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J Neuro Res. 2020;00:1–25. wileyonlinelibrary.com/journal/jnr
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1© 2020 Wiley Periodicals, Inc.
Received: 12 Augus t 2019
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Revised: 9 De cember 2019
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Accepted: 10 December 2 019
DOI: 10.1002 /jnr.24579
REVIEW
Mirror neurons and their relationship with
neurodegenerative disorders
Elisabetta Farina1 | Francesca Borgnis1 | Thierry Pozzo2,3
This wor k has been realize d for the PhD of Elis abetta Farin a at the Uni versité Bourg ogne Fra nche- Comté.
Edited by E ric Pra ger. Reviewed by Pante leimon Gianna kopoulos and Om er Linkovski.
The pee r review histor y for this arti cle is available at h ttps ://publo ns.c om/publo n/10.1002/jnr.24579 .
Abbreviations: ACE, acti on compa tibili ty effect; A D, Alzheimer' s diseas e; AOT, a ction obser vation train ing; BDNF, brain-d erived neurot rophic facto r; bvFTD, behav ioral variant o f
frontot emporal deme ntia; CBD, cort icobas al degenerati on; DBS, deep br ain stimulati on; DLB, dement ia with lewy bo dy; EEG, elect roencephalo graphy; fMRI , functional m agnetic
resona nce imaging; Fo G, freezing of g ait; F TD, front otemporal dem entia; IFG, infe rior frontal g yrus; IPL, in ferior pariet al lobule; MCI , mild cognitive i mpairment; ME P, moto r evoked
potent ials; MI , motor imagery ; MNs, mirror ne urons; MotND, mot oneuron disea se; PD, Parkinso n's disease; PDD, Pa rkinson's dise ase dementia; P ET, positi on emission tom ograp hy;
REM, ra pid eye movement s; RME, reading t he mind in the eyes t est; TMS, tra nscranial mag netic stimul ation.
1IRCCS Fondazione Don Carlo Gnocchi,
Milan, Italy
2INSERM UMR1093-C APS, U niversité
Bourgogne Franche-Comté, Dijon, France
3IT@UniFe Center for Translational
Neurophysiology, Istit uto Italiano di
Tecnologia , Ferrara, Ita ly
Correspondence
Elisabetta Far ina, IRCCS Fondazione Don
Carlo G nocchi, Via Capecelatro 66, Milan
20148, Ita ly.
Email: efarina@dongnocchi.it
Abstract
The finding of mirror neurons (MNs) has provided a biological substrate to a new con-
cept of cognition, relating data on actions and perceptions not only to integrate per-
ception in action planning and execution but also as a neural mechanism supporting
a wide range of cognitive functions. Here we first summarize data on MN localization
and role in primates, then we report findings in normal human subjects: functional
magnetic resonance imaging and neurophysiological studies sustain that MNs have a
role in motor learning and recognizing actions and intentions of others, and they also
support an embodied view of language, empathy, and memory. Then, we detail the
results of literature searching on MNs and embodied cognition in Parkinson's disease
(PD), frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS), and in mild
cognitive impairment (MCI)/Alzheimer's disease (AD). In PD the network of MN could
be altered, but its hyperactivation might support motor and cognitive performances
at least in early stages. In the ALS/FTD continuum, preliminary evidence points out
to an involvement of the MN network, which could explain language and inter-sub-
jectivity deficits shown in patients affected by these clinical entities. In the MCI/
AD spectrum, a few recent studies suggest a possible progressive involvement from
posterior to anterior areas of the MN network, with the brain putting in place com-
pensatory mechanisms in early stages. Reinterpreting neurodegenerative diseases at
the light of the new views about brain organization stemming from the discovery of
MN could help to better comprehend clinical manifestations and open new pathways
to rehabilitation.
KEY WORDS
Alzheimer's disease, amyotrophic lateral sclerosis, embodied cognition, frontotemporal
dementia, mirror neurons, Parkinson's disease
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FARINA et A l.
