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ISA’s Malignant Complex Bottom-Up Pathway for Idiopathic Psychological and Physical Dysregulation

 

Linking complex trauma-like experiences to multi-directional psycho-neuro-immune-endocrine-autonomic-drive-state interactions

 

The development of this model was not abstract for me. It grew out of years of trying to understand why serious physical suffering could persist alongside emotional and psychological patterns that did not seem fully explained by standard cognition-first models. As I lived with ankylosing spondylitis, severe asthma, and enthesitis, I became increasingly convinced that the body can carry unresolved distress in ways that are real, patterned, and not fully accessible to conscious explanation at first.

 

That gap between what the mind could understand and what the body kept expressing became one of the central problems that led me to develop ISA’s Malignant Complex Bottom-Up Pathway for Idiopathic Psychological and Physical Dysregulation. ISA is therefore positioned as a research-informed, bottom-up biopsychosocial framework grounded in lived experience as well as interdisciplinary study. It is not a clinical diagnostic system (Etkin et al., 2011; Lanius et al., 2015; Rauch et al., 2006; Shin & Liberzon, 2010; McLaughlin et al., 2019; Ruge et al., 2024; Hosseini-Kamkar et al., 2023; Harb et al., 2024; Sacu et al., 2024; Lyons-Ruth et al., 2024; Sullivan & Opendak, 2021; Diano et al., 2017).

 

Current research supports ISA’s broader claim that repeated developmental trauma-like experiences, especially forms often linked in the literature to chronic trauma-like symptoms of Complex Trauma (C-PTSD), can affect the body from the bottom up. That means long-term stress may shape systems involved in:
 

 

These are the studies that this section is citing (Etkin et al., 2011; Lanius et al., 2015; Rauch et al., 2006; Shin & Liberzon, 2010; McLaughlin et al., 2019; Ruge et al., 2024; Hosseini-Kamkar et al., 2023; Harb et al., 2024; Sacu et al., 2024; Lyons-Ruth et al., 2024; Sullivan & Opendak, 2021; Diano et al., 2017​).

 

Cognitive Behavioral Therapy (CBT) is down-stream

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The research also supports a narrower point that is central to ISA. Some of these changes begin, and keep going, before a person can fully make sense of them, put them into words, or build a clear story around them. In simple terms, the body can be affected before the person fully understands what is happening. ISA differentiates between the terms Instinctual Consciousness vs cognition (i.e. ego cognition, cognitive appraisal, self-awareness, apperception, explicit awareness, or interoception) (Etkin et al., 2011; Lanius et al., 2015; Rauch et al., 2006; Shin & Liberzon, 2010; McLaughlin et al., 2019; Ruge et al., 2024; Hosseini-Kamkar et al., 2023; Harb et al., 2024; Sacu et al., 2024; Lyons-Ruth et al., 2024; Sullivan & Opendak, 2021; Diano et al., 2017​).

 

The strongest support for ISA’s view of where these patterns originate (etiology) comes from research on early adversity. It shows that early stress can train the brain to focus more on danger, respond less to safety, and lose some of its normal response to reward. It can also distort how a person learns what is important, what feels safe, and what to expect from other people.

 

Over time, this can create lasting bias in brain systems involved in fear, judgment, and emotional meaning, especially pathways involving the amygdala, the prefrontal cortex, and early relational salience pathways (Etkin et al., 2011; Lanius et al., 2015; Rauch et al., 2006; Shin & Liberzon, 2010; McLaughlin et al., 2019; Ruge et al., 2024; Hosseini-Kamkar et al., 2023; Harb et al., 2024; Sacu et al., 2024; Lyons-Ruth et al., 2024; Sullivan & Opendak, 2021; Diano et al., 2017​).

 

Note: Mainstream science usually studies drive-state functions and changes as altered interoception, autonomic arousal, appetite, sleep-wake regulation, sexual functioning, fatigue, pain, respiration, and motivational dysregulation, rather than under an umbrella label like “drive-state functions and changes.”

