Bipolar disorder (BD) is a highly complex, chronic psychiatric illness marked by episodic disturbances of mood. While historically conceptualized as a disorder of neurotransmitter imbalance, converging evidence suggests it is better understood as a disorder of dynamic dysregulation across multiple interacting systems, including genetic and epigenetic vulnerability, HPA axis dysregulation, mitochondrial/metabolic dysfunction, immune activation, circadian disruption, and gut-brain axis disturbances. These systems comprise a hierarchically organized, bidirectionally coupled feedback network that is responsible for the oscillatory mood states that define the disorder. Here, it's proposed that a specific, testable, integrative model in which genetic/epigenetic vulnerabilities lead to destabilization of HPA axis regulation, which then leads to mitochondrial bioenergetic dysfunction (the central integrative node of the cascade), which then, through its interaction with immune activation and gut-brain signaling, causes the excitation-inhibition imbalance underlying the clinical presentation of mood-state transitions. From this model, three empirically tractable predictions are made: that co-occurring inflammatory/metabolic/circadian dysregulation will constitute a biological subtype with earlier onset, more rapid cycling, and a more negative response to lithium; that neuroendocrine/metabolic disturbances will prospectively precede rather than simply co-occur with mood-state transitions; and that interventions targeting the metabolic-inflammatory interface will produce mood-stabilizing effects whose magnitude correlates with baseline biological severity rather than symptom severity. Throughout, the importance of state-dependence, trait-level features, and medication confounds is discussed. Finally, translational implications for metabolic stratification, circadian-focused intervention, and gut-brain modulation are outlined.

Persistent Afferent Bias (PAB) represents a state-dependent alteration in sensory weighting through which Somatic Disruption influences Autonomic Regulation. While the classical concept of the facilitated spinal segment provided an early neurophysiological explanation for somatic dysfunction, contemporary neuroscience increasingly favors models based on distributed neural networks and dynamic modulation of neural gain. Recent reinterpretations of facilitation as a network-level phenomenon offer a more consistent account of altered sensorimotor processing, yet remain largely confined to musculoskeletal and pain-related mechanisms and do not fully explain the origin and persistence of such bias. The present paper proposes Persistent Afferent Bias as a mechanistic link between Somatic Disruption and Autonomic Dysregulation. Within the Somato-Psychic Pathway (SPP), a theoretical model proposed by the author, PAB represents the previously unarticulated neurophysiological mechanism linking altered somatic input to changes in regulatory state. In this context, disturbances in afferent signaling-arising from Distorted Proprioceptive Information (DPI), nociceptive input, interoceptive imbalance, or other sources-lead to a reorganization of sensory weighting within neural systems. A defining feature of this process is the persistence of altered afferent conditions. Under sustained conditions, this biased processing contributes to a shift in Autonomic Regulation conceptualized as Somato-Psychic Autonomic Dysregulation (SPAD), which may subsequently give rise to broader functional manifestations, including Somato-Psychic Syndrome (SPS). This formulation situates Persistent Afferent Bias within a hierarchical regulatory cascade consistent with Directional Developmental Sequencing (DDS), in which alterations at the level of somatic input propagate to autonomic and higher-order functional domains. In this sense, PAB is not a primary phenomenon, but a secondary expression of underlying disturbances within the somatic regulatory system. Beyond its theoretical significance, this model has direct clinical implications. It supports a shift in clinical reasoning from predominantly symptomatic modulation toward identification and targeted treatment of primary somatic drivers of altered afferent input. This is particularly relevant in patients presenting with Somato-Psychic Syndrome (SPS), in whom conventional approaches focused on higher-order manifestations may fail to address the underlying regulatory disturbance. By providing a mechanistic basis for this shift, Persistent Afferent Bias enables a more etiologically grounded and hierarchically organized approach to intervention within the Somato-Psychic Pathway.

