Miller and Cole (2012)

The Study

This was a longitudinal study, which means the researchers followed the same people over time. They studied 147 female adolescents who were healthy at the start but already at higher risk for depression, and they checked them every six months for 2.5 years. They measured depression and two inflammation markers in the blood:

• C-reactive protein (CRP): A blood marker of inflammation. It is made by the liver when the body is under stress, fighting infection, or reacting to injury. Higher CRP does not tell you the exact cause, but it can show that the body is in a more activated inflammatory state

• Interleukin-6 (IL-6): An immune signaling protein, sometimes called a cytokine. It helps immune cells send messages to each other during stress, infection, or inflammation. Higher IL-6 can be a sign that the immune system is more active and may help drive longer-lasting inflammatory responses

These are signs of immune system activity.

The study found a kind of two-way link in the adversity group. Depression was not showing up alone. It tended to appear together with higher inflammation. And the inflammation did not just rise during the depressive period. Part of it stayed active afterward, and one marker, IL-6, even helped predict later depression. That suggests early adversity may set up a lasting mind-body pattern, where emotional suffering and immune activation reinforce each other over time.

This pattern was not seen in the adolescents without that adversity history. That matters because it shows a real mind-body link over time. This suggests that early hardship may become biologically embedded, meaning the burden may show up in both emotion and body at the same time.

ISA relevance

From an ISA view, this supports one important part of the broader bottom-up framework of the immune pathway. It is consistent with the idea that early adversity can help organize a hidden body-level burden that later shows up as both depressive suffering and inflammatory activation, well below cognition.

In ISA language, a Malignant Complex could be used here as an interpretation for that hidden pattern causing the lack of interoceptive cognition. ISA places emotional signaling before cognitive interpretation and treats Malignant Complexes with Protective Ego Constructs (PEC) as a governance layer shaping dysregulation.

Reference

Miller, G. E., & Cole, S. W. (2012). Clustering of depression and inflammation in adolescents previously exposed to childhood adversity. Biological Psychiatry, 72(1), 34–40. https://doi.org/10.1016/j.biopsych.2012.02.034

Nardi, A. E., et al. (2009)

The Study

Nardi, Freire, and Zin’s 2009 review on panic disorder and breathing control, which examined how panic is linked to respiratory physiology, meaning the body systems that regulate breathing and carbon dioxide found that:

• Panic disorder is often tied to respiratory symptoms

• Breathing stimulation commonly occurs during panic attacks

• Many patients show increased sensitivity to carbon dioxide, or CO2, which is a key gas involved in breathing control.

• Evidence for subtle breathing and body homeostasis changes, meaning small shifts in the body’s normal self-regulation, even outside full panic attacks.

The authors further discussed a fear network, meaning linked brain regions involved in alarm and threat processing, that includes areas such as:

• Amygdala: the brain’s fast alarm center. In this review’s fear-network model, it helps detect threat quickly and can help trigger panic-related fear and body alarm before the person has fully thought through what is happening.

• Hippocampus: the brain region that helps place fear in context and links it to memory. In this article’s framework, it is part of the fear network that may become oversensitive, so ordinary body sensations or situations may be read as more dangerous than they really are.

• Medial prefrontal cortex: a front part of the brain involved in evaluation and regulation. In panic models linked to this review, it helps put the brakes on fear, but when that control is weaker, the alarm system can escalate more easily.

• Hypothalamus: a small brain region that helps turn fear into body reactions such as stress arousal, autonomic change, and emergency bodily readiness. It is not the main focus of the breathing review, but in the broader fear-network model behind this literature, it helps carry alarm into the body.

• Brainstem regions related to breathing: lower brain centers that help control basic breathing rhythm and respond to gases like CO2. In this article, these regions matter because breathing-related signals and CO2 sensitivity may help trigger panic symptoms from the bottom up.  

This matters because it suggests that intense fear can rise from body regulation problems and brain-body alarm circuits before cognition.

ISA relevance

From an ISA view, this may support one narrow but important part of ISA’s broader bottom-up framework at the respiratory and autonomic front end. It is consistent with the idea that a Malignant Complex, meaning a hidden trauma-shaped pattern of fear, pain, and defense, may help drive intense fear states through the body before the person clearly understands what is happening. In this reading, disturbed breathing signals, interoceptive alarm, which means the body’s internal danger sensing, and drive-state pressure, which means strong survival-based urges such as air hunger or breath urgency, may carry unresolved emotional distress upward into conscious fear.

