Neuroplasticity and phantom limb

Abstract

In recent decades, the concept of neuroplasticity has taken clear relevance associated with the patient's health and learning and behavior in the healthy individual. This ability of the nervous system involves assimilation, reorganization and modification of our biological mechanism, biochemical and physiological. With the advent of new scientific technologies that have appeared in recent years, we respond and maintain this concept of plasticity of the nervous system as a basic premise of being susceptible to external changes and dynamic. The phantom limb experience exposes permanently, the existence of an underlying mental body map and modifies the experience with our body, whose nervous system has the ability of cortical reorganization by sensory stimulation, sensory, endocrine and motor. The relationship between phantom and neuroplasticity is complex, difficult to investigate despite scientific breakthroughs, yet is dynamic, and that this capacity meets the needs of human health at different stages of his life.

Full text

Neuroplasticity
and phantom limb
Author: Rosmari de la Puerta Huertas
December- 2014
Published by the Revista de la Sociedad Española del Dolor
[Spanish Pain Society Journal] – 2014; 21(6): 345-350
ABSTRACT
In recent decades, the concept of neuroplasticity has taken clear relevance
associated with the patient’s health and learning and behavior in the healthy
individual. This ability of the nervous system involves assimilation, reorganization
and modification of our biological mechanism, biochemical and physiological. With
the advent of new scientific technologies that have appeared in recent years, we
respond and maintain this concept of plasticity of the nervous system as a basic
premise of being susceptible to external changes and dynamic. The phantom limb
experience exposes permanently, the existence of an underlying mental body map
and modifies the experience with our body, whose nervous system has the ability of
cortical reorganization by sensory stimulation, sensory, endocrine and motor. The
relationship between phantom and neuroplasticity is complex, difficult to investigate
despite scientific breakthroughs, yet is dynamic, and that this capacity meets the
needs of human health at different stages of his life.
Key words: Neuroplasticity. Pain. Phantom limb. Neuromodulation.

INTRODUCTION
Structural and functional plasticity are well known properties of the nervous system
that occur after drastic injury, such as the loss of a body part.
Plastic changes take place centrally when a person is learning a new skill, recovering
from an injury or taking part in an intervention programme. This neuroplasticity that
takes place in the brain has been intensely studied in animals, but is not easily
accessed in humans unless there are valid therapeutic reasons to apply invasive
research methods. This hinders our search for information. Moreover, animal models
do not provide information about higher mental functions such as language or
music.1
Previous studies suggest that limb amputation or deafferentation induce functional
changes in cortical area S1 (location and discrimination of sensation and pain) and
M1 (motor cortex) related to phantom limb (PL) pain. Several studies show a
functional remapping of area S1 in lower limb amputees. Nevertheless, unlike
previous studies, neuroplastic changes do not seem to depend strictly on phantom
limb pain, because these changes also occur in subjects who reported phantom limb
sensation without pain.2
New studies about cortical changes have led to a re-evaluation of the conditions that
manifest with chronic pain and their treatments. PL pain syndrome (PLPS) has been
reproposed as a central nervous system dysfunction.3
Neuroplasticity occurs on several levels. Decades of research have shown that it
produces substantial changes in the lowest areas of neocortical processing and that
these changes can profoundly alter neural activation patterns in response to
experience.4
The changes produced by neural plasticity culminate in:
 The activation of new brain regions (re-wiring or re-routing).
 CNS remapping:
a) With changes in neural representation that may occur as a response to
environmental demands.
b) Extension of the response area has been demonstrated in the human
somatosensory cortex.
c) Dynamic changes may materialise into long-lasting changes induced by
plasticity induced by learning.5

