The Stress Phenotyping Framework: A multidisciplinary biobehavioral approach for assessing and therapeutically targeting maladaptive stress physiology

Figures & data

Table 1. Stress Phenotyping Framework: Mechanistic pathways and health implications.

Stress-related system	Mechanistic pathways	Potential health implications
Sensorimotor	Altered pain processing through endogenous opioid and cannabinoid system (Kozlowska et al., 2015; Lanius et al., 2018) Gut-brain axis dysregulation and gut microbiome dysbiosis (Molina-Torres et al., 2019; O’Mahony et al., 2015) Dysregulation of the vestibular system (Kearney & Lanius, 2022)	Increased risk for chronic pain syndromes, fibromyalgia, headaches, stomach aches, dissociation, numbness, self-harming, and thrill-seeking behaviors (Kearney & Lanius, 2022; Nelson et al., 2020) Gastrointestinal issues such as constipation, diarrhea, encopresis (Hughes et al., 2017; Nelson et al., 2020) Altered felt sense of physical and emotional balance, safety and groundedness (Kearney & Lanius, 2022)
Arousal & energy	Alterations in homeostatic sleep drive and circadian rhythm (Koch et al., 2017), mitochondrial energy production (Picard & McEwen, 2018), connectivity with DMN, SN, and RAS (Thome et al., 2019), and neuronal electrical activity (Jokić-begić & Begić, 2003) Changes in reactivity and size of the amygdala (Teicher & Samson, 2016)	Hyper- or hypo-arousal, hyperactivity or fatigue, increased risk for chronic fatigue syndrome, sleep problems, depression, anxiety, and bipolar disorder (Heim et al., 2019; Kajeepeta et al., 2015; MacKinnon, 2008) Increased fear responses (fight, flight, freeze), impulsivity, aggression, reactivity to facial expressions (Shonkoff et al., 2012; Teicher & Samson, 2016)
Reward processing	Dysregulation of the ventral tegmental area and reward processing pathways (Hanson et al., 2021)	Increased health-risk behaviors and addictions (Hanson et al., 2021; Leza et al., 2021; Wiss et al., 2020)
Autonomic nervous system	Altered SNS and PNS activity (Teicher & Samson, 2016; Young-Southward et al., 2020)	Alterations in heart rate, heart rate variability, blood pressure, dysautonomia, fainting (Elbers et al., 2018)
HPA axis & endocrine	Alterations in cortisol, leptin, ghrelin, lipid and glucose metabolism, and sex steroids (Raspopow et al., 2014; Sapolsky et al., 2000)	Overweight, obesity, cardiometabolic disorders, insulin resistance, failure to thrive, poor growth, early sexual debut, teenage pregnancy (Nelson et al., 2020; Tomiyama, 2019)
Immune	Increased inflammatory markers, especially Th2-biased immune response (Elwenspoek et al., 2017; Slavich, 2015)	Asthma, allergies, increased infections, arthritis, cancers (Nelson et al., 2020)
Cognitive	Inhibition of the prefrontal cortex, shifting resources from CEN to SN, hippocampal neurotoxicity (Hermans et al., 2014; McEwen, 2007) Overactivation of the PFC and overmodulation of fear processing (Lanius et al., 2015, 2018)	Impairments in executive functioning, planning, organizational skills, learning, and memory, rumination, panic, anxiety (Burke et al., 2011; Nelson et al., 2020) Dissociation and dissociative subtype of PTSD (Lanius et al., 2015, 2018)
Attachment & relational health	Lack of safety and co-regulation from safe, supportive, nurturing caregiver (Cooke et al., 2019); alterations in oxytocin (Heinrichs et al., 2009) and neural networks for mentalization, empathy, and protective hypervigilance (Feldman, 2015)	Insecure attachment, poor self-regulation skills, trouble feeling safe in relationships (Cooke et al., 2019; Perry, 2001)
Epigenetic & genetic	Epigenetic modifications and changes in gene expression (Slavich et al., 2023; Slavich & Cole, 2013)	Chronic diseases, cancer, and early mortality (Brown et al., 2009; Nelson et al., 2020)

DMN, default mode network; SN, salience network; RAS, reticular activating system; SNS, sympathetic nervous system; PNS, parasympathetic nervous system; CEN, central executive network; PFC, prefrontal cortex.