This does not directly prove the Malignant Complex itself, but the study offers a plausible research-facing bridge for ISA’s claim that such hidden patterns may express themselves first through respiratory instability and related alarm circuitry before clear reflective understanding is in place.

Reference

ardi, A. E., Freire, R. C., & Zin, W. A. (2009). Panic disorder and control of breathing. Respiratory Physiology & Neurobiology, 167(1), 133-143. https://doi.org/10.1016/j.resp.2008.07.011

Osimo, Baxter, Lewis, Jones, and Khandaker (2019)

The Study

This was a systematic review and meta-analysis, which means the authors combined results from many earlier studies to look for a larger pattern. They reviewed 37 studies with 13,541 people with depression and 155,728 control participants.

They focused on C-reactive protein, or CRP, a blood marker that often rises when the immune system is more active, to see how often people with depression showed low-grade inflammation, meaning mild ongoing immune activation.

They found that 27% of depressed patients had CRP above 3 mg/L, a common cutoff for low-grade inflammation, and 58% had CRP above 1 mg/L, which suggests a milder elevation. Compared with matched healthy controls, depressed patients were more likely to show these raised CRP levels.

This matters because it suggests depression is not one single biological pattern, and that immune activation may be part of the picture for an important subgroup.

ISA relevance

From an ISA view, this may support one specific part of ISA’s broader bottom-up framework of the immune pathway. It is consistent with the idea that some depressed states may involve body-based dysregulation, below conscious thoughts or interpretations.

In ISA terms, this is compatible with Psychogenic Transduction as a possible interpretation, meaning unresolved emotional burden may be expressed through bodily disturbance, while the person mainly experiences the later as a dysregulated mood.

Reference

Osimo, E. F., Baxter, L. J., Lewis, G., Jones, P. B., & Khandaker, G. M. (2019). Prevalence of low-grade inflammation in depression: A systematic review and meta-analysis of C-reactive protein levels. Psychological Medicine, 49(12), 1958–1970. https://doi.org/10.1017/S0033291719001454

Pariante and Lightman (2008)

The Study

looks at the HPA axis, which is the body’s main stress-hormone system linking the brain and adrenal glands. The authors say one of the most consistent biological findings in major depression is HPA-axis hyperactivity, meaning the stress system often runs too high. They also describe weaker glucocorticoid feedback, meaning hormones like cortisol do not shut the stress system down as well as they should.

The review further argues that this pattern may be part of the risk for depression, not only a result of it, because early life stress and genetic liability may help set up this long-term stress sensitivity.

ISA relevance

From an ISA view, this may support one clear part of ISA’s broader bottom-up framework: the endocrine branch. It is consistent with the idea that a person’s distress can stay organized in body-based stress regulation even when the deeper source is not fully clear in egoic self-awareness.

In ISA language, that is compatible with the possibility that a hidden Malignant Complex, maintained through Protective Ego Constructs (PEC), could help preserve an unhealthy familiar stress pattern, while part of the original conflict remains outside of cognition in a Dissociative Field.

Reference

Pariante, C. M., & Lightman, S. L. (2008). The HPA axis in major depression: Classical theories and new developments. Trends in Neurosciences, 31(9), 464–468. https://doi.org/10.1016/j.tins.2008.06.006

Phillips and Elmadjian (1947)

The Study

This was an early observational study, not a modern experiment. Phillips and Elmadjian looked at whether a Rorschach tension score, meaning a score based on the inkblot test that was used at the time as an estimate of emotional tension or affective strain, was related to the diurnal lymphocyte curve, meaning the normal rise and fall of lymphocyte levels across the day.

Lymphocytes are a type of white blood cell involved in immune defense. The paper reported a relationship between two aspects of that daily lymphocyte rhythm and the Rorschach-based tension score in psychotic subjects, and one combined lymphocyte-rhythm measure correlated 0.67 with the tension score.

The study asked whether stronger inner tension might be linked to measurable changes in the daily rhythm of immune-related cells, and the authors reported that such a link was present in their sample.

ISA relevance

From an ISA view, this supports one narrow but important part of ISA’s broader bottom-up framework, the idea that emotional strain may be reflected in body regulation outside of cognition. This is consistent with a bottom-up reading in which affective state is not only “in the mind” but may show up in immune-linked physiology. It offers an early research-facing sign that emotional tension and bodily regulation may be linked in a way that fits a broader biopsychosocial and bottom-up direction.

