Causality, Intervention, and Psychiatric Neuroscience

A Response to Peter Sterling

This post is in response to Peter Sterling’s article “Causality in Mental Disturbance: A Review of the Neuroscience” published on Mad in America on July 29, 2023.

Peter Sterling is a distinguished neuroscientist and Professor at the University of Pennsylvania School of Medicine. So, any critique coming from Sterling is something to take seriously. At the same time, this article is very odd for a variety of reasons that will soon become obvious, and in some regards, what it has to say about psychiatric disorders is very difficult to take seriously.

An editor’s note at the beginning of the article says that this is “an original research article” and is presented “in its native format as a scientific paper.” But the piece is quite unlike a scientific paper, and I am quite confident that no respectable scientific journal would publish it in its current shape or form. If I were peer-reviewing it, I would recommend rejection without hesitation. (I wouldn’t be surprised if it was rejected from scientific journals before finding a home at Mad in America.)

Sterling introduces his article by saying it is a comment on the 2022 review article “Causal Mapping of Human Brain Function” by Siddiqi et al., in Nature Reviews Neuroscience but the scope of Sterling’s commentary is considerably greater, and one gets the impression that this is merely an opportunity for Sterling to express his grievances about psychiatry more generally and offer poorly supported, broad-sweeping conclusions (“Current medicalization of all social and psychological suffering is unjustified by the currently known biology.”) that are only tangentially related to the topic of Siddiqi et al. review.

In fact, the Siddiqi et al. paper is an odd choice for this sort of tirade against psychiatric neuroscience to begin with since the paper isn’t that particularly focused on mental disorders. This is evident even from their abstract:

“Mapping human brain function is a long-standing goal of neuroscience that promises to inform the development of new treatments for brain disorders. Early maps of human brain function were based on locations of brain damage or brain stimulation that caused a functional change. Over time, this approach was largely replaced by technologies such as functional neuroimaging, which identify brain regions in which activity is correlated with behaviours or symptoms. Despite their advantages, these technologies reveal correlations, not causation. This creates challenges for interpreting the data generated from these tools and using them to develop treatments for brain disorders. A return to causal mapping of human brain function based on brain lesions and brain stimulation is underway. New approaches can combine these causal sources of information with modern neuroimaging and electrophysiology techniques to gain new insights into the functions of specific brain areas. In this Review, we provide a definition of causality for translational research, propose a continuum along which to assess the relative strength of causal information from human brain mapping studies and discuss recent advances in causal brain mapping and their relevance for developing treatments.”

Siddiqi et al. focus on “neuropsychiatric disorders” and talk about psychiatric disorders in the same breath as they talk about neurological disorders, but there is no discussion in the paper on the nature of mental disorders or in what sense they might be brain disorders, etc., and that’s okay, since the paper isn’t really about that.

Siddiqi et al. assume that mental disorders are subject to the logic of brain mapping: “DBS sites are more likely to relieve motor symptoms of Parkinson disease if they are connected to the supplementary motor area86. TMS sites are more likely to relieve depression if they are functionally anti-correlated to the subgenual cingulate⁷². Similar approaches have now been used to map the causal neuroanatomy of movement disorders^{86,87,88,89,90,91}, mood disorders^{71,90,92,93,94,95}, anxiety-related disorders^96,97,98, psychotic disorders^99,100,101, disorders of consciousness^102,103,104 and various other neuropsychiatric phenomena^{105,106,107,108,109}.”

And it is this assumption that Sterling seems to find particularly irksome, so irksome that he thinks that this undertaking should be compared to the neuroscientific logic that justified lobotomy! (Talk about rhetoric and false equivalence!) Siddiqi et al. do talk about symptom localization, but it is also obvious that they are working with a broad notion of localization that aims to identify causal links between symptoms and neuroanatomy.

For a rambling, meandering critique devoted to Siddiqi et al.’s paper with many historical detours, it is notable that Sterling has nothing to say about the central focus of the paper, which is outlining six criteria for appraising causality in human brain mapping studies. This is entirely uncommented on by Sterling.

A hint as to why Sterling might be focused on this paper in particular emerges later in the article. Sterling writes: “Here is Dr. Siddiqi tweeting to me (@whatishealth21) in 2022 to explain condescendingly that “benzos” are only prescribed by general practitioners, plus some nonsense about GABA resembling insulin.” This is followed by a screenshot of Siddiqi’s tweet.

