Medical Hypotheses 85 (2015) 819–824

Contents lists available at ScienceDirect

Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Measureable changes in the neuro-endocrinal mechanism following

spinal manipulation
Kesava Kovanur Sampath a,⇑, Ramakrishnan Mani a, James David Cotter b, Steve Tumilty a
a
Centre for Health, Activity, and Rehabilitation Research, School of Physiotherapy, University of Otago, New Zealand
b
School of Physical Education, Sport and Exercise Sciences, University of Otago, New Zealand

a r t i c l e i n f o a b s t r a c t

Article history: The autonomic nervous system and the hypothalamic–pituitary–adrenal axis have been shown to be dys-
Received 28 July 2015 functional in a number of chronic pain disorders. Spinal manipulation is a therapeutic technique used by
Accepted 3 October 2015 manual therapists, which may have widespread neuro-physiological effects. The autonomic nervous sys-
tem has been implicated to modulate these effects. A theory is proposed that spinal manipulation has the
potential to be used as a tool in restoring the autonomic nervous system balance. Further, it is also
hypothesised that through its anatomical and physiological connections, the autonomic nervous system
activity following a thoracic spinal manipulation may have an effect on the hypothalamic–pituitary–adre
nal axis and therefore pain and healing via modulation of endocrine and physiological processes. To sub-
stantiate our hypothesis we provide evidence from manual therapy studies, basic science and animal
studies. According to the proposed theory, there will be measurable changes in the neuro-endocrinal
mechanisms following a thoracic spinal manipulation. This has far-reaching implications for manual
therapy practice and research and in the integration of spinal manipulation in the treatment of a wide
array of disorders.
Ó 2015 Elsevier Ltd. All rights reserved.

Introduction
Spinal manipulation (SM) is a specific ‘hands-on’ clinical
approach used by a variety of health practitioners such as the
physiotherapists, chiropractors and osteopaths to treat musculo-
skeletal pain [1]. Initial theories to explain the physiological effects
of SM centred on the biomechanical paradigm [2] together with
the gate control theory [3]. However an increasing number of stud-
ies show that the effects of SM are beyond biomechanical changes
only [4]. This has led to the proposal of various neurophysiological
theories to explain the effects of SM [5–7]. According to the neuro-
physiological theory, SM has the potential to initiate a cascade of
neurophysiological responses in the peripheral and central nervous
system [5].
Inflammation is a normal response to disturbed homeostasis
caused by infection, injury or trauma and is associated with the
production of numerous pro-inflammatory and immune-
regulatory cytokines and neurotransmitters [8]. The production
of such mediators has been shown to increase in patients with
lower back pain [9]. Pain in turn triggers the activation of various
protective body reactions, mediated by the central nervous system
⇑ Corresponding author.
E-mail address: kesava.kovanur-sampath@otago.ac.nz (K. Kovanur Sampath).
(CNS). The control of inflammation and thereby the immune sys-
tem by the CNS implies that the CNS can assist tissue healing or
trigger the opposite [10].
There is a functional cross-talk or reciprocal communication
between the CNS and the immune system [11]. The afferent com-
munication occurs via primary afferent nociceptive neurons and by
cytokines secreted by immune cells in the inflamed tissues. The
efferent communication occurs via the peripheral ANS (mainly
sympathetic nervous system (SNS)) and neuroendocrine system
(example: hypothalamic–pituitary–adrenal (HPA) axis) [11]. Adre-
nal glucocorticoids, the end product of the HPA axis have long been
known for their anti-inflammatory and immunosuppressive effects
[12]. Evidence also indicates that catecholamine’s, the end prod-
ucts of the SNS, modulate several immune parameters [11,12]. In
summary, both acute and chronic inflammation is modulated by
the SNS and the HPA axis.
The modulatory effect of inflammation by the SNS may be of
special interest for manual therapists. This is because at least part
of the effects observed following SM may be due to change in the
activity of the SNS. Pioneering works of Irvin M Korr have not only
demonstrated the role of SNS as a mediator between somatic and
supportive process, but also how sustained sympathetic tone plays
a significant role in disease. Through various experiments, Korr fur-
ther showed changes in cutaneous patterns of sympathetic activity

