Following the predominant transdiagnostic and dimensional approach in research-oriented classification systems, we studied rsFC differences between HC and patients with PD/AG, SAD, and SP, focusing on both diagnosis categories and symptom severity dimensions. Our key findings are: (a) PD/AG patients showed the most distinct connectivity changes, especially increased connectivity between thalamo-limbic and cortical regions and decreased connectivity between the ACC and prefrontal regions and the PAG, whereas SAD patients only show changes in OFC and insula connectivity and SP patients did not show any changes; (b) these alterations were primarily associated with the categorical diagnosis and disappeared in dimensional models of symptom severity; (c) while PD/AG patients exhibited heightened state anxiety during scans, this didn't account for the primary diagnosis variations. Observations suggest unique patterns for each AD group, diverging from prevalent transdiagnostic models.
Despite including various AD groups, only the PD/AG group exhibited notable rsFC differences compared to healthy controls. The functional anatomy of PD reveals an extensive subcortical and cortical network related to defensive reactions, highlighting areas such as the amygdala, hippocampus, thalamus, PAG, and locus coeruleus (26, 27). Dysfunctional coordination between cortical (upstream) and brainstem (downstream) regions is believed to contribute to panic attacks (26). PD/AG patients exhibit altered top-down and bottom-up processing dynamics in fear conditioning (28). Both animal and human research emphasizes the significance of midbrain areas, particularly the PAG, in defensive reactions and PD (29). Our study supports this view, showing connectivity changes in this network, including areas like the PAG, thalamus, amygdala, hippocampus, insula, ACC, and dmPFC. While we observed increased positive connectivity in limbic areas, there was a decrease between the ACC and dmPFC, as well as the ACC and PAG, reinforcing the idea of disrupted upstream and downstream processing. Although PD/AG patients reported higher anxiety during scans, did not account for the observed results. Furthermore, no clear correlation emerged between these network changes and symptom severity, aligning with prior rsfMRI results (30). However, earlier studies might have been less definitive due to limited sample sizes (all studies n < 30 per group). Our findings can be interpreted within a framework where defensive responses vary from prefrontal mechanisms, addressing potential threats, to midbrain mechanisms addressing immediate ones. Both are vital in grasping PD’s etiopathogenesis (31, 32). Our research illuminates the connectivity patterns of PD/AG but does not conclusively argue that PD/AG networks are mainly influenced by overarching anxiety elements.
Neurofunctional models for SAD, primarily derived from task-fMRI studies, indicate alterations in fronto-limbic circuits with limbic hyperactivity and reduced activity in cognitive control areas. There is also heightened activation in medial parietal and occipital regions, crucial for discerning social cues (23, 33). Alterations in connectivity are also seen in fronto-amygdala, fronto-parietal, and amygdala-temporal networks (9), with frontal regions showing the most robust results. In our study, only the OFC showed impaired connectivity with the insula in SAD patients.
Clinically, SAD is more strongly associated with cognitive symptoms than autonomic symptoms in PD/AG. Symptoms like anxiety from social evaluation and post-social interaction processing are pivotal in sustaining SAD, often leading to rumination and preoccupation. The OFC plays a role in the higher-order assessment of emotional and social signals. Mao et al. (2020) highlighted the mediating role of OFC-amygdala connectivity between social anxiety and attention biases towards emotional faces (34). In line with our earlier research, where SAD comorbidity in PD/AG altered fear conditioning and extinction patterns (35), our latest rsfMRI findings further suggest unique neural markers for these disorders.
Despite numerous task-based fMRI studies on SP (8, 36, 37), we found only one study focusing on rsFC in such a patient group (38). Given the null outcomes in a robustly sampled study, this disparity might point to a notable publication bias in this field. As for the absent rsFC findings in SP, it is plausible that this patient cohort has milder impairment, aligning more with the HC phenotype than PD/AG patients do, leading to differing results when compared to PD/AG.
Current research on disorder classification (4) focuses on identifying commonalities between disorders, thus seeking transdiagnostic explanations for psychopathology and treatment responsivity. Present findings reveal notable differences between healthy controls and PD/AG patients, some distinctiveness for SAD patients, and no differences for those with SP (direct comparisons between patient groups also show differences, see supplemental material). As thus, present results challenge dimensional approaches to psychopathology to a certain extent. However, more comprehensive research methods like meta- or mega-analyses, especially from vast neuroimaging consortiums like ENIGMA (https://enigma.ini.usc.edu/), which aggregates previously unreported data, should be explored for a deeper understanding of this issue (39).
Strength and limitations
Limitations encompass comorbidity, ongoing psychotropic medication, and missing generalized anxiety disorder (GAD) diagnoses. We accounted for comorbidity by including the presence of any AD diagnosis in our analyses. Incorporating disorders like obsessive-compulsive disorder or posttraumatic stress disorder would offer a more transdiagnostic view. Our focus was on ADs and healthy controls, but direct inter-disorder comparisons would further highlight specific signatures. ROI selection prioritized functional associations over empirical anatomical distinctions. Using the latter would have provided a more detailed perspective with smaller ROIs. However, we believe this approach would have complicated clinical interpretation.