BODY SCHEME
Body schema tends to be identified with the concept of body image, but sometimes
there is a distinction between the two terms, where "body image" refers to a
conscious representation of the body and "body scheme" to an unconscious
representation.
Occasionally, "body image" is identified with the conceptual and verbalisable
representation of our own body. Finally, we cannot ignore that "body image" is
impregnated with cultural connotations and subject to transmutation regarding the
way the term is used in a given era. In any case, these terms have been used
indistinctly.
The representation of our own body, necessary for our interaction with the
environment, is based on three interdependent systems6:
1- Body consciousness through tactile, vestibular, kinaesthetic and visual
afferents and the senses which provide us with information that, when integrated and
processed, affords awareness about body position and shape.
Moreover, in the absence of these afferents we have a "feeling" about the
position of body parts (we can point to the tip of our nose without hesitating). This
basic awareness about the limits and arrangement of our own body is known as
"body schema".7
2- General awareness about our body and its parts. This awareness can be
divided into different categories:
 A lexical and semantic awareness that defines the names,
categories and function of each body part.
 A topographical awareness of the spatial distribution of body
parts. This awareness provides information about the position of
each specific body part, where they are in relation to each other
and the limits of each one.7
3- The information we have about the current situation and shape of our
body (body direction and space) is the reference we need to plan and execute
movements directed at external objects (peripersonal space and extrapersonal
space).8
An alteration in one’s own perception of body schema could give rise to the
experience of phantom limb or hemispatial neglect.

NEUROPLASTICITY
Neuroplasticity is considered to be the capacity of neural tissue to reorganise,
assimilate and modify the biological, biochemical and physiological mechanisms
involved in intracellular communication, to adapt oneself after receiving stimuli.
This characteristic involves modifications to neural tissue, including axonal
regeneration, collateral sprouting, neurogenesis, synaptogenesis and functional
reorganisation.9
This process reveals the nervous system's susceptibility to physiological changes.
These changes are a dynamic process that lasts throughout life.4
PHANTOM LIMB PHENOMENOLOGY
PL was described centuries ago by Paré, Descartes and Von Haller. The oldest
systematic studies on this disorder were conducted by Gueniot in 1861, Weir
Mitchell in 1872, Charcot in 1892, Abbatucci in 1894, Pitres in 1897, Head and
Holmes in 1911 and Pick in 1915.
The experience of phantom limb is a clear argument in favour of the existence of an
underlying mental body schema that modifies our experience with our own body.10
The experience of PL does not only occur after the loss of extremities, but also after
the loss of other organs such as the eyes, teeth, external genitals or breasts. However,
the resection of an internal organ does not cause the PL phenomenon.
After amputation, it is common for up to 90% of patients to continue perceiving the
lost limb. Notwithstanding, this sensation normally disappears over time. When it
persists, it reappears intermittently under certain circumstances. It occurs less often
in cases of mental retardation and situations of stress.
In the description of PL it is important to distinguish between two groups of
alterations:
1. Firstly, there is the experience of PL as a perception of the amputated limb in
reference to its spatial characteristics. This constitutes the persistence of
mental body schema.
2. Secondly, unlike the above, there are the sensations perceived (thalamus) by
the PL (paraesthesia, pain, sensation of heaviness, heat, cold, cramps, etc.)

This distinction between the phenomenon of phantom limb in of itself and the
sensations perceived by the limb is essential because their pathogenesis is diverse,
and because they are experienced differently by the patient.
The phenomenon of PL is part of the normal integral experience of one's own
corporeality.
Stetter established the following distinction11:
"Phantom sensations have characteristics of sensations, while the phantom
experience is an experience of totality".
The limb is composed of somestesic components. All somestesic information
referring to the perception of size, length, weight, position and movement are
present.
Paresthesia is the most common. It occurs immediately after the amputation and is
most acute in the distal parts.
Phantom Limb without Amputation
The perception of phantom limb may occur not only after amputation, but also when
the sensory afferent pathways of the limb are damaged, a in the case of peripheral
neuropathy, plexopathy, medullary lesion and subcortical brain damage. In
these cases the deafferented limb may be experienced as an additional limb. The
sensation of PL may also occur as a temporary experience of epileptic origin. The
experience of additional or third limb PL is sometimes incapacitating and
permanent, especially in medullary lesions.
In these patients, the experience of PL may be associated with the sensation of
micturition, defecation or paraesthesia. PL after medullary lesions may not be subject
to telescoping (described by Gueniot in 1861: the PL gradually decreases in size and
becomes less defined, and the distal portion that remains stable finally withdraws
toward or into the stump).11
NEUROANATOMICAL BASES
After the amputation of a limb or the loss of its afferent pathways, there is a
remodification of the topographic representation which occurs at a parietal level, in
the primary somatosensory cortex (S1), and there is a transition from the area
dedicated to the amputated limb toward an adjacent area of the Penfield