1 | INTRODUCTION
Th e con cept of “em b odi e d cog nit i on” cons ide r s that the cl a ssi c al pe r-
ception-cognition-action architecture proposing a sequential flow of
processing with clean cuts between all modules is not appropriate
to understand the behavioral effect of neurodegenerative disorders
and to find innovative therapeutic solutions. In the last decades, the
discovery of mirror neurons (MNs) has provided a biological frame
to this theoretical perspective; MNs are now thought to associate
information about actions and perceptions to both integrate per-
ception in action planning and execution and as a neural mechanism
supporting a wide range of cognitive functions, for example empathy
and language. At the same time, it is now clear that in each neuro-
degenerative disease both cognitive and motor symptoms are rep-
resented along a continuum. The main purpose of this review is to
investigate the integrity of the MN network in neurodegenerative
diseases such as Parkinson's disease (PD)/dementia with lewy bodies
(DLB), frontotemporal dementia (FTD)/amyotrophic lateral sclerosis
(ALS), and the mild cognitive impairment (MCI)/Alzheimer's disease
(AD) spectrum. Describing the functional state of the MN network in
neurodegenerative diseases would provide us with a better compre-
hension of pathophysiological mechanisms and symptoms of these
diseases. It would also enable us to capitalize on these kinds of neu-
rons in the rehabilitation of motor and cognitive manifestations.
2 | MIRROR NEURONS
MNs represent a groundbreaking discovery in the field of neurosci-
ence. They are a special population of neurons that discharge both
when a subject accomplishes an action and when she/he watches
another subject performing the same or a similar action.
2.1 | Mirror neurons: Research from primates
MNs were originally discovered in monkey's brain through single
neurons recording in the ventral premotor area F5 (and above all its
F5c cytoarchitectural area) and in the inferior parietal lobule (IPL) (di
Pellegrino, Fadiga, Fogassi, Gallese, & Rizzolatti, 1992; Rizzolatti &
Fogassi, 2014). In area F5, besides purely motor neurons, research-
ers found two categories of visuomotor neurons, namely “canonical
neurons” (which respond to the vision of three-dimensional items;
Fadiga, Fogassi, Pavesi & Rizzolatti, 1995) and “mirror neurons.” MNs
discharge when the subjec t views motor acts performed by other
individuals (Gallese, Fadiga, Fogassi, & Rizzolatti, 1996; Rizzolatti,
Fadiga, Gallese, & Fogassi, 1996). In particular, monkey's MNs have
showed to discharge to the observation and execution of hand ac-
tions (e.g., grasping, locating, manipulating with the fingers, and
clutching) and mouth actions (e.g., eating-related gestures such as
breaking food items, chewing, and sucking, and communicative ges-
tures such as lip-smacking or protrusion and tongue-protrusion; di
Pellegrino et al., 1992; Ferrari, Gallese, Rizzolatti, & Fogassi, 2003;
Gallese et al., 1996). Even if initially F5 MN did not appear to react
if the same action (e.g., grasping) was performed with a tool, more
recent data indicate that af ter a protracted visual exposure of the
monkey to motor acts performed with a tool, a subset of MN in the
ventral par t of area F5c responds also to this type of visual stimuli
(Ferrari, Rozzi, & Fogassi, 2005). Additional generalization proper-
ties of some F5 MNs have been subsequently reported, for example
some of them reacted in a similar way to the same action executed
with different body parts (e.g., grasping with the hand and grasping
with the mouth; Ferrari et al., 2003; Rizzolatti, Fogassi, & Gallese,
2001), to the sound associated with familiar actions (Kohler et al.,
2002), and even to partially covered actions that can be deduced
only from their initial motion track (Umiltà et al., 2001). Other au-
thors have shown that the response a subset of IPL MN (i.e., in the
cy toarc hitectoni c area PF and PFG: in th e macaque monkey, the ros-
tral part of the inferior parietal lobule is divided into area PF and area
PFG; Fogassi et al., 2005), during both the observation and execu-
tion of a complex grasping act, is dependent on the final goal of the
motor act (placing or eating) for which the grasping was per formed
(Bonini et al., 2010; Fogassi et al., 20 05); MNs have a smaller re-
sponse if the piece of food is clutched to place it into a box. Another
significant charac teristic of these cells is that their activity appears
not to be strictly related to the precise timing of the observed ac-
tion; indeed, a certain part of parietal MN is activated before the
achievement of the end-goal (Fogassi et al., 2005). Fogassi and col-
leagues considered this kind of response a demonstration of the
possible explicit cognitive role of IPL MN of encoding the intentions
of other people (Fogassi et al., 2005). More recent investigations
have displayed similar reaction properties in F5 MN (Bonini et al.,
2010), even if to a lesser degree (Rizzolatti & Fogassi, 2014). Other
studies suggest that MNs assimilate into their responses additional
pieces of information that are not directly related to the action it-
self. MN activity can change accordingly to the distance at which
the observed actions were executed with respect to the monkey,
that is in the peri-personal space or in the extra-personal space of
Significance
This work deals with a groundbreaking pathway of research:
the relevance of the mirror neuron (MN) network to the in-
terpretation and possible prevention and treatment of neu-
rodegenerative diseases. We revise findings about the role
of MNs in monkeys, normal human subjects, and people af-
fected by different neurodegenerative diseases. These find-
ings may have interesting applications in aging neuroscience
as the MN exemplify a neuronal network interconnecting
perception, action, and cognition; characterizing their func-
tioning in neurodegenerative diseases could be stimulating
from a speculative point of view, shed an innovative light on
the clinical picture, and open interesting possibilities for re-
habilitative treatment.