Adapted and expanded from Bhushan et al., 2020.

Table 2. Stress Phenotyping Framework: Assessments and targeted interventions.

Systems shown to be impacted by stress and adversity	Examples of potential assessments	Examples of potential targeted interventions
Sensorimotor: somatosensory and orienting, vestibular balance, pain processing, gut-brain axis	Self-report Sensory Processing Measure (SPM) (Brown et al., 2023), Sensory Profile (Dean et al., 2016; Dunn, 1999), Sensory Processing Scale Inventory (Schoen et al., 2017), Dizziness Handicap Inventory (DHI) (Zamyslowska-Szmytke et al., 2021), Vestibular Activities & Participation (VAP) Questionnaire (Alghwiri et al., 2012), Vertigo Symptom Scale (VSS) (Wilhelmsen et al., 2008), Pain interference PROMIS short version (Amtmann et al., 2010), McHill Pain Questionnaire (Melzack & Raja, 2005), Pain Catastrophizing Scale (Sullivan et al., 1995), and the Physical & Emotional Subjective Units of Discomfort Scales (SUDS) (Tanner, 2012) Physical exam Gently touching the skin with a pin, cotton swab or vibrating tuning fork, nystagmus testing, the head impulse test, the Romberg test, and walking heel-to-toe on a straight line Biomarkers Hair endocannabinoids (Shonkoff et al., 2022), lipid extracts of serum or plasma endocannabinoids (Hillard, 2018) Imaging Positron Emission Tomography (PET) (Conway et al., 2022), nerve conduction studies (NCS), electroencephalogram (EEG), and functional magnetic resonance imaging (fMRI) (Ahmad & Zakaria, 2015; Davies & Gavin, 2007; Kearney & Lanius, 2022) Wearable devices and emerging technology Heart rate, skin conductance (Black et al., 2020; Kaski & Seemungal, 2010), and balance through accelerometers (Patterson, 2014), diary apps (Martin et al., 2020)	Somatic therapies Sensorimotor Psychotherapy (Ogden & Minton, 2000), Somatic Experiencing (Kuhfuß et al., 2021), and Sensory Motor Arousal Regulation Therapy (SMART) (Warner et al., 2014), body scan meditation, progressive muscle relaxation (Lanius et al., 2015), EMDR (Shapiro, 2014; Wilson et al., 2018), repetitive, rhythmic, patterned stimuli (Perry, 2009; Perry & Hambrick, 2008), play therapy, expressive arts therapy, animal-assisted therapy (Fisher, 2019), occupational therapy, physical therapy, yoga, tai chi, Qui-Gong, and adventure-based programs with balance-based activities (e.g., walking on logs, climbing rocks) Microbiome and gut-brain axis Probiotics, prebiotics, dietary changes, and fecal transplant (Molina-Torres et al., 2019) Supplements and medications Kappa receptor antagonists (Carlezon & Krystal, 2016; Lanius et al., 2018), low dose naltrexone (Toljan & Vrooman, 2018; Younger et al., 2014), effective pain control and higher morphine doses after trauma (Lanius et al., 2018), cannabinoid receptor agonists such as nabilone (Lanius et al., 2018), and ketamine-assisted psychotherapy (Drozdz et al., 2022)
Arousal and energy	Self-report Profile of Mood States arousal subscale (Boyle, 1987), Activation-Deactivation Adjective Check List (AD ACL) (Thayer, 1986), and Self-Assessment Manikin (Bradley & Lang, 1994). Common self-reported sleep questionnaires include the Pittsburgh Sleep Quality Index (PSQI) used to assess overall sleep quality, quantity, and disturbances; Epworth Sleepiness Scale (ESS) for assessing excessive daytime sleepiness; Insomnia Severity Index (ISI) to measure severity of insomnia symptoms; and STOP-Bang questionnaire for assessing presence of obstructive sleep apnea (Chung et al., 2016; Fabbri et al., 2021). Circadian rhythm is commonly measured through the Morningness-Eveningness Questionnaire (Horne & Ostberg, 1976) Biomarkers Orexin, catecholamines, gamma aminobutyric acid (GABA), glutamate, acetylcholine, serotonin, adenosine (Chellappa & Aeschbach, 2022), and melatonin (Caumo et al., 2019), F2isoprostane (oxidative stress) (Horn et al., 2019) Imaging