Neurovisceral expression of psychiatric symptoms

Neurovisceral phenotypes in the expression of psychiatric symptoms | Autonomic Neuroscience | Review ARTICLE |February 2015 (modified repost from 2/6/16)

This review supports what I’ve long suspected: it’s not just my body that’s hypermobile, but my emotions as well. There’s evidence that collagen disorders affect much more than joints due to the altered biochemical properties of this protein that’s ubiquitous in our bodies.

This review explores the proposal that vulnerability to psychological symptoms, particularly anxiety, originates in constitutional differences in the control of bodily state, exemplified by a set of conditions that include Joint Hypermobility, Postural Tachycardia Syndrome and Vasovagal Syncope.

Research is revealing how brain-body mechanisms underlie individual differences in psychophysiological reactivity that can be important for predicting, stratifying and treating individuals with anxiety disorders and related conditions. 

One common constitutional difference is Joint Hypermobility, in which there is an increased range of joint movement as a result of a variant of collagen.

Joint hypermobility is over-represented in people with anxiety, mood and neurodevelopmental disorders.

It is also linked to stress-sensitive medical conditions such as irritable bowel syndrome, chronic fatigue syndrome and fibromyalgia

Structural differences in “emotional” brain regions are reported in hypermobile individuals, and many people with joint hypermobility manifest autonomic abnormalities, typically Postural Tachycardia Syndrome.

Enhanced heart rate reactivity during postural change and as recently recognized factors causing vasodilatation (as noted post-prandially, post-exertion and with heat) is characteristic of Postural Tachycardia Syndrome, and there is a phenomenological overlap with anxiety disorders, which may be partially accounted for by exaggerated neural reactivity within ventromedial prefrontal cortex.

People who experience Vasovagal Syncope, a heritable tendency to fainting induced by emotional challenges (and needle/blood phobia), are also more vulnerable to anxiety disorders.

Neuroimaging implicates brainstem differences in vulnerability to faints, yet the structural integrity of the caudate nucleus appears important for the control of fainting frequency in relation to parasympathetic tone and anxiety.

Together there is clinical and neuroanatomical evidence to show that common constitutional differences affecting autonomic responsivity are linked to psychiatric symptoms, notably anxiety.


Influential theories argue that bodily states of arousal are a key component to emotions, and are the basis to emotional feeling states. Emotional processes are intrinsically coupled to autonomic bodily responses through shared neural substrates

Exaggerated patterns of autonomic responsivity can enhance the expression of panic or anxiety symptoms.

Some of the vulnerability to psychological symptoms, particularly anxiety, originates in constitutional differences in the control of bodily states of arousal.

The mechanisms underlying these brain-body interactions can be defined by combining brain imaging with detailed physiological monitoring of psychiatric and neurological patients and healthy controls. Ultimately, these interactions are relevant to the recognition, understanding and treatment of individuals with anxiety, and also for stress-sensitive medical disorders

By characterizing the interplay between brain and body in detail, clinically relevant insights can be gained into the mechanisms that underpin both adaptive and maladaptive psychological and physical states.

We argue that there are specific yet common constitutional variants (i.e., phenotypes) in physiological reactivity (i.e., related to the autonomic nervous system) that have major influences on emotional state and by extension on vulnerability to psychiatric disorder.

Below we discuss the relevance of three of these “neurovisceral phenotypes” (Joint Hypermobility, Postural Tachycardia Syndrome and Vasovagal Syncope) to psychiatric symptoms.

Neurovisceral phenotypes

Joint Hypermobility

Joint hypermobility affects up to 20% of the general population (Mulvey et al., ) yet is often poorly recognized (Grahame, ). It is characterized by a variation in the type and distribution pattern of collagen.

Joint hypermobility reflects a disordered collagen ratio (notably Type I/III) (Child, 1986) and Joint Hypermobility Syndrome (synonymous with Ehlers-Danlos Hypermobility Type–formerly Type III) (see, Tinkle et al., 2009) describes the presence of joint hypermobility with other musculoskeletal and extra articular connective tissue difficulties (Grahame et al., 2000).