ISA's Concept of Malignant Complexes as Primary Causation

 

From an ISA standpoint, the first layer of mind is not abstract thinking. It is affective or emotional. In Solms’s framework, affect is the basic form of consciousness, and cognition works in the service of managing uncertainty and restoring regulation. Put simply, we feel first and think about what we feel afterward. That fits a bottom-up model much better than a theory that treats cognitive thought as the main driver of emotional suffering (Solms, 2019).

Depression, Inflammation, and Bottom-up Causation

 

Depression is not one single dysregulation with one single cause. For a meaningful subgroup of people, depression appears to be strongly linked to inflammation. That matters because it challenges the old idea that depression is mainly a problem of thoughts, beliefs, or higher brain interpretation. A better model is that some cases begin from the bottom up transduction, through affect (ISA's Term: Affective-NeuroImmunology), body-state (ISA's Terms: Psychoneuroautonomic & Drive-States), immune signaling (Psychoneuroimmunology), and stress physiology (Psychoneuroendocrinology), with thoughts often arriving later as an explanation rather than the first cause (Dantzer et al., 2008; Miller, 2025; Miller & Raison, 2016; Osimo et al., 2019).​

Immune Signaling Response

 

This matters because inflammation can directly shift mood and motivation. In one experimental study, healthy people were given endotoxin which showed increased depressed mood and reduced ventral striatum response to reward. Endotoxins are components of the outermost membrane of the cell envelope, released mainly upon bacterial death. They cause severe inflammatory responses, including fever and septic shock. The study reveals that inflammatory activity can push the brain toward anhedonia and low mood without waiting for a person to first develop a full set of negative beliefs about themselves (Eisenberger et al., 2010).

 

A second endotoxin study sharpened the point. Acute inflammation lowered mood, but it did not significantly change general self-esteem, hopelessness, or other negative self-schemas. In other words, inflammatory activation was enough to impair mood before the classic cognitive patterns of depression shifted in the same way. That is a serious problem for any theory claiming that the reframing of distorted thoughts can counter the effects of endotoxin triggering immune signaling (Psychoneuroimmunology) of inflammatory cytokines (Kotulla et al., 2018).

 

ISA can therefore make a clear causal hypothesis. In this subgroup, trauma-like Prediction Errors are not merely bad thoughts. They are old affective forecasts of danger, defeat, rejection, or failed need satisfaction. These forecasts become embodied through repeated stress and unresolved emotional learning. Over time, they recruit autonomic, endocrine, and immune pathways. At first, inflammation may be downstream of those old affective errors. But once established, it becomes a real co-driver of depression. In this model, the body is not passively obeying the mind. The body is helping generate the depressed state itself (Dantzer et al., 2008; Felger & Lotrich, 2013; Miller & Raison, 2016).

Depression subgroup logic

 

The evidence does not show that all depressed people are inflamed. It shows something more important. Depression is heterogeneous. A major meta-analysis found that about 27% of depressed patients had CRP above 3 mg/L, which means low-grade inflammation is present in about a quarter, not in everyone. A later large UK Biobank study also found elevated CRP in only a subgroup. More recent work continues to argue for an inflammatory subtype of major depression rather than a universal inflammatory model for all cases (Miller, 2025; Osimo et al., 2019; Pitharouli et al., 2021).

 

This subgroup pattern is exactly what a bottom-up causal model would predict. The diagnosis called depression likely contains multiple pathways. Some cases may be driven more by grief, some by chronic stress, some by metabolic dysregulation, some by inflammatory loading, and some by combinations of these. If different pathways lead to the same diagnosis, then one rigid explanation will always be incomplete. The inflammatory evidence does not weaken the case for depression as a bodily condition. It shows that the syndrome label is mixing together different kinds of causal engines (Miller, 2025; Miller & Raison, 2016; Osimo et al., 2019).

