Gathering Causal Brain Data in Schizophrenia: From Lesions to TMS Targets

Causal human brain data (focal lesions, transcranial magnetic stimulation (TMS), and deep brain stimulation) have used to link discrete brain regions to specific symptoms of schizophrenia, shared Andrew Pines, MD. Pines’ presentation at the Precision Therapeutics in Schizophrenia symposium covered how lesions that caused psychosis shared functional connectivity to the posterior hippocampus, and lesions to the medial dorsal nucleus of the thalamus, along with deep brain stimulation electrodes, caused paranoid delusions.¹

Causal data addresses a limitation of the existing schizophrenia literature, Pines said, which has consisted largely of correlative findings accumulated over hundreds of years, such as abnormalities identified in postmortem analyses. Such findings cannot establish whether an abnormality drives symptoms or reflects a secondary consequence of the primary insult, a lifestyle factor, or medication exposure. Insular atrophy, for example, could arise from any of these. "Causal data really gives you access to this specific brain anatomy being causally associated with a symptom," Pines emphasized.

Schizophrenia has been slower to yield to localization than other conditions. In the early 20th century, neurobiological correlates of Alzheimer disease, Parkinson disease, and frontotemporal dementia, for example, were localized to specific brain regions, but schizophrenia did not lend itself to the same approach. The disorder later came to be understood as a network disorder, and identifying which network components were causally involved could clarify which communicating regions produced its symptoms.

The main implication of this work was a potential TMS target for schizophrenia derived in the same way as the target for depression. The dorsolateral prefrontal cortex target, now widely used as a target, was first identified through lesion data, and subsequent functional MRI work refined it using the connection between the subgenual cingulate and the dorsolateral prefrontal cortex.² Schizophrenia has no replicable, generally accepted TMS target. Work targeting the temporoparietal junction was promising, but some trials were positive, some were less so, and some showed effects that were not lasting. "We're looking to see if using this functional targeting can give us a reproducible and effective TMS target for schizophrenia," Pines said.

Dr Pines is a psychiatrist at Mass General Brigham and an instructor at Harvard Medical School.

References

1. Pines AR, Frandsen SB, Drew W, et al. Mapping lesions that cause psychosis to a human brain circuit and proposed stimulation target. JAMA Psychiatry. 2025;82(4):368-378.

2. Fox MD, Buckner RL, White MP, et al. Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate. Biol Psychiatry. 2012;72(7):595-603.