Long COVID is increasingly recognized as a multisystem condition involving persistent inflammation, autonomic dysregulation, and metabolic disturbance. The vagus nerve-mediated cholinergic anti-inflammatory pathway (CAP) provides a biologically plausible link between neural regulation and immune homeostasis, while metabolic pathways involving AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) are closely related to mitochondrial function and energy balance. In this review, we synthesize evidence from neuroscience, immunology, and metabolic research to investigate how electroacupuncture (EA) may modulate vagal-cholinergic signaling and the downstream inflammatory and metabolic processes associated with long COVID. Experimental studies indicate that EA can influence CAP-related mechanisms, including α7 nicotinic acetylcholine receptor (α7nAChR)-mediated inhibition of NF-κB/NLRP3-related inflammatory signaling, and may also regulate AMPK-SIRT1-PGC-1α-associated metabolic pathways. Although clinical evidence is more indirect, it suggests that electroacupuncture may affect autonomic function, inflammatory markers, symptom burden, and neurophysiological regulation. To support a balanced interpretation, we organize the evidence in this review into a framework based on levels of evidence, which distinguishes direct preclinical findings from indirect clinical indicators and associations used to generate hypotheses. This framework highlights the potential convergence of vagal-cholinergic anti-inflammatory regulation and metabolic recovery pathways, while recognizing that several proposed connections-particularly those linking CAP-related signaling to improvements in long COVID symptoms-require further validation. Overall, this review provides a structured basis for future mechanistic studies and phenotype-oriented clinical trials evaluating EA as a neuromodulatory strategy for long COVID and related chronic inflammatory conditions.

Chronic fatigue is widely discussed across clinical and non-clinical contexts, yet its definition and measurement remain heterogeneous and debated. In this fragmented landscape, adopting an efficacy-informed perspective grounded in mitigating interventions offers a reliable pathway to delineate the core features and regulatory mechanisms of chronic fatigue. This Mini Review aims to identify and synthesize interventions shown to be effective in mitigating chronic fatigue. A preliminary screening was conducted using the terms "fatigue" AND ("relief" OR "mitigation" OR "treatment"), thereby inherently focusing on persistent and functionally impairing forms of fatigue. The analysis was then restricted to the most cited evidence to highlight the most consolidated findings. Four classes of behavioral interventions consistently emerged as effective across heterogeneous conditions (stroke, cancer, multiple sclerosis, traumatic brain injury, and non-clinical contexts): cognitive behavioral therapy, mindfulness-based approaches, yoga, and physical activity. Their convergence suggests that chronic fatigue reflects, rather than condition-specific processes, the alteration of shared regulatory mechanisms, likely involving neurophysiological dynamics and associated biological markers, which can be further elucidated by integrating evidence from effective interventions with their neurophysiological and biomarker correlates. The evidence from this Mini Review on the transversal effectiveness of the same interventions supports leveraging their efficacy and the associated neurophysiological and biochemical changes to identify sensitive markers that track treatment response and inform the underlying mechanisms of fatigue. Future research should therefore prioritize standardized measures, shared markers, and personalized interventions, potentially supported by biochemical and neuromodulatory approaches.

Ten years ago, we published a position paper in this journal, criticizing reductionist claims of neurobiology related to mental disorders and important theoretical concepts like free will. Our interdisciplinary group of experts highlighted the need for and the challenges of integrating different approaches and system levels in neuroscience. We argued-and still argue-that such an integrative and multi-perspective approach is an important precondition for progress in the understanding and treatment of neuro-psychiatric disorders. We now review the progress towards an integrative neuroscience during the past decade in five steps: First, we examine the social and institutional context of brain research that has enabled tremendous technical developments and insights. Nevertheless, many research programs remain reductionist and fail to acknowledge differences between different system levels, their complex interactions, and domain-specific languages. We argue that scientific discourse largely lacks any critical account on the very nature of neurobiological explanations and interdisciplinary interfaces. Second, these conceptual weaknesses lead us to highlight the need for establishing an interdisciplinary neurophilosophy which tackles the challenging multiplicity of perspectives and approaches in modern neurosciences. The task is not just a collaboration between philosophers and neuroscientists, but rather the development of a critical philosophical stance within the neurosciences themselves. Third, based on this, we plead for the importance of the emerging science of complex systems, which is particularly helpful to integrate interdisciplinary knowledge and develop new strategies for modeling multi-level relations and phenomena. We suggest the application of systemic approaches in the mind sciences. Fourth, in line with this holistic view, we present an ecological perspective on human beings. The still dominating cephalocentric paradigm in neurosciences is severely limited without understanding the brain as a regulative organ in a situated organism and-in case of humans-an acting person "extended" to tools, technologies, and social structures. Fifth, in our final section, we illustrate our view using the debate about free will. We argue that any position respecting the complexity and irreducibility of mental phenomena will escape inappropriate reductionist and deterministic assumptions while fully acknowledging scientific evidence. We conclude with the demand for stronger efforts towards an institutionalized, interdisciplinary, systems-oriented neurophilosophy.

