Table 2.

Comparison of neuromodulation approaches targeting hypothalamus in TNP, migraine, and CH

Technology/Approach	Condition	Laboratory-Level Research	Clinical Use
Pharmacological Approaches	TNP	Tricyclic antidepressants, SNRIs, SST-antagonists, orexin receptor inhibitors, carbachol microinjection, GABAergic receptor inhibitors, α−2 adrenoceptor interactions [2, 10, 87, 165].	None specified, but pharmacological agents like TCAs and SNRIs are widely used in clinical settings for TNP management [39, 156].
	Migraine	Research on specific pharmacological agents targeting hypothalamic pathways such as Suvorexant (orexin receptor antagonist), glyceryltrinitrate, SST-receptor antagonist [10, 46, 70].	Ergotamine and dihydroergotamine (DHE), beta-blockers, antiepileptic drugs, NSAIDs, SNRIs, Triptan, Erenumab, Galcanezumab, pituitary adenylate cyclase-activating peptide 1–38 (PACAP1-38) and casein kinase 1 delta (CKIδ) [138, 152, 176].
	CH	Investigations into hypothalamic involvement in CH pathogenesis using muscimol, gabazine, PACAP38, naratriptan [155].	Medications like Verapamil, Topiramate, sumatriptan and corticosteroids are used [106].
Optogenetic Stimulation	TNP	Optogenetic inhibition of the PH, stimulation of dopamine D2 receptors in A11 nucleus [82, 114].	Currently limited to experimental models like CCI-ION rat model; not yet in clinical use.
	Migraine	There is a significant gap in optogenetic research targeting the hypothalamus in migraine pain models. Future research covering this gap might potentially reveal new therapeutic management.	No current clinical application; optogenetics is primarily research-focused at this stage.
	CH	There is a significant gap in optogenetic research targeting the hypothalamus in CH pain models. Future research covering this gap might potentially reveal new therapeutic management.	Not in clinical use, remains a laboratory research tool.
Electrical Stimulation	TNP	DBS focusing hypothalamus in the TNP animal model is yet to be done. However, this could open a new strategic door for TNP management.	DBS has been used in patients with TNP [50]
	Migraine	Research on hypothalamic involvement in migraine modulation via DBS, rTMS [14].	rTMS and DBS could be emerging treatments for refractory migraine; however, still under study.
	CH	DBS of the hypothalamus was explored in animal models for understanding pain and autonomic pathophysiology [3].	Hypothalamic DBS is a recognized treatment for refractory CH [31, 49, 91, 108, 173].