Fabrizio Benedetti's Neuroscience of Patienthood

Back in February I discussed the Italian neuroscientist Fabrizio Benedetti’s work on placebo responses. In his later book, The Patient’s Brain: The Neuroscience behind the Doctor-Patient Relationship, Benedetti extended this research to look at the social neuroscience of clinical encounters. (He also covers much of the same territory in a more recent journal article.)

These academic pieces pull together research from several disciplines to generate a picture of what goes on in patients’—and more sketchily, doctors’—brains. The science encompasses neurophysiology, pharmacology, experimental psychology, and neuroimaging, and includes several neural circuits and transmitter systems—pain pathways involving endogenous opioids, the dopamine reward system, the amygdala, and descending cholecystokinin tracts which antagonize the analgesic effects of µ-opiods. (A side note: cholecystokinin can also induce panic-like symptoms and is used to screen potential anti-anxiety drugs.)

In the book’s preface, Benedetti argues that with a neuroscientific perspective, “physicians, psychologists, and health professionals can better understand the kind of changes they can induce in their patients’ brains. With this neuroscientific knowledge in their hands, health professionals ‘see’ directly how their words attitudes, and behaviours activate and inactivate molecules, cortical areas and sensory systems in the brains of their patients. I believe that this ‘direct vision” of the patient’s brain will hopefully boost health professionals’ empathic and compassionate behavior further.”

How well has Benedetti succeeded? To this practicing psychiatrist interested in neuroscience, such research is fascinating. It justifies the position of social neuroscience, that all our thoughts, emotions, and interactions with others have neural correlates. It supports the clinical argument that how we approach and relate to patients strongly influences clinical outcomes. But the news is in the details, and the details are overwhelming. I am reminded of the maxim I heard when I arrived at college, that getting an education at M.I.T. was like trying to drink from a fire hose.

But let’s look more deeply at Benedetti’s findings. Helpfully, he breaks down the patient’s experience into four stages—feeling sick, seeking relief, meeting the therapist, and receiving the therapy—and summarizes his findings both in headings and in introductory sections entitled “Summary and Relevance to the Clinician.”

Much of the “feeling sick” chapter focuses on pain research, which has been most studied. The interoceptive system is the afferent sensory system which monitors the condition of tissues in the body and, via the insular cortex, generates feelings of pain, temperature, itch, touch, muscular and visceral sensations, vasomotor activity, hunger, thirst, and “air hunger.” There is no central pain center, and a complex neural network is responsible for top-down modulation of pain and other symptoms. Anxiety about pain, as well as anger and depression, activate emotional (limbic) circuits that increase perception of pain.

The motivational system, involving the dopamine reward system, is activated when a sick person seeks relief, especially when there is an expectation of improvement, and interacting with the clinician is usually experienced as a reward. (Benedetti also makes the interesting distinction between motivation to engage in basic life-preserving behaviors, such as seeking relief from hunger, thirst, or extreme temperatures, as well as obtaining care for illness, from motivated behaviors which are not necessary for individual survival, such as sexual activity, which also involve the brain reward system but are more involved with pleasure. It will be interesting at some point to look at the relationships among motivation, reward, and pleasure.)

Meeting the therapist activates mechanisms of trust and hope in the patient, and empathy and compassion in the clinician. Trust begins with visual perception of the clinician’s face and involves oxytocin, which is secreted in the hypothalamus, released from the pituitary, and binds to inhibitory receptors in the amygdala. Benedetti notes that the related emotion of admiration has two components: admiration for a clinician’s psychological state, such as virtue, recruits a circuit involving the inferior/posterior posteromedial cortices and anterior middle cingulate, which process interoceptive information. Admiration for physical states such as technical skill involves parts of the superior/anterior posterolateral cortices which are connected to lateral parietal cortices and deal with exteroception and musculoskeletal information. Hope for a positive outcome involves serotonergic and noradrenergic systems in areas such as the dorsolateral prefrontal cortex.

In a short digression into the doctor’s brain, Benedetti discusses empathy in terms similar to my post on empathy last February. Separate systems of emotional contagion and cognitive perspective-taking are involved, the latter activating medial prefrontal regions, the superior temporal sulcus, the temporal pole, and the temporo-parietal junction. Interpersonal empathy also activates somatosensory and insular cortices and the anterior cingulate cortex.

Compassion for social pain activates the inferior/posterior portion of the posteromedial cortices, whereas compassion for physical pain involves the superior/anterior portion of the posteromedial cortices. These appear to overlap with the areas activated by Benedetti’s two types of admiration.

Benedetti also describes research showing that clinicians develop mechanisms to suppress their emotional distress in the presence of suffering.

To discuss the social aspects of receiving therapy, Benedetti draws extensively on his work on placebo responses. He notes that in addition to whatever specific effect a treatment has on a patient’s disease, the ritual of the therapeutic act produces changes in the brain which are sometimes quite strong. Some of these effects are unconscious. The tendency to respond to placebos has been associated with variants in genes, some of which are the same as those related to depression, which I discussed last week. He notes that contrary to some earlier research, classical Pavlovian conditioning is not entirely unconscious; conscious expectation is also involved.

How useful is this for clinicians? As I have commented before, the problem of translating the findings of social neuroscience from the laboratory to the bedside or consulting room is huge--research findings tend to be specific, technical, and, in the case of doctor-patient relationships, too numerous and complex for clinicians to keep in mind or, sometimes, even be motivated to understand. Some of Benedetti’s findings are quite interesting, especially the importance of the dopamine reward system for treatment-seeking, the effect of oxytocin on the amygdala in regulating trust, cholecystokinin’s antagonism of opioid relief of pain, the role of monoamine neurotransmitter systems in hope, and the separate systems for types of both admiration and compassion.

Benedetti’s books and articles are academic writings with extensive descriptions of experiments heavily documented with references. This supports credibility and facilitates discussion and criticism by other scientists. Nevertheless, it is difficult to integrate his findings in a way that would be palatable and useful to most clinicians. Oliver Sacks was wonderful at using case examples (including his own experiences of illness) to illustrate neurological and neuroscientific findings, and any effort to make this material more available to clinicians would likely benefit from clinical examples. I continue to wonder if there are other formats than logical argument backed by facts, as used by Benedetti, and the narrative form of case reports, to involve clinicians in this fascinating field.

Further reading:

Fabrizio Benedetti, The Patient’s Brain: The Neuroscience behind the Doctor-Patient Relationship, 2011.

Benedetti F, Placebo and the new physiology of the doctor-patient relationship. Physiol Rev. 2013 Jul; 93(3): 1207–1246.

t relationship. Physiol Rev. 2013 Jul; 93(3): 1207–1246.

Recent Posts