Wait… is Sterling so upset because Siddiqi didn’t show him enough deference on twitter?? What kind of scientific article (which this opinionated blogpost purports to be) complains about a twitter exchange and then characterizes what a younger colleague has to say as “some nonsense”?

To summarize so far:

Sterling’s comment on Siddiqi’s et al.’s paper fails to say anything about the central goal of the paper (“In this Review, we provide a definition of causality for translational research, propose a continuum along which to assess the relative strength of causal information from human brain mapping studies…”), fails to consider the ways in which Siddiqi et al. might understand the notion of “symptom localization,” and takes issue with the fact that Siddiqi et al. assume that there are causal links between psychiatric symptoms and neuroanatomy.

Sterling writes: “To be clear: there is no neuroscience to suggest that any mental function would be improved by ablating or stimulating a particular structure in the prefrontal cortex or its associated subcortical regions. To the contrary, what we know of the intrinsic organization of the prefrontal cortex suggests that mucking with it is unlikely to help. Any suggestion to the contrary is simply wild speculation. The Review tries to justify its story by claiming efficacious results. But I have heard these claims before, and they never check out. They’re just a succession of Ponzi schemes, as here recounted.”

These are quite strong claims. What does “no neuroscience” mean here? As a general matter, it is to be expected that mental functions are mediated by brain functioning, and while it may very well be that mental functions are not caused by some localizable brain dysfunction, there can nonetheless be causal relationships such that stimulating particular regions/circuits or modifying their activity pharmacologically can produce therapeutic effects on mental functions. In fact, it’s not even something that speculative… we are already doing it via interventions such as Transcranial Magentic Stimulation (TMS) and substances such as psychedelics. Our current understanding of neuroscience certainly does not forbid such causal relationships.

As readers of this newsletter are aware, I am generally skeptical of the idea that psychiatric syndromes can be localized in the brain with strong sensitivity and specificity. I’m influenced by neuroscientists such as Luiz Pessoa and Lisa Feldman Barrett when it comes to the issue of localization of mental functions. But I wouldn’t go so far as to say that brain circuits or brain areas cannot be therapeutic targets for psychiatric disorders, or that there cannot be causal relationships between brain circuits and psychiatric symptoms.

Sterling says: “I have heard these claims before, and they never check out.” Check out according to whom? TMS for depression, for instance, is a clinically standard, actively researched, continuously refined intervention. It’s not a magic cure; its modest but non-trivial efficacy is supported by a large body of scientific research. The medical resource UpToDate, for example, summarizes efficacy of TMS as: “Multiple randomized trials have consistently demonstrated that repetitive surface cortical TMS is superior to sham TMS for treatment-resistant unipolar major depression. These trials indicate that high frequency surface cortical TMS over the left dorsolateral prefrontal cortex (high frequency left TMS) and low frequency surface cortical TMS over the right dorsolateral prefrontal cortex (low frequency right TMS) are each efficacious and well tolerated. As an example, over 40 trials show that response (reduction of baseline symptoms ≥50 percent) is at least three times more likely with high frequency left TMS than sham TMS… However, absolute rates of remission with repetitive TMS in some studies are modest [80]. As an example, two relatively large and rigorous randomized trials (n = 301 and 190) both found that remission with active high frequency left TMS occurred in only 14 percent of patients (compared with 5 to 6 percent in the sham TMS groups).”

What Sterling is offering here is not humility… this is arrogance in the opposite direction. Advocating caution when it comes to claims about symptom localization or efficacy of neuromodulation is something I’d advocate myself, but “stop mucking with the brain because psychiatry is a Ponzi scheme” is not something we should have much patience for.

Sterling: “The Review frequently returns to a particular goal: “modulate the neuroanatomy”. We can certainly conveniently “modulate” it now with TMS and such, but in what direction? What neuroscience is there to suggest that zapping the prefrontal cortex repeatedly would relieve depression? None. But when clinicians protest that “it works”, there’s the same old belief in snake oil. Most likely the benefits reported in small, short-term, poorly controlled studies will be positive. But over the longer run and larger studies, TMS won’t help because there’s not the slightest rationale. To mobilize efficaciously the frontal lobe circuits for mood, try a handshake, a touch, a smile, a hug, some praise, a walk. Not just once but daily—in place of the daily pills. Of course, this may not do for all, but it’s a start, and at least there is a strong rationale.”

In passages such as this, Sterling constantly reveals his anti-medication bias, in addition to his disregard of the clinical and scientific evidence in favor of TMS (these are not just small, short-term, poorly controlled studies). “Oh, you don’t need daily pills, you just need a daily handshake!” To use the expression Sterling used for Siddiqi’s tweet, this is some nonsense.