Consciousness remains one of the central challenges in contemporary neuroscience, in part due to the absence of an explicit framework describing the temporal constraints required for integrative processing. While influential models such as Integrated Information Theory and the Free Energy Principle characterize structural and functional aspects of conscious systems, they remain largely agnostic regarding the minimum temporal windows necessary for information to become phenomenologically accessible. We propose that temporal integration constitutes a biologically invariant constraint operating across multiple organizational scales. Drawing on recent experimental evidence of memory formation in non-neuronal cells, we introduce the concept of a minimal bioelectrical/biochemical temporal window (ΔT_b) governing cellular information consolidation. We propose that this foundational temporal constraint may contribute to organismic basal coherence (γ) through bioelectric and autonomic mechanisms, which in turn modulate higher-order perceptual and phenomenological integration. Within the Emergent Flow Theory framework, classical findings from the Libet paradigm are reinterpreted not as evidence against agency, but as reflecting necessary delays associated with multilevel temporal integration. By linking cellular memory, bioelectric signaling, vagal-autonomic regulation, and cortical dynamics, this work outlines a unified temporal architecture of conscious processing that is biologically grounded, mechanistically plausible, and empirically testable using multimodal neurophysiological protocols. The proposed pathway linking cellular temporal integration (ΔT_b) to organismic autonomic coherence (γ) is classified as mechanistically plausible, requiring empirical validation within the EFT framework.

Peripheral nerve injury (PNI) imposes significant burdens, requiring therapies targeting both mechanical compression and inflammatory pathophysiology. While neurolysis addresses extrinsic compression and methylcobalamin promotes intrinsic nerve repair, their combined potential is underexplored. This study compared the efficacy of neurolysis monotherapy, methylcobalamin monotherapy, and combination therapy across functional, electrophysiological, and inflammatory outcomes in PNI.

The nucleus tractus solitarii (NTS) is a highly conserved brainstem structure that has served as a principal hub for visceral sensory integration across vertebrate evolution. While the NTS has long been described as a relay for cardiovascular and respiratory reflexes, recent work increasingly frames it as an integrative node that transforms diverse afferent signals into adaptive, context-sensitive responses. In this review, we synthesize evidence on the developmental origins of the NTS (including contributions from the dorsal alar plate and epibranchial placodes) and its comparative organization across vertebrate taxa. We argue that many interspecies differences are more plausibly interpreted as functional reweighting within a conserved circuit framework-shaped by species-specific respiratory-feeding strategies and ecological demands-rather than as wholesale rewiring of the core network. Within this comparative context, the extensive supranuclear modulation observed in humans is discussed not as biological "superiority," but as layered control that has become particularly prominent in response to human-specific anatomical constraints and behavioral demands, including those associated with speech and complex social interaction. Clinically, we revisit dysphagia, cough hypersensitivity, and nausea/vomiting as manifestations of network-level dysregulation and gating failure rather than isolated breakdowns of single reflex arcs. Finally, we suggest that neuromodulation strategies, including vagus nerve stimulation, may be best conceptualized as delivering patterned afferent input capable of shaping NTS network plasticity, rather than as non-specific electrical activation.

