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Causal mapping of human brain function

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.

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Fig. 1: Evolution of brain mapping literature since 1950.
Fig. 2: Appraising causality in human brain mapping studies.
Fig. 3: Heterogeneous lesions causing the same symptom can complicate causal inference.
Fig. 4: Coherence between LNM and iES studies.
Fig. 5: Coherence between TMS, DBS and brain lesions.

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Acknowledgements

The authors thank the National Institute of Mental Health, the Brain and Behaviour Research Foundation, Brigham and Women’s Hospital, and Stanford University BioX for funding the present work.

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S.H.S and M.D.F. wrote the manuscript. The authors all researched data for the article, provided substantial contributions to discussion of its content, and reviewed and edited the manuscript before submission.

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Correspondence to Shan H. Siddiqi.

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S.H.S. serves as a consultant for Kaizen Brain Center, Acacia Mental Health and Magnus Medical, and owns stock in Brainsway Inc. (publicly traded) and Magnus Medical (not publicly traded). S.H.S. and M.D.F. have jointly received investigator-initiated research support from Neuronetics Inc. None of these organizations were involved in the present work. S.H.S. and M.D.F. each own independent intellectual property on the use of brain network mapping to target neuromodulation. The present work did not utilize any of this intellectual property. The authors report no other conflicts of interest related to the present work.

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Glossary

Causality gap

The missing logical link between correlation and causation, particularly as it relates to identifying treatment targets.

Deep brain stimulation

(DBS). An invasive technique for modulating brain activity using surgically implanted depth electrodes, commonly used as a treatment for Parkinson disease.

Transcranial magnetic stimulation

(TMS). A non-invasive technique for modulating brain activity via magnetic pulses applied over the scalp, commonly used as a treatment for major depressive disorder.

Functional neuroimaging

A non-invasive technique for measuring changes in brain activity, commonly based on changes in blood oxygenation or metabolic activity.

Causal inference

The process of assessing whether one event directly contributed to the occurrence of another event.

Counterfactual

The hypothetical outcome if a causal event had not occurred.

Causal chain

A sequence of events leading to a particular outcome.

Bradford Hill criteria

A widely used framework for objectively appraising the strength of causal inference based on observed data.

Randomized controlled trials

Research studies that randomly allocate clinical participants to active or control interventions.

Natural experiments

Observed situations in which an intervention was incidentally assigned in a near-random manner.

Symptom localization

The process by which a neurological or psychiatric problem is linked to a specific brain region.

Effective connectivity

The influence that one neural unit exerts over another.

Probabilistic causality

An approach that assesses whether an event modifies the probability of an outcome, even if it is not necessary or sufficient to induce the outcome.

Voxel lesion symptom mapping

(VLSM). A probabilistic technique that analyses the relationship between tissue damage and behaviour on a voxel-by-voxel basis.

Diaschisis

The phenomenon by which damage to one brain region can cause a change in function of distant regions.

Brain circuit

Any interconnected network of units, potentially including monosynaptic structural connections and/or polysynaptic functional connections.

Lesion network mapping

(LNM). A technique that identifies shared connectivity patterns among lesions associated with a specific symptom or behaviour.

Intracranial electrical stimulation

(iES). Invasive technique for modulating brain activity using depth electrodes or subdural electrodes, commonly used for mapping brain function prior to brain surgery.

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Siddiqi, S.H., Kording, K.P., Parvizi, J. et al. Causal mapping of human brain function. Nat Rev Neurosci 23, 361–375 (2022). https://doi.org/10.1038/s41583-022-00583-8

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