental neurobiologist, Paul Patterson describes multiple sources of inspiration for this work: the serendipitous path of his research lab into the study of neuroimmune interactions, his lectures on mental illness, and perhaps most importantly, his personal experiences, including his nephew with autism. He states in the Introduction that the intended audience for this book is intentionally broad—including those in the general public desiring to learn more about brain function, as well as those with a more specific interest and background in neuropsychiatric disorders. (For that, I will forgive the lack of in-text citations for many of the fascinating studies, and instead will scour the Further Reading section at the end.) He walks this tightrope well—the book is simultaneously accessible to the lay reader and insightful to the reader with more expertise. It flows like a professor who rolls up his sleeves and delivers an engaging talk to his audience without once looking at his slides.
One of the most important points in the book is made in the Introduction. Dr. Patterson speaks of an ongoing revolution in our understanding and treatment of mental disorders, including autism, schizophrenia, and depression. Such words—like music to the ears of this schizophrenia researcher—no doubt caused some epigenetic changes in some of the genes governing my stress response (for the good). As a clinician-scientist, I was taught in medical school that schizophrenia was a psychotic disorder, that psychosis was synonymous with hallucinations and delusions, and that dopamine dysfunction was the cause of psychosis. Why then, despite treatment with dopamine-blocking antipsychotic medications, do many of my patients have persistent symptoms, such as apathy, anhedonia, and cognitive impairments that significantly interfere with their social and occupational functioning? Although the field of psychoneuroimmunology is inherently complex, there is growing evidence to suggest that brain–immune connections hold promise to improve quality of life for patients.
If we are to advance our understanding of the causes and treatment of mental disorders, however, a paradigm-shift is necessary. Dr. Patterson grasps this point particularly well. At the heart of this paradigm-shift is the need to appreciate heterogeneity—with respect to etiology, symptoms, and clinical course—among patients who meet the descriptive criteria for a given mental disorder. “The ability to subdivide this heterogeneous illness [schizophrenia] based on objective, biological features will be a critical step forward in understanding its etiology and also for targeting individualized treatments, also known as personalized medicine.” The same rationale applies not only to autism and depression, but also to other mental disorders for which there is evidence of immune dysfunction, such as bipolar disorder and Alzheimer’s dementia.
In Chapter 1: Fever and Madness, Dr. Patterson begins with a historical perspective of manipulations of the immune system in the treatment of mental illness, both natural (the impact of the 1918 “Spanish flu” pandemic) and seemingly more unnatural (Dr. Julius Wagner-Jauregg, who won a Nobel prize for his work on “pyrotherapy”, which involved injecting psychiatric patients with blood from patients with malaria.) While the latter may sound like a Hollywood movie (perhaps starring Jennifer Aniston), nonetheless there are reports of transient improvement in fever-treated patients with schizophrenia, a fascinating observation.
Chapter 2: Brain–Immune Connections, Stress, and Depression describes the multiple levels of bidirectional cross talk between the brain and the immune system. This chapter emphasizes two key points related to the issue of heterogeneity in mental disorders. “There is a great deal of evidence that the brains of females and males are different”. All jokes aside, sexual dimorphism has important implications for the etiopathophysiology and treatment of autism, schizophrenia, and depression, and this factor must be considered. The role of gene- environment interactions—that the impact of a given environmental exposure depends on an individual’s genetic background—is also emphasized.
In Chapter 3: The Battleground of the Fetal–Maternal Environment, Dr. Patterson reviews aspects of embryology relevant to neuroimmune interactions. He appropriately uses the term “battleground” to describe the immune paradox of pregnancy, namely that the mother has immunologic tolerance for the “foreign body” that is the developing conceptus. The key point is made that only two-thirds of monozygotic twins share the same placenta, whereas the remaining third (and all dizygotic twins) do not. Thus, the majority of twins do not have the same in utero environmental exposures, and so placental status is yet another important potential source of heterogeneity.