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FARINA et A l.
the monkey (Caggiano, Fogassi, Rizzolatti, Thier, & Casile, 2009). The
distance between viewer and performer can be impor tant in choos-
ing possible subsequent behaviors (e.g., interactive or approaching
behaviors). Thus, the MN system could be par t, together with other
brain areas, of a system whose aim was not only to understand what
other people are doing, but also in deciding the most appropriate
behavioral response (Caggiano et al., 2011). According to another
study, the majority of F5 MNs appear to visually encode motor acts
in a view-dependent way (Caggiano et al., 2011). In this study, MN’s
firing to action observation was studied by displaying the same ac-
tions from different points of view, comprising the per former's own
point of view. The responses of MNs were modulated not only by
the kind of action being obser ved but also by the point of view under
which it was observed (e.g., a frontal or a side view).
2.2 | Mirror neurons: Studies in humans
In humans, the presence of MNs has been suggested through
neuroimaging (functional magnetic resonance imaging, fMRI) and
neurophysiological techniques (electroencephalography—EEG,
evoked potentials, transcranial magnetic stimulation—TMS; Cochin,
Barthelemy, Roux, & Martineau, 1999; Fadiga et al., 1995). MN’s ac-
ti v i t y ha s be en fo u n d in th e pr em o t o r co r tex (p o s te r i o r re gi o n s of th e
inferior frontal gyrus—IFG—which is thought to be th e human hom-
ologue of the monkey F5; Ferri et al., 2015; Kilner, Neal, Weiskopf,
Friston, & Frith, 2009) and in the IPL (Arnstein, Cui, Keysers,
Maurit s, & Ga zz ol a, 2011; Chong , Cu nning to n, Williams , Kanw is her,
& Matti ngl ey, 20 0 8; Mole nbe rgh s, Cu nni ng ton, & Ma tti ngl ey, 2012;
Rizzolatti, 2005; Rizzolatti & Craighero, 2004; Rizzolat ti et al.,
2001). The pres ence of MN activity was additionally signaled in the
primary motor cortex (Fadiga, Craighero, & Olivier, 2005) and even
in the hippocampus (Mukamel, Ekstrom, Kaplan, Iacoboni, & Fried,
2010). Moreover, the functional properties of Superior Temporal
Sulcus neurons suggest that these neurons supply the essential cor-
tical visual input to MNs (Nelissen et al., 2011). STS could also be
fundamental in social communication (Allison, Puce, & McCarthy,
2000). In fact, Montgomery, Isenberg, and Haxby (2007) discovered
signif ic ant respo nse in the STS and the MN sys tem for the obs er va -
tion, imitation, and execution of both object-directed hand move-
ments and communicative hand gestures.
Studies utilizing fMRI have shown that a parietofrontal network,
analogous in monkeys and humans, is activated during the observa-
tion and execution of hand grasping actions (Grèzes, Armony, Rowe, &
Passingham, 2003), as well as during the observation of grasping acts
performed with tools ( Peeters et al., 2009), accordingly with previ-
ous single neuron studies in monkeys (Ferrari et al., 2005). fMRI has
identified regions of premotor cortex (BA6 and BA44) and inferior pa-
rietal areas that are functioning during both action observation and
execution (Aziz-Zadeh, Wilson, Rizzolatti, & Iacoboni, 2006; Buccino,
Binkofski, & Riggio, 2004; Carr, Iacoboni, Dubeau, Mazziotta, & Lenzi,
2003; Grèzes et al., 2003; Iacoboni et al., 1999; Leslie, Johnson-Frey, &
Grafton, 200 4; Tanaka & Inui, 2002; Vogt et al., 2007).