Quantitative electroencephalogram (qEEG), evoked response potentials (ERPs), fMRI, and polysomnography (Fabbri et al., 2021) Wearables Sleep trackers (Berryhill et al., 2020) Polysomnography (Kim & Dimsdale, 2007; Zhang et al., 2019)	Arousal Alpha neurofeedback training (Fisher, 2019; Lanius et al., 2015a), breathing techniques, mindfulness practices (Rusch et al., 2019), Deep Brain Reorienting (DBR) (Kearney & Lanius, 2022) Sleep Address stressors, nightlights, weighted blankets, co-sleeping, journaling, to-do lists, light therapy, (Blume et al., 2019), Tai Chi (Irwin et al., 2014, 2017; Raman et al., 2013), Cognitive Behavioral Therapy for Insomnia (CBT-I) (Muench et al., 2022) Supplements and medications Melatonin, prazosin, and anti-oxidants (Agorastos et al., 2020; De Berardis et al., 2015; George et al., 2016; Kowalczyk et al., 2021)
Reward processing	Biomarkers Dopamine, GABA, and adenosine (Deighton et al., 2018; Hanson et al., 2021; Linnstaedt et al., 2019) Testing paradigms Delay Discounting (Lempert et al., 2012), Willingness to Pay Task (Plassmann et al., 2007), the Effort Expenditure for Rewards Task (Treadway et al., 2009), the Go/No-Go task (Korgaonkar et al., 2021) Imaging fMRI (Herzberg & Gunnar, 2020)	Psychosocial interventions Skill building to increase healthy coping strategies and distress tolerance and target reward processing pathways (Dutcher, 2023; Garland, 2020; Maté, 2008; Ryan et al., 2022), Transcranial Magnetic Stimulation (Ryan et al., 2022), Behavioral Activation Therapy (Dutcher, 2023), positive affect treatment (Craske et al., 2023), brain training for cognitive reappraisal of cravings (Fisher & Berkman, 2015), meditation (Kjaer et al., 2002), neurofeedback (Greer et al., 2014) Medications Ketamine-assisted psychotherapy (Drozdz et al., 2022), other psychedelic-assisted therapies (Reiff et al., 2020)
Autonomic nervous system	Autonomic cardiovascular reflexes Valsalva maneuver, deep breathing, isometric handgrip test, cold pressor test, active standing (orthostatic), head-up tilt test, baroreflex sensitivity testing, and mental arithmetic Wearables Heart rate, respiratory rate, and blood pressure, heart rate variability (Deighton et al., 2018; Grégoire et al., 2023) Biomarkers Urine and plasma norepinephrine, epinephrine, and salivary alpha amylase (Ali & Nater, 2020; Zygmunt & Stanczyk, 2010)	Psychosocial interventions Heart rate variability biofeedback (e.g., HeartMath) (Fournié et al., 2021; Lehrer et al., 2020), yoga (Kearney & Lanius, 2022), somatic psychotherapies (Kearney & Lanius, 2022) (e.g., Somatic Experiencing, Sensorimotor Psychotherapy, Sensory Motor Arousal Regulation Therapy [SMART]), prolonged expiratory breathing (Balban et al., 2023; Kearney et al., 2023; Komori, 2018) Medications Beta-blockers or midodrine (Raj et al., 2009; Thijs & van Dijk, 2006) Alpha-2-adrenergic agonists including clonidine and guanfacine (Arnsten, 2015; Arnsten & Pliszka, 2011)
Hypothalamic-pituitary-adrenal axis (HPA) & endocrine processes	HPA biomarkers Salivary and serum cortisol, diurnal cortisol assessments (taken multiple times per day across multiple days), the cortisol awakening response, dehydroepiandrosterone (DHEA), ACTH, CRF, AVP, DHEA, calculating a cortisol/DHEA ratio (Ahmed et al., 2023; Deighton et al., 2018; Djuric et al., 2008; Linnstaedt et al., 2019; Piazza et al., 2010), Hair cortisol, cortisone, and dehydroepiandrosterone (DHEA) (Shonkoff et al., 2022) Metabolic biomarkers Fasting serum levels leptin, ghrelin, GLP-1, blood pressure, glucose, hemoglobin A1c, insulin resistance, cholesterol levels, high-density lipoprotein, low-density lipoprotein, and triglycerides (Joung et al., 2014; McEwen, 2015; Tomiyama et al., 2012; Wiley et al., 2016; Yam et al., 2015; Yousufzai et al., 2018)	Trauma-informed stress mitigation strategies Supportive relationships, quality sleep, physical activity, mindfulness, experiencing nature (Bhushan et al., 2020; Gilgoff et al., 2020, 2022; Jones et al., 2021; Koncz et al., 2021; Pascoe et al., 2017) Psychosocial interventions (Purewal Boparai et al., 2018; Slopen et al., 2014)