 

Childhood adversity is one of the strongest clues to how this subgroup may form. In a longitudinal adolescent study, Miller and Cole found that childhood adversity promoted a clustering of depression and inflammation. Among those with high adversity, the shift into depression was accompanied by increases in CRP and IL-6, and some of these inflammatory changes remained even after mood symptoms had improved. The authors described this pattern as a neuroimmune pipeline. That is very close to the ISA idea that repeated trauma-like affective errors can become biologically embedded and later reactivate as both emotional and bodily suffering (Miller & Cole, 2012).

 

So the public question should change. Instead of asking, “Is depression mental or physical?” we should ask, “Which pathway is driving this person’s depression?” For a meaningful subgroup, the best answer appears to be affective-immunological. In those cases, the emotional system, stress system, and immune system are part of the same dysregulation process (Felger & Lotrich, 2013; Miller, 2025; Miller & Raison, 2016).

Downstream self-perpetuating loop

 

Once this form of depression is established, it can start feeding itself. Inflammatory cytokines can alter neurotransmitters, reduce reward sensitivity, increase fatigue, disrupt motivation, and bias the brain toward sickness behavior and withdrawal. At the same time, stress circuitry, poor sleep, low activity, and ongoing social pain can keep inflammatory signals active. What began as one pathway can become a loop with many entry points and many feedback channels (Dantzer et al., 2008; Felger & Lotrich, 2013; Miller & Raison, 2016).

 

The autonomic nervous system is a major part of that loop. The vagus nerve helps regulate immune activity through bidirectional signaling between body and brain. Reduced vagal tone means weaker anti-inflammatory braking. That gives one plausible mechanism by which chronic threat states, unresolved affect, and body dysregulation can help sustain inflammatory activation over time (Bonaz et al., 2017).

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The loop also has timing problems. In the adversity subgroup described by Miller and Cole, inflammation did not simply rise and fall at the same time as mood. Some inflammatory signals lingered after depressive symptoms improved, and some inflammatory markers predicted later depression. This suggests desynchronization. The system loses rhythm, not just balance. That is one reason these states can feel persistent, recurrent, and hard to explain through thought alone (Miller & Cole, 2012).

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ISA’s contribution is to say that trauma-like Prediction Errors may sit upstream of this whole process in some people. Repeated affective forecasts of danger, abandonment, defeat, or unmet need can keep recruiting body-level defenses. Then the downstream biology begins to amplify and preserve the pattern. At that stage, the dysregulation is no longer only “psychological,” and it is no longer well described as a simple organ disorder either. It is a distributed, self-reinforcing affective-immunological process. That is why a purely top-down model is too narrow. It is trying to explain a systems dysregulation as if it begins and ends with thought (Dantzer et al., 2008; Kotulla et al., 2018; Miller & Raison, 2016; Solms, 2019).

 

The needed shift in the zeitgeist is straightforward. Depression should no longer be treated as though it is mainly a cortical story or mainly a problem of wrong thoughts. For a meaningful subgroup, depression is better understood as an affective-immunological condition shaped by bottom-up stress learning, biological embedding, and feedback loops between brain, body, and immune signaling. That does not deny biology. It expands biology into a fuller and more accurate model of human suffering (Dantzer et al., 2008; Miller, 2025; Miller & Raison, 2016; Osimo et al., 2019).

Supported epigenetic citations

 

On the epigenetic side, current reviews support the idea that severe or chronic early adversity can become biologically embedded through mechanisms such as DNA methylation and related stress-sensitive pathways. Older studies in the broader source set also support the long-arc biological embedding logic through altered hippocampal structure, glucocorticoid sensitivity, cortisol regulation, and clustering of adversity with later inflammatory-depressive burden, even when they are not all epigenetic studies in the narrow molecular sense (Bremner et al., 1995; Kumsta et al., 2007; Yehuda et al., 1996; Miller & Cole, 2012; Zhou & Ryan, 2023).

