Cold Hands, Warm Heart: Quality of life, wellbeing, and mental health in Raynaud's disease - An international survey study.

Bipolar disorder (BD) is characterized by recurrent mood episodes contributing to a progressive accumulation of cognitive burden (). Within this neuro-progressive framework (), clinical staging has been proposed as a promising tool to support prognosis and treatment planning (). Crucially, staging models describe a continuum that begins before clinical onset, progressing from familial risk through prodromal symptoms to chronic illness. Recent studies validated these models in BD patients, showing that they may transition across stages and that illness progression is associated with episode burden and functional impairment (; ; ; ). Nevertheless, the application of these staging models remains largely retrospective and primarily based on clinical indicators (; ; ; ; ), lacking the standardization required for clinical practice. The initial phase of this continuum is driven by the strong genetic basis of BD (). Identifying the relationship between genetic risk and BD is complex, since it frequently involves shared heritable vulnerabilities with other psychiatric disorders. However, it is well established that first-degree relatives have a seven- to ten-fold higher lifetime risk of developing BD compared to the general population (). Thus, considering these high-risk relatives provides a critical window into the preclinical phase of the staging trajectory, prior to symptomatic onset. Identifying biological markers for such a trajectory is difficult (). Available markers are confined to structural phenotypes, such as ventricular enlargement and gray matter volume loss (; ), and inflammatory alterations, such as increased Tumor Necrosis Factor-alpha (TNFα) (; ). In the context of functional neuroimaging, biomarkers of illness staging remain scarce (; ) and typically relate to separate phases of the BD spectrum, rather than addressing the complete staging. At its initial phase, functional alterations preceding clinical onset, and thus reflecting inherited vulnerability (), have been reported in the default-mode network (DMN), cortico-limbic, fronto-thalamic-striatal, and fronto-occipital circuits (e.g., reduced prefrontal-limbic and fronto-striatal coupling). Further, in terms of connectivity dynamics, offspring of BD patients show an intermediate profile between patients and controls, characterized by a reduction in the dynamics of hippocampal-somatomotor network as opposed to an increase in the hippocampal-limbic one (). At the final BD stages (well-established illness), most studies () report an altered communication at rest mainly centered on the DMN, frontoparietal (FPN), and salience (SAL) networks (; ; ), collectively described as the Triple-Network Model (TNM) (). Within TNM, where SAL regulates the switching between DMN (internally oriented) and FPN (externally oriented), four main findings have been linked to BD. First, a reduced connectivity within these resting-state networks (RSNs) was reported (; ; ; ; ). Second, altered interactions among them were observed (; ), including decreased FPN-SAL (; ) and DMN-SAL coupling (; ), and reduced DMN-FPN anticorrelation (; ). Third, altered RSN dynamics were described, suggesting reduced network flexibility (; ). Within the DMN, decreased switching rates () and reduced temporal variability were observed (; ; ). In contrast, the FPN showed increased dynamic connectivity in both euthymic and depressed BD patients (; ; ). In the SAL, variability increased in interactions with externally oriented systems while decreasing with internally oriented ones, such as the DMN (). Fourth, BD also seems to affect the functional brain topology (). Unlike schizophrenia, where widespread topological alterations are consistently reported (; ), topological changes in BD are more regionally confined: altered segregation or integration in specific functional subsystems involving DMN, sensorimotor, and mid-cingulate areas (; ; ; ). These findings seem to suggest that fMRI-based features represent promising candidate biomarkers for BD staging.