Chapter 4: Prenatal Origins of Adult Health and Disease explores the concept of “fetal programming”, the concept that the fetal environment during development can have lifelong effects on the health of the offspring. This discussion spills into Chapter 5: Infections and Behavior, in which Dr. Patterson reviews the specific influence of maternal infection on fetal brain development. Here he asks another important question: why are the majority of offspring exposed to prenatal maternal infections—a replicated risk factor for mental disorders—unaffected? Again, heterogeneity appears to be the answer: the severity of the infection, the magnitude of the mother’s inflammatory response, and the genetic constitution of the offspring are all determinants of the outcome.
In Chapter 6: Animal Models of Autism, Schizophrenia, and Depression?, Dr. Patterson is most in his element. While he acknowledges that “whether mouse neurons would respond to pictures of Jennifer Aniston after having seen her movies is an open question,” he clearly demonstrates the feasibility of modeling particular features of neuropsychiatric disorders in rodents. The relevance of his findings to the potential addition of prodromal or high-risk psychosis as a diagnostic category in DSM-V is also considered.
Human studies evidence for immune dysfunction in neuropsychiatric disorders is reviewed in Chapter 7: Immune Involvement in Autism, Schizophrenia, and Depression.
In response to seemingly contradictory findings that fever has been associated with symptomatic improvement in some patients with autism and schizophrenia, while there is also evidence for an increased inflammatory response in acute neuropsychiatric illness, the issue of heterogeneity is again broached. “There is a critical balance that must be maintained in immune status, and that deviating up or down can be harmful.”
In Chapter 8: Pre- and Postnatal Vaccination: Risks and Benefits, Dr. Patterson systematically and objectively evaluates the evidence on this hot topic. While he concludes that the evidence for an association between postnatal vaccination and autism is negligible, there is more uncertainty regarding the balance of safety and efficacy for prenatal maternal vaccination, depending on the stage of pregnancy and other maternal factors.
The final chapter, Chapter 9: Reasons for Optimism, describes recent experiments that suggesting that immune-based interventions in the post-natal period and adulthood can lead to positive outcomes in neurodevelopmental disorders. Accordingly, the final section, Perspectives, concludes with “There is hope!” This sentiment is certainly the other most important point made in the book, as I would argue that the primary goal of clinical care for patients with autism, schizophrenia, depression, and other neuropsychiatric disorders is to instill hope. Dr. Patterson’s book has captured the hope that neuroimmune interactions will play an important role in our revolution of increased understanding of the causes and treatments of mental disorders.
Throughout the book, key terms are italicized and their word origins are defined. Boxes are set apart from the main text for sub-commentary to highlight the work of cutting-edge research and key figures in the field, important concepts, and occasionally humor (e.g., a photograph of an enriched environment for a human). Each chapter ends with a brief summary, and often a prelude to the next chapter, which is helpful to the reader to assimilate new knowledge. Periodically, Dr. Patterson offers “pearls”, suggestions for future research based on interesting observations that warrant further scrutiny.
As suggested by the title, the book does not delve into the evidence for immune dysfunction in bipolar disorder and dementia, although this is understandable given the breadth of topics covered. In Chapters 7 and 9, I was left hoping for a more expanded discussion of existing human studies. While trials of adjunctive treatment with non-steroidal anti-inflammatory agents in depression are briefly mentioned, similar successful trials in schizophrenia were not highlighted. As another example, the association between interferon-alpha and depression is noted, but it is also important to emphasize that a number of autoantibodies are associated with psychosis in conditions outside of schizophrenia, such as lupus. Such studies are also another important “Reason for Optimism”, that targeted immune-based treatments, whether as monotherapy or in adjunct to other medications, may improve and/or ameliorate symptoms of mental disorders. Nonetheless, Dr. Patterson’s Infectious Behavior: Brain–Immune Connections in Autism, Schizophrenia, and Depression by Paul Patterson is a well written, enjoyable read for any audience.