A brain-first framework for perimenopause management: the case for non-invasive neuromodulation

The menopause transition affects approximately half the global population yet remains substantially under-researched and under-treated. Standard care is dominated by menopausal hormone therapy (MHT), with adjunctive use of selective serotonin and noradrenaline reuptake inhibitors and, more recently, neurokinin-3 receptor antagonists. While these approaches have transformed care for vasomotor symptoms, they leave significant unmet needs across cognitive, affective, and sleep-related domains, and remain unsuitable or undesirable for many women. In this Perspective, we argue for a complementary brain-first framework for perimenopause management. Four converging lines of evidence support this framing: perimenopause is fundamentally a loss of cyclical predictability rather than a gradual hormone deficiency, with progesterone-driven loss of inhibitory neurosteroidal tone preceding estradiol variability; vasomotor symptoms originate centrally in hypothalamic kisspeptin/neurokinin B/dynorphin circuits; the perimenopausal brain undergoes measurable structural, metabolic, and network-level reorganization; and these brain-mediated changes can precede and outlast peripheral hormonal markers, with marked inter-individual variability that systemic hormone levels alone do not capture. Within this framework, we examine non-invasive brain stimulation-specifically transcranial direct current stimulation (tDCS)-as a candidate brain-first intervention. We synthesize existing tDCS evidence relevant to perimenopausal symptom clusters, identify gaps in dedicated trials, and outline future research priorities, including outcome measures, study populations, and integration with digital health platforms. The brain-first framing is offered as complementary to, not in place of, established hormonal and pharmacological approaches.