http://dx.doi.org/10.1016/j.mehy.2015.10.003
0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.
820 K. Kovanur Sampath et al. / Medical Hypotheses 85 (2015) 819–824
in clinical abnormalities of the musculoskeletal system [13–18].
Therefore SNS changes following SM may have important implica-
tions. However, depending on the segment manipulated these
effects could vary. Specifically, cervical manipulation elicits a
parasympathetic response and a thoracic/lumbar SM elicits a sym-
pathetic response [19].
SM may also have an effect on the HPA axis [20]. Early works of
Andrew Taylor Still (founder of osteopathic medicine) and Daniel
Palmer (founder of chiropractic) have debated the potential role
of SM on endocrinal mechanisms and thereby various immune dis-
orders [21,22]. Although the influence of SM on the transmission
and transduction of pain stimulus has been well understood
[5,23]; the mechanism through which SM influences tissue healing
through reduction of inflammatory response is still unclear. There-
fore a hypothesis is proposed that takes into account the auto-
nomic effects following SM and the sequential effect it may have
on tissue healing via co-activation of endocrine systems.
The hypothesis
Null hypothesis: A thoracic SM will not result in measureable
changes in the neuro-endocrinal system response.
Alternate hypothesis: A thoracic SM will result in measureable
changes in the neuro-endocrinal system response.
Evaluation of the hypothesis
The hypothesis is proposed based on the following. Anatomi-
cally the ganglion of the sympathetic nervous system lies just ante-
rior to the costovertebral joint of the thoracic spine. Thoracic SM
may therefore result in direct or indirect excitation of pregan-
glionic sympathetic cells in the thoracolumbar spine. Further, the
transduction of mechanical input (SM) excites various mechanore-
ceptors. The volley of innocuous stimuli then travels up from the
dorsal horn to several regions of the brain stem including the cen-
tral nucleus of amygdala (CeNa), the paraventricular nucleus
(PVN), rostral ventrolateral medulla (RVM), periaqueductal grey
matter (PAG), autonomic and endocrine centres.
Of particular importance is the PAG in the midbrain. The PAG
then initiates a flight-or-flight response characterised by sympa-
thetic activation. This activation is also associated with opioid-
independent analgesia. Corticotropin-releasing hormone (CRH)
neurons present in the CeNa and the PVN would then modulate
the ANS and HPA axis response. Therefore, it can be argued that
spinal manipulation would also result in co-activation of both
the systems namely the ANS and endocrine systems (HPA axis).
The end products of these two systems (Catecholamine’s and glu-
cocorticoids) would then modulate inflammatory response and tis-
sue healing.
To substantiate our hypothesis we provide a brief summary of
pain-autonomic interaction, evidence from manual therapy studies
that have explored the influence of spinal manipulation on the
supraspinal structures, ANS and endocrinal biomarkers. We also
discuss findings from basic science and animal studies that provide
the link between the ANS and the HPA axis.
Pain-autonomic interaction
A significant factor that underpins the neurophysiological
model is the interaction between the nociceptive (pain) system
and the ANS. Evidence indicates multiple levels of interaction
between the pain system and the ANS [24]. These areas include
the periphery, dorsal horn of spinal cord, brain stem and fore brain.
For a comprehensive review of pain-autonomic interaction please
refer [24]. A summary has been provided here. Lamina I neurons
of the dorsal horn project to several regions of the brain stem
involved in autonomic, endocrine and antinociceptive control.
These include the noradregenic A1 (caudal ventrolateral medulla),
A5 (ventrolateral pons) and A7 (dorsolateral pons) groups, and to
the adrenergic C1 group in the RVM, PAG, nucleus of the solitary
tract (NTS) and the parabrachial nucleus (PBN) [24]. The PAG is
heavily interconnected with the hypothalamus and limbic fore-
brain structures including the amygdala. The PAG projects to the
RVM, which in turn sends its output to the dorsal horn. Together,
the PAG-RVM system has been recognised as the central site of
action of analgesic agents including opioids, cyclooxygenase inhi-
bitors and cannabinoids [25].
Effects of spinal manipulation on the ANS
The effects of spinal manipulation on various functions of the
ANS (Fig. 1) have been well identified in manual therapy literature
[26,27]. The common physiological mechanism proposed for these
ANS changes involves possible influence on segmental and extra-
segmental reflexes with a prominent role given to the peripheral
sympathetic nervous system (PSNS) [5,28]. Skin blood flow (SBF)
indexes have been used as an outcome measure to record PSNS
changes following spinal manipulation [29]. SBF changes are usu-
ally assessed through skin temperature, skin conductance, plethys-
mography, and laser Doppler flowmetry [30]. Blood pressure
changes as indicators of ANS function have also been reported
[19,31]. In one study, pupillary reflex was used as a marker of
ANS activity [32]. Heart rate variability (HRV) represents a valid
and reliable non-invasive marker that reflects the sympathetic
and para-sympathetic components of the ANS [33].
A few studies have examined the role of SM in influencing the
HRV. In a crossover controlled trial conducted on 28 healthy indi-
viduals, Budgell and Polus [27] investigated the effects of thoracic
SM on HRV. Thoracic SM had a significant effect on HRV in favour
of the sympathetic component, which was not evident in the sham
procedure [27]. Contrary results were reported by Zhang et al. [34].
Those authors conducted a multi-site study, collecting data from a
total of 96 participating chiropractors. Healthy subjects were
recruited for the study and their HRV measured at two different
time points (after a single visit and after 4 weeks). The authors
reported an increase in HRV following a thoracic SM suggesting a
dominance of the para-sympathetic system [34]. Welch and Boone
[19] used a pre-post study design and demonstrated that based
upon the area of spine manipulated the response of the ANS will
vary. Specifically, cervical manipulation elicits a parasympathetic
response and a thoracic/lumbar SM elicits a sympathetic response
[19]. In summary, it is evident that SM has an effect on the ANS
though the direction of effect may vary.
Effects of spinal manipulation on supraspinal structures – evidence
from imaging studies
Two imaging studies have demonstrated the influence of SM on
the supraspinal mechanisms [35,36] (Fig. 2). A chiropractic study
[35] investigated the status of regional brain activity immediately
after a cervical SM. In a cross-over trial, 12 men with neck pain and
shoulder stiffness were assigned to the treatment and the resting
conditions. Positron Emission Tomography (PET) was used in the
study to examine the regional cerebral metabolism. The research-
ers noted significant changes in the cerebellar vermis, which was
deactivated in the treatment condition compared to the resting
condition. The cerebellar vermis is concerned with mental stress
and is also involved with the ANS [37,38]. Removal of cerebellum
impairs performance of autonomic functions including salivary,
cardiac and respiratory conditioning [39]. Further, other areas of
the brain such as the anterior cingulate cortex, inferior prefrontal
 K. Kovanur Sampath et al. / Medical Hypotheses 85 (2015) 819–824 821

