Abstract Episodic migraine (EM) sufferers can develop a progressive state of their disease with more than 15 attacks per month. This state is referred to as chronic migraine (CM), a disorder that significantly impacts a patient’s daily life with more frequent sensory and emotional suffering and potential for substance abuse, especially opiates. Built on rigorous scientific data from our initial R01 on EM, our next goal is to expand the investigation and modulation of endogenous µ-opioid neurotransmission to more complex CM patients. We will investigate how this µ-opioid dysfunction impacts other crucial central neurotransmitters (D2/D3 dopamine) and systems (sensory and reward), leading to a worsening of pain/emotional suffering. The endogenous μ-opioid and D2/D3 dopamine are arguably two of the most crucial molecular mechanisms responsible for pain and emotional regulation; they are the primary targets for the action of the most potent exogenous analgesic and psychotic drugs available. Our initial EM study using PET with [11C] carfentanil, a selective μ-opioid receptor (μOR) radiotracer, has demonstrated a decrease in μOR availability (non- displaceable binding potential [BPND]) in the brains of EM patients during attacks. Notably, our preliminary data shows that with the progression to CM, there is a further increase in μ-opioid (peptide) release in the amygdala that correlates with attack severity and allodynia. The EM attacks were also accompanied by an increase in DA D2/D3 BPND measured by [11C]raclopride in the basal ganglia, and the longer the history and recurrence of attacks, the lower the ictal endogenous DA release. We were the first group to demonstrate that a non-invasive neuromodulatory method targeting the primary motor cortex (M1), transcranial direct current stimulation (tDCS), can immediately modulate the µOR system. We further developed a M1 high-definition tDCS montage (M11 HD-tDCS) that significantly reversed μOR BPND in more frequent EM patients and reduced CM-specific clinical endpoints (e.g., moderate/severe days per month). Built on solid and persuasive data from our prior R01 in EM, our renewal project expands its relevance by directly evaluating and modulating crucial neurotransmitters, systems/symptoms associated with pain suffering in the most resilient migraine, CM: Aim1. Demonstrate with PET that patients who progress to CM display higher dysfunction than EM in endogenous μ-opioid and D2/D3 dopamine neurotransmission that correlates with their attack frequency and severe pain suffering; Aim2. Evaluate the impact of CM on the neuronal systems’ connectivity and BOLD signal variability and their association with dysfunction in neurotransmission and worsening of attacks; Aim3. Investigate whether 20 daily lab/home-based unilateral and bilateral M11-2 HD-tDCS modulation have different effects on the molecular, system, and clinical states in CM patients.