The Somato-Psychic Pathway (SPP) is proposed as a universal ontogenetic developmental trajectory through which somatic structural-functional integrity and autonomic regulation shape the emergence and stability of the mind under both physiological and pathological conditions. Integrating insights from developmental neuroscience, evolutionary biology, and clinical neurodevelopment, SPP conceptualizes mental functions as interpretive extensions of bodily and autonomic states rather than as their primary generators. The framework delineates a developmentally constrained directional sequence beginning with somatic organization, proceeding through proprioceptive and interoceptive accuracy, and culminating in autonomic regulation, emotional stability, and cognitive-social maturation. Disruption of this trajectory-most prominently through axial dysfunction, distorted joint-muscle-fascial proprioception, persistent low-grade nociceptive drive, or direct mechanical influences on peripheral autonomic structures-is proposed to lead to Somato-Psychic Autonomic Dysregulation (SPAD), a state characterized by chronically reduced autonomic flexibility and heightened threat responsivity. Prolonged operation of the pathway in this pathological mode gives rise to the clinical phenotype termed Somato-Psychic Syndrome (SPS). The SPP framework emerged from longitudinal clinical observation of disrupted and restituted developmental trajectories, providing a unique ontogenetic perspective on the directionality of neurodevelopmental regulation. By integrating the somatic, autonomic, emotional, and cognitive domains into a single regulatory continuum, SPP offers a biologically grounded model with implications for understanding childhood neurodevelopmental disorders and guiding future therapeutic strategies.

Brain damage (BD) caused by stroke, traumatic brain injury (TBI), or neurodegenerative conditions often results in persistent cognitive, motor, and emotional impairments. Music-based interventions (MI) have been explored as adjunctive rehabilitation strategies; however, the evidence remains fragmented. This systematic review and meta-analysis synthesize available research on the effects of MI on functional recovery following BD, due to acquired brain injury (ABI), including both TBI and non-TBI. From a total of 868 publications screened in PubMed, Embase, Scopus, Cochrane Library, Web of Science, and ClinicalTrials.gov, 90 were included, of which 41 met the criteria for quantitative evaluation and meta-analysis, to assess the state-of-the-art of research on music and BD in the fields of neuropsychology and cognitive sciences. The reviewed studies span a range of methodologies, including randomized controlled trials and qualitative research, and incorporate diverse MI strategies, such as active music-making, structured listening, and improvisational techniques. The findings indicate that music supports recovery across motor, cognitive, and, albeit to a lesser extent, communicative and psychosocial domains. The findings suggest beneficial effects of MI, particularly in gait function (z = 3.46, P < 0.01), upper extremity function (z = 6.11, P < 0.01; UEF), communication (z = 3.21, P < 0.01), cognitive rehabilitation (z = 3.29, P < 0.01), and emotional, behavioral, and social outcomes (z = 2.35, P = 0.02); notably, these effects were often supported by consistent statistical significance across multiple subgroup analyses (e.g., gait, UEF). This study highlights the therapeutic potential of music in neurorehabilitation and supports its integration into multidisciplinary treatment programs. Despite these promising findings, methodological heterogeneity, small sample sizes, and short intervention durations limit the generalizability of results. The evidence suggests that music may modulate key neurobiological pathways in BD, supporting its integration into evidence-based neurorehabilitation programs.

Eye Movement Desensitization and Reprocessing (EMDR) is an established therapeutic intervention for post-traumatic stress disorder and related conditions, yet its neurobiological mechanisms remain incompletely understood. While prevailing models emphasize cognitive processes such as working memory taxation and memory reconsolidation, these accounts may not fully explain the durability and generalization of therapeutic effects. Here, we propose a hypothesis in which bilateral rhythmic stimulation associated with EMDR modulates neuroimmune interactions through state-dependent changes in autonomic balance and meningeal lymphatic dynamics. Within this framework, regulatory T cells are conceptualized as contributors to baseline neuroimmune tone, influencing microglial activation states, synaptic stability, and network-level regulation. By integrating findings from autonomic physiology, lymphatic biology, and neuroimmunology, this hypothesis generates testable predictions linking behavioral interventions to sustained neural and behavioral outcomes. The model is intended to guide future experimental investigation rather than assert definitive causal pathways.