Fig. 1. Effects of spinal manipulation on the ANS. ANS – autonomic nervous system; BP – blood pressure; HRV – heart rate variability; and TSM – thoracic spinal
manipulation.

Fig. 2. Effects of spinal manipulation on supraspinal structures. ACC – anterior cingulate cortex; ANS – autonomic nervous system; AP – action potential; PAG –
periaqueductal grey; PFC – prefrontal cortex; PPC – post parietal cortex; S1 – primary somatosensory cortex; S2 – secondary somatosensory cortex; and SMA –
supplementary motor area.
822 K. Kovanur Sampath et al. / Medical Hypotheses 85 (2015) 819–824
cortex, and middle temporal gyrus were also activated in the treat-
ment condition compared to the resting condition. All these areas
of the brain are involved in the generation of autonomic responses
[40]. Hence the authors argued that activation of the anterior cin-
gulate cortex combined with deactivation of the cerebellar vermis
resulted in reduced sympathetic tone and pain levels.
Recently, another imaging study [36] investigated if supraspinal
activation in response to noxious stimuli varied pre- and post-
thrust manipulation to the thoracic spine. Using functional mag-
netic resonance imaging (fMRI), the researchers imaged various
areas of the brain during a thoracic spinal manipulation. The
results of the study revealed significant reduction of activation in
the insular cortex and anterior cingulate cortex. The reduction in
activation of insular cortex was correlated with a significant reduc-
tion in subjects’ perception of pain. The insular cortex and the
anterior cingulate cortex are both engaged in pain processing and
both participate in high-level control of autonomic function
[40,41]. Although these two areas are interconnected, they operate
independently and analyse different components of pain sensation.
Insular cortex, as part of the limbic system is involved in detect-
ing saliency of sensory information, memory and pain perception,
and in selective transmission of this information to other areas
within the pain matrix [42]. Through its projections to many com-
ponents of the central autonomic network; stimulation of insular
cortex elicits changes in all autonomic functions [42]. The primary
function of anterior cingulate cortex is to predict and avoid noxious
stimuli. Further, the PAG of the brain has been suggested to be
involved in manipulation-induced hypoalgesia [43]. The PAG is
an important structure that is associated with behavioural
responses to threat, stress and pain. Stimulation of the PAG pro-
duces a profound and selective analgesia [44]. Moreover, depend-
ing on which column (lateral or medial) is activated,
sympathoexcitation or sympathoinhibition may be produced
[45]. Taken together, the evidence clearly points out that spinal
manipulation will have an effect (excitatory or inhibitory) on the
ANS.
Co-activation of the neuro-endocrinal systems
From the evidence presented above it is clear that spinal manip-
ulation may have an effect on the supraspinal mechanisms con-
cerned with the generation of ANS response. We propose that
this ANS response will be associated with HPA axis response.
Ongoing functional studies suggest that these two physiological
systems work together, both in terms of overlap in the underlying
neural circuitry and in terms of their physiological functions [12].
For example, CRH receptors are found in the hypothalamus, amyg-
dala, hippocampus, locus coeruleus, PBN, prefrontal cortex and
anterior cingulate gyrus. The presence of CRH receptors in the LC
and other areas such as the cingulate cortex is indicative of its role
in generating as well as mediating the autonomic response [46].
Functionally, the CRH and LC systems seem to participate in a pos-
itive feedback loop so that activation of one system tends to acti-
vate the other. Hence activation of CRH may also activate the
noradrenergic neurons in the LC resulting in sympathetic activa-
tion mediated via CRH-1 receptors [47]. However, glucocorticos-
teroid (cortisol) seem to exert inhibitory effect on nor-
epinephrine release and sympathetic activation. For example, a
week treatment with 20 mg prednisone reduced SNS activity and
plasma nor-epinephrine levels in healthy subjects [47].
The adrenal glands (medulla and cortex) represent another area
of integration between the sympathetic nervous system and the
HPA axis. Through a series of experiments conducted in rats, Janig