Immune system	Clinical biomarkers Complete blood count with differential, high-sensitivity c-reactive protein (hs-CRP), Total IgE, Aeroallergen panel, FeNO, pulmonary function tests Research biomarkers Interleukins, TNF-alpha, TNF-receptor type 2 (sTNF-R2) (Deighton et al., 2018; Djuric et al., 2008; Linnstaedt et al., 2019)	Trauma-informed stress mitigation strategies Mindfulness, meditation, yoga, Tai Chi, anti-inflammatory diets, quality sleep, physical activity (Black & Slavich, 2016; Bower, 2019; Gilgoff et al., 2020; Hewson-Bower & Drummond, 2001; Shields et al., 2020; Wang & Young, 2016) Psychosocial interventions CBT (Shields et al., 2020b) Supplements and medications Omega-3 fatty acids, curcumin, ginger (Jalali et al., 2020; Kiecolt-Glaser 2010; Morton et al., 2021; Portnoy et al., 2018)
Cognitive	Self-report and functional tests Mini mental state examination (MMSE) (Tombaugh & McIntyre, 1992), the mental test score (MTS) (Hodkinson, 1972), and the Addenbrooke’s cognitive examination (ACE-R) (Mioshi et al., 2006) Formal neuropsychological assessment (Kipps & Hodges, 2005), CNS Vital Signs (Gualtieri & Johnson, 2006), NIH Toolbox (“NIH Toolbox”, 2023) Health technology Mobile applications that measure eye movement, attention, concentration, memory, response time, and visual processing, as well as tracking symptoms, commercial headbands and eyewear using EEG signals and near infrared spectroscopy (Moore et al., 2017; Peake et al., 2018) Imaging Functional magnetic resonance imaging (fMRI), qualitative electroencephalogram (EEG), and functional near-infrared spectroscopy (fNIRS) (Lanius et al., 2015; Schaal et al., 2019; Teicher & Samson, 2016)	Abstract cognitive processes Trauma-Focused Cognitive Behavioral Therapy (TF-CBT) (Kar, 2011; Lorenc et al., 2020; Ramirez de Arellano et al., 2014), Dialectical Behavior Therapy (DBT) (Bohus et al., 2020), and Prolonged Exposure Therapy (Powers et al., 2010); physical activity (Erickson et al., 2011; Firth et al., 2018; Kandola et al., 2016; Li et al., 2017) Cognitive function Practice needed/lagging skills and build/strengthen these brain circuits (Lanius et al., 2015), brain training (Nouchi et al., 2013; Scionti et al., 2019)
Attachment and relational health	Self-report The Relationships Questionnaire (Bartholomew & Horowitz, 1991), Berkman-Syme Social Network Index (Berkman & Syme, 1979), Loneliness Questionnaire (Ebesutani et al., 2012), Toronto Empathy Questionnaire (Spreng, 2009), Revised Dyadic Adjustment Scale (Busby et al., 1995), Medical Outcomes Study (MOS) Social Support Survey (Sherbourne & Stewart, 1991), Convoy Circles of Support (Antonucci et al., 2014; Fuller et al., 2020), National Institute of Health emotional support toolset (NIH, 2022) Neurosequential Model of Therapeutics (Perry, 2001, 2013, 2020; Perry & Dobson, 2013) Biomarkers Oxytocin, vasopressin (Baracz et al., 2020; Heinrichs et al., 2009; Meyer-Lindenberg et al., 2011; Toepfer et al., 2017)	Individual Attachment-based Therapy, Transference-focused Therapy, Interpersonal Psychotherapy, Internal Family Systems, and mentalization-based treatments (Berry & Danquah, 2016; Lucero et al., 2018; Slade & Holmes, 2019). Caregiver-child Parent Child Interaction Therapy (Luby et al., 2020), Child Parent Psychotherapy (Lieberman et al., 2006; Lieberman, 2004), and Collaborative & Proactive Solutions (Greene & Winkler, 2019; Mulraney et al., 2022) Couples Emotionally Focused Therapy, Integrative Behavioral Couples Therapy (Doss et al., 2022) Potential medication Oxytocin (Baldi et al., 2021) Psychedelic-assisted therapy (Reiff et al., 2020)

