A New Approach to Treating Brain Disorders

Review of Elusive Cures: Why Neuroscience Hasn’t Solved Brain Disorders – And How We Can Change That. By Nicole Rust. Princeton University Press.

More than a billion people around the world suffer from mental disorders such as Alzheimer’s, Parkinson’s, ALS, Huntington’s, epilepsy, schizophrenia, depression, and anxiety. Brain diseases cost the United States about $1.5 trillion in 2016, 9 percent of our country’s gross domestic product.

Source: Elf Moondance/Pixabay

Breakthroughs in neuroscience in the last 40 years—the discovery and sequencing of the genetic code, advances in biotechnology, computational power, and non-invasive imaging—led to expectations that brain diseases would soon be cured, or at least more effectively treated. While advances have been made, psychologist Nicole Rust points out, progress on the vast majority of them has been frustratingly slow.

In Elusive Cures, Rust, a professor of psychology at the University of Pennsylvania, explains why. And she makes a compelling case that understanding the brain as a complex and constantly changing system instead of a “thing” improves the chances of understanding the relationship between “mental disorders” and “brain disorders,” the role of neural networks, and finding cures. Accessible to lay readers, informed by the latest research, and filled with concrete examples, Elusive Cures is immensely useful to a subject that is relevant to all of us.

For decades, Rust indicates, most researchers studying neurological disorders operated within a “broken domino chain” framework in which a mutated gene precipitated a cascade of events ending in cognitive impairment. The ethos was captured in the phrase, “one gene, one drug, one disease.” Conceding that this framework has led to some important discoveries, Rust uses the “amyloid hypothesis” to demonstrate that it is often problematic. The discovery that a mutation in a single DNA base pair in a gene called APP was followed by an accumulation of toxic amyloid plaques in the brain led researchers to conclude it is a cause (not a consequence) of Alzheimer’s. Drugs were produced to clear the plaques, but clinical trials found only a modest impact on slowing cognitive decline. Although debate continues over whether administering the drugs earlier will produce better results, Rust endorses a view of Alzheimer’s as the product of a “non-linear dynamic” brain system, characterized by multiple interactions, feedforward and feedback loops, emergent properties, and time delays, where causation and correlation are difficult to define.

Genes matter, Rust emphasizes. Huntington’s, for example, can be traced to a single gene mutation. That said, most brain disorders, including schizophrenia and autism, are linked to hundreds of genes. Equally important, genes also play a role in mRNA, proteins, and neurons, which combine into neural circuits, whose activation contributes to behavioral function and dysfunction. Complexity, Rust adds, “can enter at every stage.” Nor, we learn, is schizophrenia exclusively genetic: if one identical twin is schizophrenic, there is only a 50 percent chance the other sibling will be similarly afflicted. And other factors, including infections and injuries in utero, increase the risk of schizophrenia.

Rust notes that although the idea that the brain is an information processing machine that computes has helped us understand how vision and memory work, the metaphor cannot explain anxiety, insomnia, depression, or anorexia.

The “take-home message” of Elusive Cures, then, is that brain function and dysfunction occur in a complex system, comparable in some respects to the weather, in which properties that emerge from interactions between and among (internal and external) causes need to be studied simultaneously. Brains are also subject to “the butterfly effect,” where small perturbations can have large consequences. And the system, which is built to be robust, is also fragile.

To build on these insights, Rust suggests, involves enlisting artificial intelligence to model how the brain system operates, making informed guesses to reduce the variables to a manageable number, and trying to identify anomalies or sudden changes to “iterate our way to good solutions.”

Implementing this “Grand Plan,” Rust recognizes, will be extremely expensive and logistically and conceptually challenging. But it seems clear, we have oversimplified how we think about the brain and urgently need a more accurate and effective approach.