Over recent years there has been growing recognition of extra-articular features of Joint Hypermobility:

these affect almost every system of the body (unsurprisingly as collagen is not confined to joints).

Conditions associated with joint hypermobility go beyond rheumatology to include

  • Chronic Fatigue Syndrome (Nijs et al., 2006),
  • Fibromyalgia (Ofluoglu et al., 2006), and
  • Irritable Bowel Syndrome (Zarate et al., 2010). See Table 2 


Summarizes extra-articular disorders associated with joint hypermobility with example references.

Condition References
Attention deficit hyperactivity disorder Koldas Dogan et al., 2011
Anxiety See later review, e.g., (Martin-Santos et al., 1998)
Asthma Morgan et al., 2007
Carpal tunnel syndrome Aktas et al., 2008
Chiari malformation type I Milhorat et al., 2007
Chronic constipation De Kort et al., 2003
Chronic fatigue syndrome Nijs et al., 2006
Chronic regional pain syndrome Stoler and Oaklander, 2006
Crohn’s disease Vounotrypidis et al., 2009
Developmental co-ordination disorder Kirby and Davies, 2007
Fecal incontinence Arunkalaivanan et al., 2009
Fibromyalgia Ofluoglu et al., 2006
Functional gastrointestinal disorder Zarate et al., 2010
Headache attributed to spontaneous cerebrospinal fluid leakage Schievink et al., 2004
Hiatus hernia Al-Rawi et al., 2004
Mitral valve prolapse (MVP) Yazici et al., 2004
Migraine Bendik et al., 2011
New daily persistent headache Rozen et al., 2006
Pelvic organ prolapse Lammers et al., 2012
Postural tachycardia syndrome Mathias et al., 2012
Psychological distress Baeza-Velasco et al., 2011
Rectal evacuatory dysfunction Mohammed et al., 2010
Somatosensory amplification Baeza-Velasco et al., 2011
Urinary stress incontinence Karan et al., 2004
Extra-articular disorders associated with joint hypermobility, adapted from Castori (2012).

Association with psychiatric disorder

Psychiatric phenomena are increasingly recognized as another important extra-articular manifestation of joint hypermobility.

This means that I have pain not because I’m crazy, but that I’m crazy from my pain.

Bulbena et al. reported the first association between joint hypermobility and anxiety disorder in rheumatology patients in a case-control study (Bulbena et al., 1993), the overrepresentation of hypermobility in anxiety disorder patients was subsequently confirmed in later studies (e.g., Bulbena et al., 1996; Martin-Santos et al., 1998). 

Further studies have consistently demonstrated this association in non-clinical populations (e.g., Bulbena et al., 2004a,b) and in a large general population cohort (Bulbena et al., 2011). 

This association with anxiety is consistently replicated over the years (Bulbena et al., 1993; Garcia Campayo et al., 2010; Bulbena et al., 2011; Sanches et al., 2012).

A recent meta-analysis of 3597 subjects demonstrates consistently that in both healthy and clinical population’s hypermobile people experience significantly more intense fears, agoraphobia, panic, anxiety, and depressive disorders (Smith et al., 2014).

Additionally significantly higher rates of joint hypermobility can be observed among patients with Bipolar Disorder and Neurodevelopmental disorders, such as Attention Deficit Hyperactivity Disorder and Autism Spectrum Disorder Eccles et al., 2014a,b).

The underlying neurobiological mechanisms associating joint hypermobility with psychiatric disorders have not been studied in detail. However, brain and body are intrinsically and dynamically coupled; perceptions, emotions and cognitions respond to, and change, the state of the body.

These interactions form much of the content of psychophysiological research identifying bodily signatures of mental activity. The central interaction of processes supporting the generation and the representation of autonomically-mediated changes in visceral state may be the critical mediator of autonomic influences on cognition and emotion.