homunculus.12
When afferent nerves are cut as a result of limb amputation, a series of anatomical
and physiological changes occur affecting not only the axons of primary sensory
neurons, but also the parts removed from these, such as somas and synapses in the
spinal cord dorsal horn.
It is known that nerve transmission of somatic sensations is mentally produced by A-
beta, A-delta and C fibres. A-beta fibres are insulated with myelin associated with
highly-specialised peripheral mechanoreceptors. A-delta and C fibres respond to
highly intense stimuli and their activation generates a painful sensation. It has been
hypothesised that in a chronic state of pain a change likely occurs in A-beta fibre
excitability, causing a pain response to low intensity stimuli (Treede, 1992; Wolf and
Doubelll, 1994).13 This could be considered an error in the neural representational
plasticity process of the cerebral cortex. However, the experience of PL may persist
even when there is no tactile stimulation of adjacent skin areas (where the
topographic representation of the amputated limb may have been transferred to), and
therefore it seems doubtful that the neurological substrate of this alteration isn’t in
the primary sensory cortex itself.
It has been described that some patients with posterior parietal lobe damage and
preserved primary sensory cortex have lost the perception of contralateral PL. Thus,
there must be association area integrity in the contralateral posterior parietal lobe for
the disorder to exist.
No cases have been described in patients with this alteration when there is damage
located exclusively in the primary sensory cortex; it seems clear that this area must
also be preserved for the perception of PL.
There must be preservation of the primary sensory cortex in which an error in
topographic plasticity has occurred after the loss or deafferentation of a limb,
although this is not sufficient. Remodification in the representation of the different
body parts occurs erroneously.
Instead of eliminating the areas where the amputated limb is represented cortically,
they are preserved or are simply relocated. This results in an erroneous interpretation
of the information. This interpretation is carried out in the most posterior association
areas, in the parietal lobe where the supposed mental body schema is thought to
reside.
These studies show that the homuncular representation of the body surface in the

somatosensory cortex is subject to functional modifications when afferent nerves that
transmit somatosensory information from the periphery are cut. These alterations
only affect the cortical maps of the hemisphere in charge of processing
somatosensory information from the side of the body corresponding to the
amputation.
The perception of phantom limb proves the existence of a mental body schema that
persists even after losing its real correlation. Having demonstrated its existence, we
can now ask whether this mental body schema is innate or acquired.12
In favour of the argument that it is innate, we have the experience of PL in small
children with congenital limb absence. Nevertheless, the frequency of this alteration
of bodily perception is much lower the younger the subject who lose a limb. This
suggests that the perception of body schema becomes more intense and long-lasting
through the continual experience of one's own corporeality.
Girls do not have the experience of "phantom breasts" before they develop, which
also goes against the argument of the existence of an innate body scheme.
Similarly, as time passes after limb amputation the experience of PL disappears.6
It should be highlighted that neural plasticity enables reorganisation and/or
adaptation changes under normal or pathological conditions.
It is possible to induce neuroplasticity in humans by means of central deafferentation.
These interventions have led to advances in the understanding of plasticity in normal
individuals and even in pathological conditions, by studying their generation
mechanisms in motor, sensory and association areas.
NEUROMODULATION
In strict terms, the concept of neuromodulation refers to the capacity of neurons to
alter their electrical properties in response to biochemical changes resulting from
hormonal or synaptic stimulation.14
In recent years, it has been clearly demonstrated that pain includes peripheral and
central characteristics. Scientists now have good evidence of the cortical changes
produced when patients suffer from chronic pain.3
The modern concept of neuromodulation emerged around 1970, when Greenfield
stated that this process is "a variant response to an invariant stimulus", associating
this to electrical neural excitation processes.15

