Neuroscience requires periodic reminders that its current methods are too crude

In a piece for the Transmitter, Nicole Rust uses the question, “What, if anything, makes mood fundamentally different from memory?” to explore different issues related to the scientific understanding of brain-behavior relationship. One strand of this discussion is the mental-disorders-vs-brain-disorders debate, which readers of Psychiatry at the Margins will be well-familiar with by now.

Rust rightly notes that for many experts the question is one of the appropriate level of focus. Some focus on causal explanations at the psychological-behavioral level, others on the neurobiological level (including how the influence of psychosocial variables is realized in neurobiological terms), and many seek to integrate the two or switch back and forth between the levels depending on contextual needs. A promising contemporary version of the integrationist effort comes from the study of complex systems, with a focus on feedback loops and emergent, dynamic properties.

Rust invited comments from a diverse group of experts and researchers working in this area, and these provide a potent complement to her discussion. These quotes are interesting and insightful, in addition to being wonderfully concise, and provide a excellent snapshot of current views in neuroscience and neuroscience-adjacent communities. I am only going to mention quotes by a few folks below, but I do recommend taking a look at the entire piece.

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Here’s my quote published in the Transmitter article:

“Whether mood disorders (and mental disorders generally) are “brain disorders” is an interesting philosophical question. Unsurprisingly, the answer depends on how we understand the notion of a brain disorder. It is important to recognize that this question is motivated by daunting epistemic challenges in brain-behavior research. Neuroscientists have been fortunate that classic memory disorders have turned out to be cases of cellular neurology gone awry, with downstream effects on brain circuits and cognitive domains. Mood disorders, in contrast, appear largely to involve brain-body-environment interactions locked into dysfunctional patterns. Historically, neuroscience has lacked the tools to meaningfully articulate such higher-order dynamic interactions, and its current abilities to do so are fairly rudimentary; psychological concepts describe these interactions, albeit in a manner that is often idiosyncratic and socially constructed. Concepts such as narcissism, shame, projective identification—so familiar to psychodynamic clinicians—resist easy articulation in neurological terms. Maybe one day neuroscience will develop the language to adequately describe and explain these higher-order phenomena, but it is not there yet. Neuroscience requires periodic reminders that its current methods are too crude, that it should not be so arrogant as to think it can make psychology and the social sciences redundant. Mood disorders are multi-level phenomena, not categorizable simply as problems of “mental software,” nor as problems of “neurological hardware.” Their scientific understanding requires the “piecemeal integration” of multiple scientific disciplines and a great deal of epistemic humility.”

Eric Turkheimer emphasizes that biological explanations have to contend with the full range of human behaviors, and appeals to biology per se are not guaranteed to offer any coherent neurobiological explanation:

“Enthusiasts and skeptics of a biological explanation of human behavioral traits face twin challenges. For us skeptics, the trick is to avoid ghost-in-the-machine dualism. No soul, no free will, no mind, unless it is unambiguously rooted in physical, evolved organic reality. Enthusiasts must avoid tautological materialism. I get it: all thinking, wanting and believing is done with the brain, and if all you have to say is that therefore aphasia and religious devotion are all equally “in your brain,” fine, but it gets you nowhere. All assertions that a complex behavior is “biological” should be paired with an example of something that is not. In 1998, I imagined two silent people: a person who had a stroke in the left frontal lobe that resulted in a deep aphasia, and a monk who had taken a vow of silence as a matter of religious devotion. No dualism: Both silences are in their brains, somehow. Why do they seem so different? The answer is mostly about entities and the language we use to define and describe them. Aphasia, as a category, corresponds to a class of neurological events resulting from stroke. There is no class of neurological events that corresponds to devotional silence.”

Given that psychopathology is on a continuum with the rest of psychological-behavioral phenomena, we should expect that psychiatric conditions will be distributed along the aphasia-silence dimension. We cannot artificially restrict our hypotheses (e.g. confidently assuming the existence of localizable neurobiological dysfunctions) and have to explore every possibility with an open mind. In all likelihood, most psychiatric disorders are not as neurologically incoherent as devotional silence, but most are not as discrete and localizable as aphasias either; they occupy a middle-ground with partial neurological coherence.

The necessity of trying to match the appropriate explanatory framework to the appropriate condition is also illustrated in Russell Poldrack’s comments:

“The fact that limited lesions to a small set of brain structures in the medial temporal lobe can result in punctate memory disorders has provided a platform for subsequent analysis and modeling of those neural circuits. There does not appear to be any similar high-value target for mood. Instead, it seems that mood disorders can result from lesions across a widespread set of brain regions. The “localize and decompose” strategy may have worked well for memory, but mood may require a different strategy, such as one grounded in complex systems theory.”

