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Bottom-up and top-down neuroscience: overcoming the clash of research cultures

Mindset
Professor Federico Turkheimer

Director of King's Institute for Human and Synthetic Minds

03 October 2025

The brain is a complex system made of numerous elements across different scales, from genes to molecules, to cells, to micro- and macro-organized systems. All these elements interact with each other, across scales and, ultimately, generate behaviour by interacting with the environment. We call the latter interaction the “mind”. These interactions are nonlinear, making the brain a dynamic and highly unpredictable organ. Hence, a question still lingers in the Neuroscience circles: how do we best set out to study the brain and the mind?

Neuroscience: bottom-up and top-down

Bottom-up neuroscience (also called the Neuroscience of Behaviour) describes the belief that that you need to study the brain starting from its genetic and molecular bases to understand behaviour and its disorders. Neurobiology research tends to take this approach.

Top-down neuroscience approaches the problem from the opposite perspective and focuses on behaviour and its abnormalities first, placing emphasis on how external factors, such as environmental and social factors, affect mental health. This approach is still practiced in clinical psychology and clinical psychiatry.

Neuroscience & Mental Health: Past and Present

In the last few decades, the Neuroscience of Behaviour has benefited from technological advances that enabled the whole scale mapping and functional measurement of genes, transcripts, proteins and cells. The Human Genome Project (1990-2003) prompted the hope that the deciphering of human individual DNAs would create the conditions to make personalised medicine a reality also for psychiatric and neurodegenerative conditions. Things however have not turned out as hoped.

Thomas Insel, as director of the National Institute of Mental Health, oversaw the allocation of over $20 billion in federal funds in such a project from 2002 to 2015. As he admitted in his 2022 book “Healing”, this investment produced a great deal of interesting neuroscience research but, sadly, has not impacted the way care is delivered to mental health patients. This is contrary to the great progress that has taken place in other areas of medicine, such as cancer. This realization spurred him to critique his former approach and to propose a broader one that emphasizes social support and its integration with medical and therapeutic interventions.

The top-down approach is exemplified by the DSM (Diagnostic and Statistical Manual of Mental Disorders), the current manual for the classification of mental health disorders that provides a framework of diagnoses and criteria developed by expert committees to help practitioners detect behavioural abnormalities to formalize treatment decisions.

The plain assumption of this approach is that, with a few exceptions, the observation of the upper scale of brain functional output, e.g. human behaviour, trumps organic measurements (e.g. genetic, fluid biomarkers, EEG, imaging) as the better indicator of medical solutions to the disease.

However, this approach also has limitations. Diagnostic categories tend to overlap and patients with similar profiles can be placed in different clinical categories, hence receiving different treatments. Moreover, mental disorders evolve in time and current approaches struggle to follow the evolution of the symptoms and adapt therapies to a moving and changing set of symptoms.

Moving Forward

To move forward we believe that the best question to be asked is quite general and should sound something like “how do you study a complex system”? And to begin to address this question, the first important realization is that, in these systems, the classical methods of enquiry, where someone uses experiments and data to obtain cause-effect inferences, do not really work.

The brain is complicated, very adaptive and dynamic, sensitive to initial parameters and environmental conditions. Hence each experiment allows only “partial” inferences, e.g. produces evidence that is not definitive but just a piece of a complex puzzle, evidence that is valid in certain contexts but could become not relevant in others. It may not seem much, but those that practice research in this area may appreciate how important this realization may be.

The second important factor stands in adopting a collaborative approach; this is where neuroscientists should place a conscious effort to be different from all those other medical researchers. Neuroscience is really an enormous amorphic space that spans genetics, chemistry, biology but also physics, mathematics, social and economic sciences, and human studies. An ecological valid research programme should then encompass all this and should employ specialists, people that excel in their silos, but also generalists, able to transcend scales with a focus on their interplay.

Thirdly, we should be conscious that neuroscience is difficult and that understanding the human brain may require, above all, versatility, patience and humility.

Top-down and bottom-up neuroscience: overcoming the clash of research cultures.

Rosas FE, Luppi AI, Mediano PAM, Kringelbach ML, Pessoa L, Turkheimer F. Top-down and bottom-up neuroscience: overcoming the clash of research cultures. Nat Rev Neurosci. 2025 Sep;26(9):513-515. doi: 10.1038/s41583-025-00946-x. PMID: 40696003. 

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Federico Turkheimer

Federico Turkheimer

Professor in Neuroimaging (Analysis & Statistics)

Mindset

Think pieces from the King's Institute for Human and Synthetic Minds

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