Over time, other authors have declared that this process is not only involved the
potential for action but that it includes the exchange of substances that seem to
exercise prolonged effects on neural excitability and the membrane.
Neuromodulation has been characterised by the application of electrotherapy and
more recently has included high and low density magnetic stimulation (MS),
somatosensory and somatoperceptual stimulation, electromagnetic neuronavigation
and even acupuncture.
Neuromodulation differs from the classic concept of nerve transmission. In the case
of the latter, the information received uses several neurotransmitters that move from
the presynaptic to the postsynaptic region, depolarising or hyperpolarising the latter,
producing an immediate effect that may last up to hundreds of milliseconds. It should
be clarified that neuromodulation of the postsynaptic region does not depend so
much on neurotransmitters but more on the receptors to which they bind, called
metabotropic receptors.16 Thus, while classic ionotropic receptors directly affect
permeability, metabotrophic receptors produce postsynaptic changes in neurons
through intracellular molecular activation, using "second messengers". Although
first messenger effects may be rapidly inactivated, second messenger effects may last
several days. Moreover, some proteins may affect the genome of a postsynaptic cell,
permanently altering its activity.16
CORTICAL REORGANISATION IN PL
Different hypotheses have been proposed, including that by Melzack (1999), by
which an innate network produces a single pattern of neural activity that represents
body scheme.
When information cannot be updated with this "wiring" it remains unchanged, even
after an amputation, generating conflicts in perception, thus arising in cases of PL
syndrome. (Doetsch 1997-Sirigu 2008).
Functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI)
have been combined to research cortical and corpus callosum plasticity in lower limb
amputees with "pain" or phantom sensations, to clarify whether plasticity phenomena
can be generalised beyond upper limb amputation with phantom pain and to check
whether they could be related to corpus callosum disorders.
It was found that the deafferented hemisphere shows an overlapping, expanded

representation of the stump (after stump simulation) and of the intact limb (after
stimulation). These structural changes occur in somatomotor sectors of the corpus
callosum.
Conventional MRI did not show abnormalities in the brains of amputees. However,
fMRI and DTI did reveal clear functional and white matter microstructural changes
in amputees. None of the patients reported pain during tactile stimulation on pre-
examination or interview.
In amputees, sensory stimulation of the stump resulted in activation of S1 and M1
contralateral to the amputation (deafferented hemisphere), in addition to the
supplementary motor area (M2). Other significant activation sites were the insula,
S2, thalamus and striatum in the hemisphere contralateral to the amputation.
According to the results of experiments conducted in upper limb amputees, there was
expanded representation of the stump in the deafferented cortex, in addition to
functional reorganisation in the "non-deafferented" hemisphere. In some patients
structural deformities of central sulcus and atrophic contralateral parietal lobe were
also found, suggesting bilateral and anatomical functional reorganisation.2
In many individuals, PL phenomena appear as early as 24 hours after traumatic
amputation, and may be related to the unmasking or reactivation of pre-existing
connections, leading to the suppression of local inhibition (Borsook 1998,
Ramanchadrán and Hirstein 1998; Werhahn 2002, Giummarra 2008).
On the other hand, sometimes weeks or months were necessary after amputation
before the onset of phantom sensations, including pain (Pascual Leone 1996).
Future studies directly comparing “painful” and “non-painful” cases will be needed
to explore the exact role and impact of phantom pain in somatosensory functional
and structural brain reorganization.
Ramachandrán and Hirstein (1998) proposed a multifactorial model to explain
phantom sensations, stating that they depend on integrating experiences of
reassignment and vivid somatic memories of the original limb and on genetically
determined internal body image.
Moreover, cross-referencing between phantom and intact limbs has recently gained
importance.2