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Here are the conclusions of Sterling’s article, as stated by him.

Sterling: “(1) Current medicalization of all social and psychological suffering is unjustified by the currently known biology.”

For an article that offers no discussion of the concept of medicalization, when medicalization is justified/unjustified, and doesn’t bother to make any argument that “all social and psychological suffering” is being medicalized, this is an odd conclusion. Is currently known biology the only justification for medicalization? Whatever the merits of this Szaszian claim, it is clearly not a conclusion to be derived from a discussion of the Siddiqi et al. article that preceded it.

Sterling: “(2) Therefore, all the jiggering with human brains from childhood onward are wild empirical guesses—effects are claimed to “work” over a short time, and so are adopted and promoted for commercial reasons and for reasons of social control.”

Sterling is telling us what he thinks of psychiatric treatment. “jiggering with human brains” “wild empirical guesses” “effects are claimed to work” “commercial reasons” “social control”… There is no acknowledgement of the legitimate therapeutic effects over short-term and long-term even for a subset of patients, or that the motivations behind these treatments may be quite therapeutic and with the intent to relieve suffering, and that while justification may be clinical, we nonetheless have hypotheses about mechanisms of actions that can be productively investigated.

Sterling: “(3) Over my 50 years of following such treatments, I have observed that over the long term, none of them work, but meanwhile they cause considerable brain damage. Moreover, they deprive the sufferers of a sense of their own agency.”

Forgive me for not taking Sterling’s word for it. Sterling may have testified in courts against ECT, but he is not a clinician, he offers no systematic and objective review of the efficacy and safety of psychiatric interventions, and his personal observations carry little scientific weight here. And the effects on agency are certainly multifaceted. It is common for patients to rediscover their sense of agency because of psychiatric interventions and what they allow them to do.

Sterling: “(4) By far the most potent measures to prevent and ameliorate mental “illness” and deaths of despair are social: stable housing for those who cannot manage without help; support for prenatal care and childcare; support for families, reduction of rampant childhood sexual abuse; education for young adults leading to decent work with decent pay; paid vacations; access to nature, such as neighborhood parks (South et al, 2021).”

There is no doubt about the importance of social determinants of health — and that applies generally to both medicine and psychiatry — but social interventions are not a substitute for clinical interventions. To insist only on the social is an abdication of responsibility clinicians have to the suffering individual in front of them in the clinic. The biological vs social binary is also a tired one at this point. (It is also interesting that Sterling makes no mention of psychotherapy.)

There is one point, however, on which I do agree with Sterling: “I object strongly when prominent neuroscientists promote theories far beyond what is justified by their data and then start talking about therapeutic strategies.” The story of psychiatric neuroscience is one of repeated arrogance and repeated failure, of prominent researchers promoting theories far beyond what is justified by data, and of psychiatric community not being sufficiently critical of such claims. This is one issue on which we should all channel the critical spirit that Sterling has to offer.

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Appendix

I can’t go into all the little ways in which Sterling misrepresents the available body of evidence around psychiatric interventions and neuroscience, but here are a few more points.

a) Sterling: “Practitioners of ECT deny that it causes much long-term loss of memory…”

This isn’t quite true. For a good clinical review of this topic, I suggest the article “Cognitive side-effects of electroconvulsive therapy: what are they, how to monitor them and what to tell patients” by Porter et al. (2020)

b) Sterling: “As practitioners of ECT switch over to transcranial magnetic stimulation (TMS), they finally acknowledge that it is “much safer”. That is, they finally admit that ECT is not safe. But TMS is just now taking off, so whether it is also unsafe may not be apparent for a decade.”

Is relative safety that difficult a concept to understand? If a physician tells you that intervention A is safer than intervention B, it doesn’t mean intervention B is “unsafe” to an extent that it can’t be utilized clinically. Why is TMS safer? It is safer because it doesn’t involve general anesthesia, its administration doesn’t involve a generalized seizure, and it doesn’t have the same adverse effects on memory. TMS has been in use for many years now. Furthermore, the sort of treatment-resistant patients who are suitable candidates for ECT generally respond poorly to TMS, hence TMS isn’t really a substitute for ECT.

c) At one point, while talking about a trial of DBS for OCD, Sterling sarcastically says: “Yikes! 25% improvement for 2 weeks?? Nature Medicine??”

