The Human Dorsolateral Prefrontal Cortex in Pain and Pain Modulation: A Review and Activation-Likelihood Estimation Approach

Eur J Pain. 2026 Jul;30(6):e70318. doi: 10.1002/ejp.70318.

ABSTRACT

BACKGROUND: The dorsolateral prefrontal cortex (dlPFC) has become a cornerstone of pain neuroscience, believed critically involved in processing acute and chronic pain, as well as in pain modulation. The dlPFC is thought to balance sensory perception with the cognitive appraisal of noxious stimuli. In humans however, the dlPFC spans several cortical nodes, and little attention has been given to precisely which subareas are tethered to these delineable processes. The primary goal of this review and co-ordinate based meta-analysis was to precisely map dlPFC areas engaged under varied effects on overall pain perception.

METHODS: Here, we combined a stringent meta-analytic approach of neuroimaging studies reporting dlPFC activation as a core finding (i.e., within title, abstract, or keywords of each manuscript), with activation likelihood estimation to determine dlPFC engagement across experimental acute pain (combined n = 814), chronic pain (combined n = 2467), and the pain modulatory phenomenon of placebo analgesia (combined n = 791), conditioned pain modulation (combined n = 184), and offset analgesia (combined n = 47). Through activation likelihood estimate and foci analysis, we produced schema of the similar and disparate locations of dlPFC activity within and between pain perceptual and modulatory effects.

RESULTS: During both acute and chronic pain and in placebo analgesia, we identified remarkably similar activation patterns predominantly within Brodmann areas 8, 9, and 46-with no clear laterality effect and the left and right cortical hemispheres engaged regardless of the site of experimentally applied or conditionally-present pain. Offset analgesia and conditioned pain modulation appeared to preferentially engage Brodmann areas 8 and 45, and 9 and 46, respectively.

CONCLUSIONS: Despite the dlPFC large cortical surface area, these findings suggest that both the percept and inhibition of pain by placebo engage a similar focussed area of this region. Better understanding of exactly which cortical components of the extensive cortical pain system are involved in pain perception and modulation is critical for refining novel treatments such as non-invasive brain stimulation which seek to target and modulate specific sites of cortical processing to alleviate pain.

SIGNIFICANCE STATEMENT: This meta-analysis precisely maps the dorsolateral prefrontal cortex (dlPFC) subregions engaged across acute pain, chronic pain and major endogenous pain-modulation paradigms. By integrating data from more than 4000 participants, it provides the most anatomically resolved evidence to date that dlPFC engagement is a shared feature of pain perception and modulation. These findings refine the cortical targets most relevant for therapeutic neuromodulation and strengthen the rationale for dlPFC-focused interventions in pain treatment.

PMID:42340106 | DOI:10.1002/ejp.70318