Reference

Phillips, L., & Elmadjian, F. (1947). A Rorschach tension score and the diurnal lymphocyte curve in psychotic subjects. Psychosomatic Medicine, 9(6), 364-371. https://doi.org/10.1097/00006842-194711000-00002

Porges (2011)

The Study

Porges argued that the body’s automatic regulation state, meaning the nervous system’s background condition of safety, alarm, or shutdown, helps shape how a person acts before the person has clearly thought about it. In this view, cognition does not begin from a neutral place. It begins already biased by the body’s state. A person may believe they are “just reacting,” but the nervous system may already be steering tone of voice, facial expression, closeness, withdrawal, urgency, or collapse outside clear reflective awareness:

• Emotion: Emotion is how a person feels inside, such as RAGE, LUST, FEAR, CARE, PLAY, SEEKING, ANXIETY/DESPAIR. These feelings are not always first created by deliberate thought. They are often strongly shaped by the body’s regulation state.

If the nervous system is in a safer state, the person is more likely to feel settled, open, curious, or warm. If the system is in alarm, the person is more likely to feel anxious, irritable, watchful, or overwhelmed. If the system is in shutdown, the person may feel flat, frozen, detached, or unable to respond. So the body is already setting the emotional tone before the person has fully explained it to themselves.

• Attachment: Attachment means how a person bonds, trusts, seeks closeness, and responds to other people. In Porges’s view, this is not guided by ideas alone. It is shaped by whether the body senses enough safety for connection. When the nervous system is regulated, the person is more able to trust, receive care, stay present, and tolerate closeness.

When the system shifts into danger mode, the person may pull away, cling, mistrust, become controlling, or expect rejection even if they do not consciously decide to do that. Attachment behavior can be driven by body-state long before the person has a clear thought like “I do not feel safe with this person.”

• Communication: Communication means not only words, but also tone of voice, facial expression, rhythm, eye contact, and the ability to listen and respond. Porges argued that these social behaviors are deeply shaped by autonomic state.

If the body is in a safe and regulated state, speech tends to sound more flexible, warm, and connected, and the person is more able to listen, respond, and stay engaged.

If the body is activated for defense, speech may become sharp, fast, tense, flat, quiet, or confused. A person may think they are simply “having a conversation,” while their nervous system is already pushing them toward guardedness, aggression, or withdrawal without clear cognitive awareness of why.

• Defense: Defense means how the organism protects itself when danger is sensed. This includes fight, flight, freeze, collapse, or social withdrawal. Porges’s core claim is that these are not usually chosen through slow reasoning. They are body-led response patterns.

When the nervous system detects threat, it can move the person into urgency, avoidance, attack, freezing, or shutdown automatically. The person may later invent a reason for the reaction, but the defensive shift often started first at the level of body regulation. Behavior that looks irrational, extreme, or confusing may partly reflect an automatic protective state that took hold before reflective thought caught up.

The basic idea is that these body states help organize how a person feels, relates, and responds, so body-state comes first and later emotion and behavior are shaped by it. This matters because it offers one integrated way to connect physiology, relationships, and emotional response instead of treating them as separate problems.

ISA relevance

From an ISA view, this may support one important part of ISA’s broader bottom-up framework, especially the autonomic front end. It is consistent with the idea that a Malignant Complex, understood in ISA as a hidden trauma-like pattern of pain, fear, and defense, may hijack the autonomic nervous system in order to keep the person organized around the original danger conditions.

In that interpretation, the body is pushed to keep signaling alarm, shutdown, withdrawal, or defensive readiness, and this can help keep egoic self-awareness partly dissociated from what is actually driving the reaction.

That matters in ISA because it offers a plausible way to think about how old Prediction Errors, meaning outdated danger expectations shaped by earlier trauma-like conditions, may be kept in place through body-state before the person clearly knows what is happening.

Note: ISA acknowledges a major caution. Recent critique literature has argued that key parts of polyvagal theory are too simple or not well supported as anatomy and physiology, especially claims about how different vagal centers uniquely map onto complex social and defensive states.

A 2026 expert commentary reported that 39 invited specialists disputed core polyvagal claims, and earlier reviews argued that its basic premises were untenable or highly implausible. At the same time, newer vagus reviews still support the broader idea that the vagus is important for brain-body regulation, while stressing that it is bidirectional, meaning afferent and efferent, not a simple one-way calming brake.