25% improvement can be quite significant for someone with debilitating OCD that has neither responded to pharmacotherapy and psychotherapy. And it is not the case that the improvement lasted only 2 weeks. The blinded phase was followed by a longer open phase, with 46% score reduction. This is quite significant for treatment refractory, debilitating OCD.

Sterling also misrepresents the “crisis of access” that is being discussed in the Nature Medicine article. The article notes how patients with treatment-refractory debilitating OCD, who are candidates for DBS are being denied coverage even though there is evidence from clinical trials suggesting benefit and other treatment options have been exhausted.

Consider this 2022 systematic review and meta-analysis of deep brain stimulation for treatment-resistant obsessive-compulsive disorder. The authors state: “Thirty-four studies from 2005 to 2021, 9 RCTs (n=97) and 25 non-RCTs (n=255), were included in systematic review and meta-analysis based on available outcome data. A random-effects model indicated a meta-analytical average 14.3 point or 47% reduction (p<0.01) in Y-BOCS scores without significant difference between RCTs and non-RCTs. At last follow-up, 66% of patients were full responders to DBS therapy. Sensitivity analyses indicated a low likelihood of small study effect bias in reported outcomes. Secondary analysis revealed a 1 standardised effect size (Hedges’ g) reduction in depressive scale symptoms. Both RCTs and non-RCTs were determined to have a predominantly low risk of bias. A strong evidence base supports DBS for TROCD in relieving both OCD and comorbid depression symptoms in appropriately selected patients.”

These are pretty promising results for a group of patients for whom few, if any, treatment options are available.

d) Sterling: “This bouillabaisse of results, if written by neuroscientists studying rodents, would not be published.”

Rodents don’t get debilitating OCD and interventions on rodents can be randomized however the neuroscientist desires, unlike in humans, where blinding and randomization can only go so far before they become unethical.

e) Sterling writes at one point: “But the claim for DBS [for depression] is that the patients hop off the operating table good to go. So, the gradual improvement can be taken for a placebo effect…”

This was never the claim for DBS, that patients would hop off the operating table good to go, and it is unfair to hold DSB to such standards. Sterling also has a tendency to attribute any improvement that happens with any open label intervention as being placebo. I wonder what he thinks of psychotherapy (open, uncontrolled) and whether this is also simply placebo. (Psychiatry critics don’t usually advertise their views on psychotherapy but many of them think psychotherapy is as ineffective as medications; I don’t know if Sterling is one of them.)

f) Sterling: “whereas the mouse’s “prefrontal” cortex forms a narrow anterior crescent, like the pale margin on your thumbnail, the human prefrontal cortex, expanded disproportionately to occupy roughly one-quarter of the whole brain. The human prefrontal cortex includes about 20+ areas (Figure 4). None of these are present in the mouse brain, which therefore cannot serve as a model for their functional organization.

Regarding this grotesque comparison, one distinguished neuroscientist wrote to me: “I have a similar disdain for the rodent-psychiatry-industrial-complex. For example, it seems accepted that a mouse avoiding an open field is suffering from anxiety, when that’s the only intelligent choice if you happen to be a mouse. By analogy one might say that humans who refuse to swim across the English Channel are overly anxious. So let’s find a drug that makes them plunge in more readily…””

I don’t know if Sterling realizes this, but investigating the behavioral effects of medications in rodents is quite different from using the mouse brain/prefrontal cortex as a model for the functional organization of the human brain/prefrontal cortex.

g) Sterling: “To be clear, current prescribing of “anti-psychotics” is without any neuroscientific rationale. It is simply an empirical treatment that should be judged on its benefits vs. costs (long-term as well as short-term) without pretense of justifying these drugs based on neuroscience.”

It is the case that the use of antipsychotics is primarily based on empirical clinical evidence, and the discovery of antipsychotics didn’t originate from a neuroscientific understanding of psychotic disorders. But it’s also not the case that we are completely ignorant about the neurobiological mechanisms of antipsychotics. We understand many crucial pieces. For instance, we know that there is a link between dopamine antagonism and antipsychotic effects, and as our understanding of dopamine signaling improves — and its role, for instance, in a predictive coding account of psychosis — so does our understanding of how antipsychotics work.

h) Sterling: “I have friends who were depressed for 30 years and then recovered, so there’s no such thing as “intractable”.”

This is an astounding comment, I’m at a loss for words. Intractable doesn’t mean permanent for life. What comfort is it to a depressed person that they might recover in 30 years? Should we let people languish in depression for half their lives?!

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