 

Reproducibility is still an issue

 

The support from the cited literature is real, but it remains probabilistic rather than deterministic. In other words, the field supports “associated with” and “mechanistically plausible” more strongly than “proven in every case.” Reproducibility, tissue specificity, causal inference, and the strength of intergenerational claims remain active issues. That means the epigenetic layer is defensible, but it should still be presented as a meaningful candidate mechanism rather than a settled one-to-one trauma signature (Zhou & Ryan, 2023).

Supported psychoneuroimmune citations

 

On the psychoendocrine side, the HPA-axis literature remains robust. The endocrine layer of the source set supports the claim that chronic threat exposure can reorganize stress regulation rather than simply intensify it. Across the cited studies, this appears through altered glucocorticoid receptor sensitivity, cortisol timing changes, HPA-axis dysrhythmia, stress-mediator overload, and hormonal-immune coupling, which fits a model of chronic regulatory desynchronization rather than a simple “too much stress” account (Kumsta et al., 2007; McEwen, 1998; Miller et al., 2007; Pariante & Lightman, 2008; Yehuda et al., 1996; Zierau et al., 2012; Lawrence & Scofield, 2024).

 

This supports the proposition that prolonged trauma can produce endocrine changes before a person has a full conscious account of what is happening, meaning cognition may already be operating downstream of a dysregulated stress physiology.

 

This is one of the strongest parts of the total research stack because it directly supports the claim that chronic trauma-like dysregulation is not merely “in the head,” but can be propagated and amplified through real immune and inflammatory pathways

Supported psychoendocrine citations

 

On the psychoendocrine side, the HPA-axis literature remains robust. Recent reviews describe PTSD as associated with altered glucocorticoid regulation, abnormal feedback dynamics, and downstream immune and physical health effects. That directly supports the proposition that prolonged trauma can produce endocrine changes before a person develops a psychopathology beyond any self-awareness of the changes, meaning fixing how a person thinks is not as important to addressing how a person emotionally and physically feels.

Supported autonomic and drive-state citations

 

Threat processing can begin outside ego cognition, and interoceptive regulation is deeply shaped by bodily signaling that is only partly available to reflective self-report. Reviews on amygdala processing support the claim that emotionally relevant threat signals can be processed without awareness, while PTSD-interoception and allostatic-interoceptive models support the claim that bodily rhythms, internal prediction, and regulatory demand-shaping are deeply implicated in trauma-relevant states (Diano et al., 2017; Leech et al., 2024; Santamaría-García et al., 2025). In parallel, the autonomic and respiratory literature shows that trauma-linked dysregulation can appear in vagal tone, heart rate variability, panic sensitivity, respiratory chemistry, and body-brain switching systems (Clancy et al., 2014; Gorman et al., 1984; Harper et al., 2005; Laffey & Kavanagh, 2002; Nagpal et al., 2013; Nardi et al., 2009; Porges, 2011).

 

The newer adversity-and-decision literature strengthens the bridge to drive-state logic by showing altered reward valuation, expected-value coding, and risk weighting after adversity (Ruge et al., 2024; Sacu et al., 2024; Smith et al., 2025).

 

From a systems perspective, that is exactly the terrain where drive-states live: interoception, autonomic tone, sleep-wake shifts, appetite, respiration, fatigue, pain, sexuality, salience, motivational intensity, and bodily urgency states. ISA’s drive-state taxonomy is therefore strongly theoretically aligned with this literature, but only partly empirically supported as a formal taxonomy, because mainstream science usually studies these functions under interoception, autonomic regulation, reward learning, allostasis, and symptom dimensions rather than under one unified “drive-state” model.