From an ISA view, Porges remains useful as a strong autonomic and relational heuristic, but not as a complete or settled explanation of the vagus nerve.

Reference

Porges, S. W. (2011). The Polyvagal Theory: Neurophysiological foundations of emotions, attachment, communication, and self-regulation. W. W. Norton.

Rauch, S. L., et al. (2006)

The Study

Rauch and colleagues reviewed brain scan studies on post-traumatic stress disorder to see whether PTSD looks like a problem in a specific fear system in the brain, rather than just a mixed group of symptoms. In other words, they asked whether the findings point to a recognizable brain pattern behind the condition:

• Amygdala: They proposed that one key part of this pattern is the amygdala. The amygdala is a brain region that quickly detects possible danger and helps trigger fear responses. In PTSD, they argued that this system often reacts too strongly, so the brain may treat cues as threatening even when the danger is not actually present.

• Frontal cortical regions: They also pointed to frontal cortical regions, which are parts of the brain involved in regulation and control. These regions help slow fear down, make sense of what is happening, and update the system when a cue is no longer dangerous. That updating process is sometimes called extinction, which means learning that something linked to past danger is now safe. Rauch and colleagues proposed that in PTSD these frontal regions may not regulate fear effectively, so the fear response is harder to turn off.

Put simply, their model suggests that the brain’s alarm system may be too strong, while the brain systems that would normally calm the alarm and relearn safety may be too weak or less effective.

They also proposed weaker hippocampal function:

• Hippocampus: The hippocampus is a brain region that helps you place experience in context. In simple terms, it helps the brain answer questions like: Where am I? What is happening now? Is this situation actually the same as the earlier danger, or does it only remind me of it?

The hippocampus also helps with explicit memory, which means memory you can consciously recall and describe in words, such as what happened, when it happened, and how it differs from the present moment.

If this system is not working well, the brain may have more trouble separating past danger from present safety. A harmless place, sound, face, or situation may feel dangerous because the brain is not clearly tagging it as different from the original threat. As a result, safe situations can be misread as unsafe.

The brain scan findings were starting to fit the proposed fear-circuit model, but the evidence was still somewhat indirect because researchers had not yet tested PTSD patients often enough with brain-scan tasks that directly measured fear learning and fear reduction.

This matters because it suggests that trauma-related suffering is not only a matter of fearful thoughts or poor reasoning. It may arise from brain circuits involved in threat detection and fear response that can activate automatically, before the person has time to think clearly or consciously assess whether danger is actually present.

ISA relevance

From an ISA view, this supports one important part of ISA’s broader bottom-up framework of the brain-threat pathway. It is consistent with the idea that stress-linked dysregulation can begin in fast threat and context circuits before the person has clear reflective awareness of what is driving the reaction, which fits ISA’s broader picture of a hidden fear-shaped pattern, such as a Malignant Complex, operating beneath later explanation. This is also consistent with the idea that a Protective Ego Construct may react from an old danger map rather than from the present situation.

Reference

Rauch, S. L., Shin, L. M., & Phelps, E. A. (2006). Neurocircuitry models of posttraumatic stress disorder and extinction: Human neuroimaging research-past, present, and future. Biological Psychiatry, 60(4), 376-382. https://doi.org/10.1016/j.biopsych.2006.06.004

Ruge, Ehlers, Kastrinogiannis, Klingelhöfer-Jens, Koppold, Abend, and Lonsdorf (2024)

The Study

Ruge and colleagues reviewed 81 studies on Adverse Childhood Experiences, or ACEs, and asked whether early adversity is linked to changes in associative learning, meaning the basic way the brain learns which cues or triggers predict danger or reward. They found a converging pattern across the literature that people with ACE histories often showed:

• Blunted threat learning, meaning weaker learning from danger cues

• Poorer threat-safety discrimination, meaning more difficulty telling danger cues from safe ones.

• Attenuated reward learning, meaning lower accuracy and a slower learning rate, or slower updating from reward feedback.

The authors argue that these altered learning processes may be one route by which early adversity becomes biologically embedded over time.

This matters because it suggests that part of later suffering may begin in implicit memory, meaning deep emotional learning that works automatically before clear thinking is involved. These unconscious systems learn basic patterns such as “this is dangerous,” “this is safe,” or “this is not worth pursuing.” That learning can remain active even when the person cannot clearly explain it.