Where there is mismatch between intended and actual autonomic state, corrective efferent reactions are accompanied by interpretative processes.

The unconscious operation of autonomic nervous system can be interrupted by deviations from expected state, i.e., we become aware of our autonomic bodily state when we experience changes in internal state that are “unpredicted” by control centers (Seth et al., 2011; Critchley et al., 2013)

In disorders that typically involve impaired collagen (present in blood vessels) such as joint hypermobility and postural tachycardia syndrome it is likely that reduced venous return during standing due to venous pooling or denervation causing low plasma volume may be responsible for a an increased sympathetic state –as the body attempts to compensate for these abnormalities—resulting in orthostatic intolerance and associated symptoms. (Bohora, ; Benarroch, ; Mathias et al., )..

Thus, we postulate that a major factor is the dysregulation of the autonomic nervous system, which particularly drives the expression of anxiety, a pervasive symptom across almost all psychological disorders.

Evidence of autonomic dysfunction in Joint Hypermobility

Symptoms related to the autonomic nervous system, such as

  • syncope and presyncope,
  • orthostatic intolerance, palpitations,
  • chest discomfort,
  • fatigue, and
  • heat intolerance,

are significantly more common among hypermobile patients.

Patients with Joint Hypermobility Syndrome have a greater mean drop in systolic blood pressure during hyperventilation, and a greater increase in systolic blood pressure after a cold pressor test, than controls.

They also have evidence of heighted vasoconstriction mediated by alpha-adrenergic and beta-adrenergic hyper-responsiveness.

Symptoms suggestive of autonomic dysfunction are also more common in patient with Joint hypermobility Syndrome. These include including presyncope, palpitations and gastrointestinal disturbances (Hakim and Grahame, ). 

Measures of heart rate reactivity and reactions to the Valsalva maneuver, during autonomic functional testing also indicate autonomic dysregulation in Joint Hypermobility Syndrome patients compared to controls, including (De Wandele et al., ).

Overall, hypermobile patients had higher mean autonomic dysfunction and orthostatic intolerance than non-hypermobile patients.

Evidence of brain-body interactions from neuroimaging

Structural differences in key emotion processing brain regions, notably affecting the amygdala bilaterally, are observed in these otherwise healthy individuals.

The hypermobile group as a whole also display decreased anterior cingulate and left parietal cortical volume while the degree of hypermobility correlates negatively with both superior temporal and inferior parietal volume (Eccles et al., ).

In a recent functional neuroimaging study of healthy volunteers, hypermobile, compared to non-hypermobile, participants displayed heightened neural reactivity to sad and angry scenes within brain regions implicated in anxious feeling states, notably insular cortex (Mallorqui-Bague et al., 2014).


These data suggest that specific brain regions mediate the interaction between psychological processes and the physiological state of the body, in a manner ultimately crucial to the generation of anxiety and related symptoms in the joint hypermobility phenotype.

The amygdala is a key region supporting motivational behaviors and emotional memory; it is implicated in threat processing, generation of bodily arousal reactions and the expression of mood symptoms.

These neuroimaging data implicate the amygdala and insular cortices as the most likely neural substrate underlying the association between of hypermobility, clinical anxiety and psychosomatic disorders.

there is evidence to suggest that the autonomic nervous system is dysregulated in hypermobile individuals. Theoretically, anxiety is linked to the unpredictable states of bodily arousal, engaging regions such as amygdala and insula (Paulus and Stein, 2006).

Hypermobility syndrome is associated with pain syndromes such as fibromyalgia, irritable bowel syndrome and chronic regional pain syndrome. Differences in amygdala reactivity are also reported for these (Tracey and Bushnell, ).

Moreover, there is evidence to suggest that the autonomic nervous system is dysregulated in hypermobile individuals.

Theoretically, anxiety is linked to the unpredictable states of bodily arousal, engaging regions such as amygdala and insula (Paulus and Stein, ).