Note. This table describes evidence-based and emerging stress-related assessments, and examples for possible corresponding interventions to guide future research for a precision medicine approach to treating toxic stress. This is not meant to be a treatment guideline nor is it an exhaustive list of assessments and interventions. In addition, interventions may have a direct impact on more than one system and/or may have a primary target effect that has downstream impacts on other systems.

Figure 1. The Stress Phenotyping Framework.

Ax, Example assessments; Tx, Example Treatments; GI, gastrointestinal; OT, occupational therapy; EMDR, Eye Movement Desensitization Reprocessing; LDN, low dose naltrexone; qEEG, quantitative electroencephalogram; CBT-I, Cognitive Behavioral Therapy for Insomnia; TMS, Transcranial Magnetic Stimulation; HR, heart rate; RR, respiratory rate; BP, blood pressure; HRV, heart rate variability; DHEA, dehydroepiandrosterone: HgbA1c, hemoglobin A1c; CBC with diff, complete blood count with differential; hsCRP, high-sensitivity c-reactive protein; EF, executive function; TF-CBT, Trauma-Focused Cognitive Behavioral Therapy; DBT, Dialectical Behavior Therapy

Figure 2. The Stress Phenotyping Framework and the potential for identifying stress phenotypes. (A) Commonly used stress response cluster model. Stress reactivity clusters are often simplified to reactive or blunted and focus on ANS and HPA axis reactivity. This model can be very helpful in the clinical encounter to quickly describe complex processes to clients and patients. However, people likely differ in their stress reactivity across systems and may need a broader assessment and treatment strategy. (B) The Stress Phenotyping Framework. Within each of the stress-related systems described in this narrative review, an individual could have a reactive (↑), blunted (↓), disorganized (bi-directional arrow), or well-regulated (∼) stress response. We suggest that clinicians can provide more targeted interventions by identifying individual differences across different stress-related systems. In addition, we hypothesize that future research can identify clinically distinct stress-response clusters or “stress phenotypes” that could further predict health behaviors and disease risks and provide an opportunity to advance therapeutic interventions. (C) Potential patterns of cortisol reactivity to acute stress (adapted from McEwen, 2000a, 2000b, 2006). This graph depicts an example of differential regulation of HPA-axis reactivity. Mapping the patterns of dysregulation for all stress-related systems following ELA and chronic stress may better inform classification of common stress phenotypes and targeted therapeutic interventions.

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