The problem may not begin in cognition. It may begin lower down in stored emotional learning that shapes reactions without words. A person may first suffer through automatic fear, confusion, or reduced motivation, and only later try to make sense of it through cognition.

ISA relevance

From an ISA view, this supports an early part of ISA’s broader bottom-up framework. It is consistent with the idea that later dysregulation may begin in fast emotional learning systems below cognition, where danger, safety, and reward are being sorted before reflective explanation catches up.

In ISA language, this is consistent with the possibility that a hidden stress-shaped pattern, such as a Malignant Complex, could be built on altered threat and reward learning and later shape defensive habits in the ego without the person fully knowing the source.

Reference

Ruge, J., Ehlers, M. R., Kastrinogiannis, A., Klingelhöfer-Jens, M., Koppold, A., Abend, R., & Lonsdorf, T. B. (2024). How adverse childhood experiences get under the skin: A systematic review, integration and methodological discussion on threat and reward learning mechanisms. eLife, 13, e92700. https://doi.org/10.7554/eLife.92700

Santamaría-García, Migeot, Medel, Hazelton, Teckentrup, Romero-Ortuno, Piguet, Lawor, Northoff, and Ibáñez (2025)

The Study

Santamaría-García and colleagues reviewed research on allostasis and interoception. Allostasis means the body does not only react after something happens. It also tries to predict what will be needed next, such as more energy, a faster heart rate, changes in stress hormones, or shifts in attention.

Interoception means the brain’s ongoing sensing of signals from inside the body, such as heartbeat, breathing, pain, hunger, stomach tension, and internal discomfort. The review examines how these two systems work together to help a person anticipate demands, monitor body state, and adjust before strain becomes too great.

They looked across psychiatric and neurological conditions and argued that these systems help the brain and body predict upcoming needs, monitor internal strain, and coordinate adjustment across many body systems at once. The review suggests that dysregulation can arise when this predictive system misjudges the body’s real needs. In plain language, the body may prepare too strongly, too weakly, or at the wrong moment. Over time, that repeated mismatch can create cumulative strain across stress, immune, autonomic, metabolic, and brain-body regulatory systems.

The review also points to linked pathways involving the brain, heart, breathing, gut-microbiota system, inflammation, immune activity, stress hormones, and epigenetic processes. This matters because it suggests that some disorders may involve whole-system regulatory strain rather than one isolated symptom or one isolated organ problem. The authors also say the field is still early and that much of the evidence is still correlational rather than strongly causal.

ISA relevance

From an ISA view, this study may support the broader bottom-up claim that body and survival systems can shift before cognition. The review describes a network that links limbic and interoceptive brain regions with heart, breathing, gut, inflammatory, immune, and stress-hormone systems, and it frames these as anticipatory regulation systems rather than as mere after-effects of thought. That is consistent with ISA’s idea that cognition may be downstream here, meaning the body-state shift happens first and the person’s later thoughts may only be an interpretation of that shift. This is indirect support for ISA, not direct proof of ISA’s own terms.

From an ISA view, the study is consistent with ISA’s claim that a person may show body-wide overload while the ego is mainly trying to manage symptoms at the surface.

From an ISA view, the paper also fits Psychogenic Transduction, meaning unresolved emotional material may be converted into body symptoms through stress, autonomic, endocrine, immune, and brain-body pathways. The study’s emphasis on whole-body cascades, inflammatory and immune processes, stress-hormone systems, and brain-body prediction makes that link plausible inside ISA. But again, this is an interpretive bridge, not something the review proves in ISA’s own language.

On ISA’s broader bottom-up pathway, this study partly supports brain and threat processing, because it includes the amygdala, insula, cingulate regions, and anticipatory response to demands and threats. It supports immune signaling, endocrine or stress-hormone regulation, autonomic regulation, and interoception, because those are explicit parts of the review’s model.

Overall, this paper is best treated as a strong systems-level parallel.

Reference

Santamaría-García, H., Migeot, J., Medel, V., Hazelton, J. L., Teckentrup, V., Romero-Ortuno, R., Piguet, O., Lawor, B., Northoff, G., & Ibáñez, A. (2025). Allostatic interoceptive overload across psychiatric and neurological conditions. Biological Psychiatry, 97(1), 28–40. https://doi.org/10.1016/j.biopsych.2024.06.024