Cognitive Behavioral Therapy (CBT) is down-stream

 

The research stack is much closer to ISA’s bottom-up model: the organism detects, predicts, and regulates first, with self-aware narrative often arriving later. This does not eliminate cognition. It demotes cognition from prime mover to downstream interpreter in many trauma-linked states. The strongest support for this comes from the literature showing that inflammation can reduce reward response and mood before negative self-appraisal is fully formed, that endotoxemia can lower mood without equivalently shifting negative self-cognition, and that amygdala-mediated threat processing can occur without awareness (Dantzer et al., 2008; Eisenberger et al., 2010; Kotulla et al., 2018; Diano et al., 2017). The same downstream logic is reinforced by the early adversity literature showing that distorted affective learning, vigilance, salience assignment, and attachment-mediated threat organization can be installed before reflective egoic cognition becomes the main organizer of experience (McLaughlin et al., 2019; Ruge et al., 2024; Lyons-Ruth et al., 2024; Sullivan & Opendak, 2021; Harb et al., 2024; Hosseini-Kamkar et al., 2023). In that restricted sense, CBT-style understanding may still be useful, but it is often addressing downstream organization rather than the full origin and propagation of the state itself.

 

ISA’s bottom-up signaling architecture, in which autonomic, respiratory, endocrine, and immune pathways feed into observable drive-state expressions such as hunger, fatigue, breathing urgency, and yawning, is therefore best understood as a research-informed synthesis. It is strongly aligned with the literature at the component level and partly supported at the systems level, but it is not yet a mainstream diagnostic category or a single empirically validated model.

Conclusion

 

Supported. Prolonged developmental trauma is associated with epigenetic, immune, endocrine, autonomic, and interoceptive changes, many of which operate partly or substantially below conscious appraisal. The evidence is strongest for biological embedding, altered threat and reward learning, psychoneuroimmune propagation, HPA-axis dysregulation, and nonconscious or partially nonconscious affective-autonomic processing (Bremner et al., 1995; Kumsta et al., 2007; Yehuda et al., 1996; Miller & Cole, 2012; Zhou & Ryan, 2023; Etkin et al., 2011; Lanius et al., 2015; Rauch et al., 2006; Shin & Liberzon, 2010; McLaughlin et al., 2019; Ruge et al., 2024; Hosseini-Kamkar et al., 2023; Harb et al., 2024; Sacu et al., 2024; Lyons-Ruth et al., 2024; Sullivan & Opendak, 2021; Diano et al., 2017; Afrin et al., 2017; Arck et al., 2006; Bonaz et al., 2017, 2018; Dantzer et al., 2008; Eisenberger et al., 2010; Felger & Lotrich, 2013; Foster et al., 2017; Karimi et al., 2000; Leon et al., 1994; Michopoulos et al., 2017; Miller, 2025; Miller & Raison, 2016; Osimo et al., 2019; Theoharides et al., 2004; Tracey, 2009; Zagaria et al., 2024; Zierau et al., 2012; McEwen, 1998; Miller et al., 2007; Pariante & Lightman, 2008; Lawrence & Scofield, 2024; Clancy et al., 2014; Gorman et al., 1984; Harper et al., 2005; Laffey & Kavanagh, 2002; Nagpal et al., 2013; Nardi et al., 2009; Porges, 2011; Leech et al., 2024; Santamaría-García et al., 2025; Smith et al., 2025).

 

Supported with caution. These changes plausibly extend into altered drive-states such as hunger, sleepiness, respiratory urgency, pain, sexual arousal, fatigue, and motivational intensity, but mainstream science usually studies them under interoception, autonomic regulation, HPA-axis function, reward learning, allostasis, and symptom dimensions rather than as one unified “drive-state complex” model (Leech et al., 2024; Santamaría-García et al., 2025; Ruge et al., 2024; Sacu et al., 2024; Smith et al., 2025).

 

Not yet established. There is not yet a single dominant research program showing the full complex-trauma formulation as one integrated epigenetic-psychoneuroimmune-psychoendocrine-autonomic-drive-state model. That is the gap. The field supports the components more strongly than the total synthesis.

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