Phantom Limb Pain
PL pain is one of the chronic pain syndromes that is difficult to treat. Treatment
options for PL are largely conditioned by the level of understanding of the
mechanisms and nature of PL. Results from research and clinical experience
recognise the neuropathic nature of PL and suggest that both central and peripheral
mechanisms may contribute to PL, including plasticity changes in the CNS.
Neuroimaging studies in PL have suggested a clear relationship between PL and
neuroplastic changes. Moreover, it has been demonstrated that pathological
neuroplastic changes could be reversed, and there is a relationship between an
improvement (reversal) in neuroplastic changes in PL and pain relief.
These findings have led to new neuromodulation treatments strategies, in addition to
the variety of approaches to PL treatments.
In general, the treatment options available for PL include: pharmacological
treatment, non-pharmacological non-invasive support strategies (e.g.:
neuromodulation by transcranial magnetic stimulation, visual feedback therapy,
transcutaneous electrical stimulation of the peripheral nerve, physical therapy,
reflexology or various psychotherapeutic approaches).
The capacity to induce cortical plasticity with non-invasive brain stimulation
techniques has provided new and exciting possibilities to examine the role of the
human cerebral cortex during a variety of behaviours. Moreover, importantly, the
induction of long-lasting changes on cortical excitability may, under certain
conditions, reversibly modify conduct and behaviour and interact with normal
learning.
The latest advances have shown that a multitude of determining factors may
influence the magnitude and direction of plasticity induced in the human brain. These
factors play an important role in explaining the known variability in individual
response. It is important to bear in mind that a number of these factors may interact,
such as: genetic profile, age, time of day (because of its relationship to cortisol), sex,
pharmacological influences, exercise/activity, motivation, etc., giving rise to a
complex multifactorial influence in the induction of neuroplasticity in both
therapeutic and healthy cases. All the above-mentioned determining factor are
considered to predict the best individual plasticity response in each case to improve
efficacy with a therapeutic purpose.17

NEUROREHABILITATION. CONCLUSIONS
Rehabilitation is the best known method to facilitate the expression of neural
plasticity. The scientific origins of neurological rehabilitation are relatively recent.
The pharmacological approach used by all biomedical disciplines has blurred and, on
occasions, the possibility of offering patients a scientifically-oriented neurological
rehabilitation programme has been erased from the mind of many health
professions.18
We must develop therapies in which the primary objective is to modify cortical map
alterations found in amputee patients.
This is currently possible thanks to the scientific advances made by several groups19
including those who have used new tools such as low and high intensity or direct
current magnetic stimulation (TMS),20 graded motor imagery (GMI) through mirror
neurons (MN)3 in patients with PL, among other scientific advances to prove that the
adult nervous system may experience somatosensory cortex reorganisation even at
an advanced age, something that was considered to be physiologically impossible
until recently.
It is important for neurorehabilitation to be holistic but individualised, inclusive and
participatory; it should generate independence, be applicable for life if needed; it
should always be suitable to the patient's needs and community-oriented.
This involves an interdisciplinary approach, carried out by a team with experience
in the area, integrated by professionals with different training and scientific
approaches, and indispensably led by a neurorehabilitation specialist.21
Theoretical and practical elements help to establish suitable sensory and motor
control in patients, with an aim to strengthen functional recovery and an
improvement in these individuals' quality of life, which is the primary objective. We
must guarantee that scientific advances are on the right track toward the future.
ABBREVIATIONS
 PL: phantom limb.
 PLPS: Phantom limb pain syndrome.
 fMRI: Functional magnetic resonance imaging

 DTI: diffusion tensor imaging.
 MN: Mirror neurons.
 TMS: Transcranial magnetic stimulation.
 GMI: Graded motor imagery
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