Observed differences in dorsal right anterior cingulate cortex were also observed. This region is implicated in autonomic reactivity, and engaged in the cognitive control of pain and negative feeling states (Critchley, ; Tracey and Bushnell, ).

Hypermobility was also linked to reduced right superior temporal volume. Right superior temporal cortex supports the sensory processing of social emotional information and structural abnormalities of this region are observed in autism (Boddaert et al., 2004), where neurodevelopmental emotional deficits are frequently accompanied by heightened anxiety

Patients with joint hypermobility show heightened interoceptive sensibility compared to those without (Eccles et al., ) and interoceptive sensitivity has been show to mediate the relationship between state anxiety and hypermobility and it could be hypothesized combining functional neuroimaging with autonomic monitoring will show that inefficient neural co-ordination of efferent autonomic drive with imprecise interoceptive representations may be amplified in hypermobile individuals.  

The article continues with the same kind of writeup for two other autonomic disorders: Postural Tachycardia Syndrome and Vasovagal Syncope.


Together these data argue for the recognition of neurovisceral phenotypes that underlie constitutional predisposition to affective symptoms and that reflect the interaction and emergence of affective feelings with representations and control of bodily arousal.

There is circumstantial evidence for a genetic basis to some neurovisceral phenotypes, such as in relation to certain collagen disorders.

Neuroimaging techniques, particularly when combined with physiological measurement, have the potential to dissect brain mechanisms mediating the interplay between physiological control and psychological response to emotion.

Data in neurovisceral phenotype models implicate a discrete set of brain regions that include the amygdala, cingulate and insula cortex along with specific levels of the brainstem, basal ganglia and ventromedial prefrontal cortex.

Further work is needed to extend what is already known regarding the distinct and overlapping contribution of these regions to subjective feelings of anxiety, perception and misperception of bodily arousal, generation of stereotyped patterns of affective reactions (faints, tachycardia, sweating and hyperventilation).

A detailed understanding of these processes in clinical and non-clinical groups, alongside greater clinical recognition of neurovisceral phenotypes and their expression across neuropsychiatric disorders, will inform the innovative development of pharmacological and biobehavioral interventions for the management of psychosomatic symptoms, panic and anxiety states.

Another article in this journal “Frontiers of Neuroscience” also explores the link between neurological and neuropsychiatric disorders:

Potential interactions between the autonomic nervous system and higher level functions in neurological and neuropsychiatric conditions

In this review, we will discuss potential relationships between ANS and higher level dysfunctions in a selection of neurological and neuropsychiatric disorders.

From all this information, I’ve come to believe that mental instability (anxiety, depression, bipolar, etc.) is the neurological manifestation of physical instability (hypermobile, EDS).


2 thoughts on “Neurovisceral expression of psychiatric symptoms

  1. canarensis

    Huh, interesting. It’s becoming ever clearer (tho the simple-minded types refuse to let such complex ideas in) that the brain & body & behavior are a lot more interactive & affect each other. I was talking to someone the other day about the fox domestication experiment in Russia, where they chose fox kits to breed based solely upon their temperaments, & within 10 years ended up not only with domestic foxes that were basically dogs, but who had numerous physical changes as well, though physical traits were no part of the selection process; they just happened with the behavioral trait selection.

    Physiology is one heckuva lot more complicated than anyone ever imagined, & this piece on EDS & neuro/emotional links is a vivid example. And further evidence that anything that helps individuals with complex conditions should be allowed…it’s beyond asinine to base dosages or anything else based on a non-existent “average/normal” person.

    Liked by 1 person

    1. Zyp Czyk Post author

      I read about that project too and was amazed how quickly it happened. Later I found this clever 3-minute explanation of how dogs’ temperament is genetically intertwined with certain physical traits:

      Why do domesticated animals tend to have floppy ears, short snouts and lighter skin?

      You can apparently learn quite a bit about an individual just from their appearance, so it makes sense that we have a tendency to “judge a book by its cover”.



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