Steven Hyman wrote:

“The most certain path to better treatments for mood disorders depends on insight into their mechanisms—and thus into brain biology. Whether the onset of a depressive episode follows an adverse experience such as loss of a job or seems to come from nowhere, it is grounded in neural mechanisms, as are the ultimate treatment targets, regardless of how treatment is delivered—via psychotherapy, medicine or electrical stimulation. Such assertions do not represent reckless reductionism. Brains support the fitness of all free-living animals, including ourselves, because they are remarkably powerful integrators. To select actions and regulate our physiology in response to threats, rewards or complex social interactions, the brain must synthesize information that comes from each person’s DNA, prior developmental events and their bodies, with current sensory inputs that refine its predictions of what is happening in the present and what will happen in the future. To discover better treatment, we must understand how such mechanisms go awry. Some who accept the brain as the substrate of thought, emotion and behavior—nature’s lesion “experiments” are quite convincing—but nonetheless devalue the brain’s importance, often hold an erroneous model that analogizes the brain to a digital computer that could run any software. They construe the neural hardware as a dumb machine programmed by the important stuff, thought and experience. But the brain is nothing like a digital computer. There is no software independent of biology. Even as neural circuits are computing the current moment and predicting the next, the brain’s structure, including molecules, dendrites and synapses, is changed forever. It is the biology and plasticity of the brain itself that matter for all experience and action and all psychiatric illness. There is nothing left over.”

I don’t disagree with Hyman. The biggest obstacle to developing fundamentally new treatment options, including new psychological treatments, is our ignorance of the brain mechanisms involved in psychopathology. A scientific research program aimed at understanding brain mechanisms of psychopathology is therefore necessary and valuable. However, I would qualify my agreement in two ways:

1) We should be open to the possibility that understanding these brain mechanisms will likely involve going beyond the neurophysiological to the neurocomputational, that the relevant brain mechanisms may turn out to be best understood in informational and dynamical terms, that the mechanisms and processes involved in psychopathology may form causal loops distributed across brain, body, and environment (including interactions with other brains), and that all this may require new scientific ways of thinking about brain mechanisms that we cannot at present anticipate.¹

2) The project to understand the brain mechanisms of psychopathology should exist concomitantly with scientific projects that are grounded in psychological and social science methods, and the project to develop new treatments should co-exist with the project of refining existing treatments, combining them in more effective ways, and improving the manner in which they are delivered. A lot of resentment towards psychiatric neuroscience comes from the marginalization (perceived or otherwise) of clinical and psychological research over the past 3 decades, and one reason for poor psychiatric outcomes at the population level is, arguably, the false hope that better treatments can overcome the current social and structural barriers that have prevented the optimization and delivery of existing treatments.

I was intrigued by Joseph LeDoux’s comments:

“Medicinal treatments are especially useful in altering behavioral and physiological symptoms. But mental anguish is subjective, conscious suffering. That does not mean that conscious experience is not physical. It just means that it involves higher-order circuits that operate independently of those that control behavioral and physiological responses. It is not surprising that medications that alter behavioral and physiological responses in animals do not do much to relieve mental anguish in humans. Possibly medications developed in human studies would do a better job. But only if the researchers accept that changing a person’s behavior or physiology is not going to do the trick. The target has to be subjective experience itself. The core problem of mental anguish might be best treated with psychosocial approaches. Medications can also have a role in helping to ease process, but not as a cure or primary treatment.”

I welcome the emphasis on “subjective experience,” but given the embodied nature of subjective experience, I don’t see how we can alter subjective experience without altering a person’s behavior or physiology. I suspect what LeDoux means is that we shouldn’t be content with using behavioral or physiological change as a proxy for a change in subjective experience and that subjective experience of psychopathology should be our primary focus. That part I agree with. I have reservations about the rest. Almost all existing classes of psychiatric medications go back to serendipitous observations of effects in humans. While it is true that any particular medication or any particular behavioral intervention does not do much to relieve mental anguish in humans on average, it is nonetheless striking that they can and do relieve mental anguish tremendously in some people, providing a powerful proof of principle of the relevance of physiological and behavioral change. What approach will lead to the most change in subjective experience is an empirical question — we don’t quite know. But we should avoid supposing that it must be “psychosocial” (or “neurophysiological”). At the moment, for example, it is difficult to think of an intervention that changes subjective experience in the short-term more drastically and more powerfully than psychedelics do. A focus on subjective experience does not by itself tell us what modality of treatment is going to be the most effective for any particular condition and for any particular person.

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1. Douglas Hofstadter writes in I Am a Strange Loop, “[I] don’t see why physical mapping should constitute the be-all and end-all of neurological inquiry” and I completely agree. “Saying that studying the brain is limited to the study of physical entities [such as synapses, neurons, brain cortices] would be like saying that literary criticism must focus on paper and bookbinding, ink and its chemistry, page sizes and margin widths, typefaces and paragraph lengths, and so forth… My point is simple: abstractions are central, whether in the study of literature or in the study of the brain.” (p. 25-26)

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Advancing Neuroscientific Understanding of Brain-Behavior Relationship: A Conversation with Nicole C. Rust

Mental Disorders Both Are and Are Not Brain Diseases

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