and Green [10] investigated the co-ordination and integration of
the neuroendocrine, sympathetic and the central nervous system
in acute experimental inflammatory model. The study demon-
strated that an acute inflammatory response is controlled by both
the HPA system and the sympatho-adrenal system [10]. Animal
models further demonstrate that adrenal medullary function may
be modulated by somatic stimulation (both nociceptive and
innocuous) [48–51]. This may imply that PSNS response following
a somatic stimulation (Ex: thoracic SM) may influence the activity
of the adrenal medulla. This in turn may result in the release of cat-
echolamine such as epinephrine. Although evidence of SM on
endocrinal function in humans is still contradictory [52–54], it is
reasonable to propose that somatic stimulation (thoracic SM)
might result in changes in the function of HPA axis modulated
via the ANS (Fig. 3).
Discussion
We proposed that a SM of the thoracic spine in humans will be
associated with a neuro-endocrinal response. Substantial evidence
has demonstrated the neurophysiological effects of SM
[7,34,55,56], with a prominent role given to the SNS [5,28]. Recent
systematic reviews further confirm the short-term sympatheto-
excitatory effects associated with SM [29,57]. These SNS changes
following SM may also be associated with changes in supraspinal
mechanisms that control pain. Supraspinal structures such as the
anterior cingular cortex, amygdala, PAG, RVM and cerebellar ver-
mis have been implicated in manipulation induced analgesia and
concurrent autonomic effects [58].
Our hypothesis is in agreement with a comprehensive model
proposed by Bialosky et al. [5]. They argued that while a mechan-
ical input is essential to initiate a physiological response; multiple
mechanisms may be involved in producing the neurophysiological
changes. However, it is to be noted that the comprehensive model
assumes that the neurophysiological responses following joint
based or soft tissue based or nerve based MT will be similar. There-
fore, the utility of the comprehensive model to joint based MT
alone (Ex: SM) is unclear. This becomes highly relevant considering
that different techniques (joint based vs soft tissue based) on dif-
ferent regions (cervical or thoracic or lumbar) of the body may pro-
duce different effects [52]. For example Stimulation of
mechanoreceptors, although manipulation and mobilisation are
joint-based MT, they may stimulate different sensory receptors
and produce different outcomes [59]. A very recent study further
demonstrated that pain-related neuronal responses can be differ-
entially influenced by bottom-up and top-down-mediated modu-
lations of pain [60]. Taken together these findings indicate that
the origin of stimulation, whether soft tissue based or joint based
(mobilisation or manipulation) may be important to determine
the nature of outcome.
Future implications and conclusion
The ANS and the HPA axis are commonly involved in various
chronic pain syndromes. These clinical disorders include chronic
fatigue syndrome [61], fibromyalgia, auto-immune diseases [62];
diabetes [63], gastro-intestinal disorders [64]; cardiovascular
problems [65]; and asthma [66]. An important strategy in manag-
ing these syndromes is to identify effective treatments that target
multiple key mechanisms involved in pain [67]. Therefore the
neuro-endocrinal mechanisms could be such targets of interests.
Further, these chronic pain syndromes are characterised by
increased SNS activity and increased HPA axis activity [68]. Hence
restoring ANS balance can be considered as a valid strategy in
treating these clinical disorders. In this context, thoracic SM has
the potential to be used as a tool in restoring ANS balance. Balanc-
ing the ANS in turn may help rectify HPA axis dysfunction com-
monly associated with ANS dysfunction. Taken together, a
 K. Kovanur Sampath et al. / Medical Hypotheses 85 (2015) 819–824
Fig. 3. Effects of spinal manipulation on neuro-endocrinal mechanisms. ACTH – adrenocorticotropic hormone; ANS – autonomic nervous system; CRH – corticotropin
releasing hormone; HPA – hypothalamic–pituitary–adrenal; SNS – sympathetic nervous system; and TSM – thoracic spinal manipulation.
thoracic SM has the potential to be used as a viable treatment
option in a multitude of clinical problems characterised by ANS
and HPA axis dysfunctions.
Conflict of interest
None.
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