BACKGROUND: A clinical hallmark of alcohol use disorder is persistent drinking despite potential adverse consequences. The ventromedial prefrontal cortex (vmPFC) and dorsomedial prefrontal cortex (dmPFC) are positioned to exert top-down control over subcortical regions, such as the nucleus accumbens shell (NAcS) and basolateral amygdala, which encode positive and negative valence of ethanol (EtOH)-related stimuli. Prior rodent studies have implicated these regions in regulation of punished EtOH self-administration (EtOH-SA). METHODS: We conducted in vivo electrophysiological recordings in mouse vmPFC and dmPFC to obtain neuronal correlates of footshock-punished EtOH-SA. Ex vivo recordings were performed in NAcS D 1 receptor-expressing medium spiny neurons receiving vmPFC input to examine punishment-related plasticity in this pathway. Optogenetic photosilencing was employed to assess the functional contribution of the vmPFC, dmPFC, vmPFC projections to NAcS, or vmPFC projections to basolateral amygdala, to punished EtOH-SA. RESULTS: Punishment reduced EtOH lever pressing and elicited aborted presses (lever approach followed by rapid retraction). Neurons in the vmPFC and dmPFC exhibited phasic firing to EtOH lever presses and aborts, but only in the vmPFC was there a population-level shift in coding from lever presses to aborts with punishment. Closed-loop vmPFC, but not dmPFC, photosilencing on a postpunishment probe test negated the reduction in EtOH lever presses but not in aborts. Punishment was associated with altered plasticity at vmPFC inputs to D 1 receptorexpressing medium spiny neurons in the NAcS. Photosilencing vmPFC projections to the NAcS, but not to the basolateral amygdala, partially reversed suppression of EtOH lever presses on probe testing. CONCLUSIONS: These findings demonstrate a key role for the vmPFC in regulating EtOH-SA after punishment, with implications for understanding the neural basis of compulsive drinking in alcohol use disorder.

Background: Results reported in the existing literature have shown intermittent theta burst stimulation (iTBS) to be noninferior to 10 Hz repetitive transcranial magnetic stimulation (rTMS) in treating major depressive disorder (MDD) when targeted at the left dorsolateral prefrontal cortex. The goal of this naturalistic observational study was to further explore potential differences between these 2 treatment modalities in treating depression in a real-world cohort. Methods: The participants were 105 patients, 18 years of age or older with a diagnosis of MDD who received standard clinical 10 Hz rTMS or iTBS treatment between 2016 and 2020. Clinical outcomes of depression treatment were assessed on the basis of changes in scores on the Patient Health Questionnaire-9 and on the Montgomery-Åsberg Depression Rating Scale. Results: Reduction in depression symptoms was measured with the Patient Health Questionnaire-9 and Montgomery-Åsberg Depression Rating Scale from baseline to end of treatment, and no discernible differences in percent change, response, remission, or minimum clinically important difference were found between the 10 Hz rTMS and iTBS treatment groups. Conclusions: Findings in an observational, real-world clinical sample showed no significant differences in outcomes between 10 Hz rTMS and iTBS targeted at the left dorsolateral prefrontal cortex in the treatment of MDD. Because of the shorter treatment time involved, the choice of iTBS may reduce hospital exposure and increase savings and the treatment capacity of clinics without sacrificing effectiveness.