{"doi":"10.1016/j.jad.2024.08.143","title":"The unique face of comorbid anxiety and depression: Increased frontal, insula and cingulate cortex response during Pavlovian fear-conditioning","abstract":"Dysregulation of fear processing through altered sensitivity to threat is thought to contribute to the development of anxiety disorders and major depressive disorder (MDD). However, fewer studies have examined fear processing in MDD than in anxiety disorders. The current study used propensity matching to examine the hypothesis that comorbid MDD and anxiety (AnxMDD) shows greater neural correlates of fear processing than MDD, suggesting that the co-occurrence of AnxMDD is exemplified by exaggerated defense related processes. 195 individuals with MDD ( N = 65) or AnxMDD ( N = 130) were recruited from the community and completed multi-level assessments, including a Pavlovian fear learning task during functional imaging. Visual images paired with threat (conditioned stimuli: CS+) were compared to stimuli not paired with threat (CS-). MDD and AnxMDD showed significantly different patterns of activation for CS+ vs CS- in the dorsal anterior insula/inferior frontal gyrus (partial eta squared; ηp 2 = 0.02), dorsolateral prefrontal cortex (ηp 2 = 0.01) and dorsal anterior/mid cingulate cortex (ηp 2 = 0.01). These differences were driven by greater activation to the CS+ in AnxMDD versus MDD. Limitations include the cross-sectional design, a scream US rather than shock and half the number of MDD as AnxMDD participants. AnxMDD showed a pattern of increased activation in regions identified with fear processing. Effects were consistently driven by threat, further suggesting fear signaling as the emergent target process. Differences emerged in regions associated with salience processing, attentional orienting/conflict, self-relevant processing and executive functioning in comorbid anxiety and depression, thereby highlighting potential treatment targets for this prevalent and treatment resistant group. • Few studies examine differences between anxious- and non-anxious depression. • Neural responses during fear conditioning were recorded in these groups. • Groups showed differential activation in insular, cingulate, and prefrontal regions. • Differences were driven by greater reactivity to the CS+ in anxious depression.","journal":"Journal of Affective Disorders","year":2024,"id":456377,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9598,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":651791,"name":"Maria Ironside","orcid":"0000-0003-2781-1711","position":1,"is_corresponding":false},{"id":297642,"name":"Rayus Kuplicki","orcid":"0000-0003-2954-6421","position":2,"is_corresponding":false},{"id":510371,"name":"Robin L. Aupperle","orcid":"0000-0003-2173-6140","position":3,"is_corresponding":false},{"id":906213,"name":"Salvador M. Guinjoan","orcid":"0000-0002-1958-4259","position":4,"is_corresponding":false},{"id":370860,"name":"Sahib S. Khalsa","orcid":"0000-0003-2124-8585","position":5,"is_corresponding":false},{"id":274086,"name":"Jennifer L. Stewart","orcid":"0000-0003-0123-9438","position":6,"is_corresponding":false},{"id":510373,"name":"Teresa A. Victor","orcid":"0000-0002-0112-2902","position":7,"is_corresponding":false},{"id":242790,"name":"Martin P. Paulus","orcid":"0000-0002-0825-3606","position":8,"is_corresponding":false},{"id":701989,"name":"Namik Kirlić","orcid":"0000-0003-4153-8774","position":9,"is_corresponding":false},{"id":991710,"name":"Tate Poplin","orcid":"0000-0002-2299-9922","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-19T02:03:27.785212Z","pmid":"39187192","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}