In human subjects, both goal-directed actions with the object
present and goal-directed pantomimed actions (Buccino et al., 2001;
Montgomery et al., 2007) seem to implicate the MN system, in the
sam e way as commu n i c a t i v e ac tions do. In a fMR I ex p e r i m ent in which
subjec ts obse rved, imitated, and produced communicative hand ges-
tures and object-directed hand movements, the observation and ex-
ecution of both types of hand gestures activated the MN system to
a similar degree (Montgomery et al., 2007). A fMRI study in humans
(Buccino et al., 2001) also showed the activation of dif ferent subdi-
visions of Broca's area and premotor cor tex during the observation
of hand, mouth, and foot actions. This activation is associated with
the effector of the observed action, following a somatotopic pattern
which looks like the classical motor cortex homunculus. Therefore,
some authors (Buccino, Solodkin, & Small, 20 06; Rizzolatti & Arbib,
1998; Tettamanti et al., 2005) have claimed that there is a homology
between the motor-related part of Broca's region, contained in the
opercular portion of the inferior frontal premotor cortex (mainly in
area 44 of Brodmann) and the area F5 in monkey.
As far as more posterior areas of MN human system are consid-
ered, a precise part of human IPL (left anterior supramarginal gyrus,
aSMG) would be a region exclusive to hominid evolution as it is acti-
vated in humans, but not in monkeys, during observation of actions
made with tools (Peeters et al., 20 09). Figure 1 shows the cerebral
location of human MN regions.
An extensive quantitative meta-analysis (Molenberghs et al.,
2012) of fMRI data from 125 studies revealed that human MN areas
FIGURE 1 Cerebral location of human MN regions. Areas
belonging to the “classical” mirror neurons network are represented
in orange. STS is highlighted in red. Turquoise areas represent other
cerebral regions in which neurons with mirror properties have
been signaled and/or regions functionally stric tly linked to MN
areas. BA44, Broadman area 44; BA45, Broadman area 45; BA46,
Broadman area 46; IPL, inferior parietal lobule; IFG, inferior frontal
gyrus; IT, inferotemporal cortex; M1, primary motor cortex; MTG,
middle temporal g yrus; S1, primary somatosensory cortex; S2,
secondary somatosensory cortex; SMC , sensorimotor cortex; SMG,
supramarginal g yrus; STS, superior temporal sulcus
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FARINA et A l.
are localized in the inferior frontal gyrus, in the ventral premotor
cor tex, and in the IPL (which are con sider ed “clas sical” MN areas an d
are expected to be part of the MN system based on studies in mon-
keys), but also in the primary visual cortex, in the cerebellum, and in
the limbic system.
Several studies based on neurophysiological recordings
showed a reduction in magnitude of the μ rhythm—an EEG oscil-
lation occurring within the standard “alpha” band (i.e., ~8–13 Hz
in adults; ~6–9 Hz in children) in the rolandic areas (e.g., Fox
et al., 2016)—during action observation and execution. These
studies led to the conclusion that this rhythm is an indicator of a
brain system that is functionally comparable to the monkey's MN
network (Lepage & Théoret, 20 06; Muthukumaraswamy, Johnson,
& McNair, 2004; Pineda, 2005). μ suppression studies in humans
revealed that a stronger suppression occurred when viewing an-
other's hand in a precision grasp (i.e., a grasp to be used to get
an object) rather than in a neutral, non-grasping position, and
that interaction with an object determined greater μ suppression
than situations without object interaction (Muthukumaraswamy &
Johnson, 2004; Muthukumaraswamy et al., 2004). These ground-
breaking studies, indicating that μ suppre ssion refle cts human MN
system, have led to many action observation experiments. Fox
et al. (2016), who recently reviewed this branch of investigation
in a meta-analysis, concluded that μ suppression can be used as
a surrogate for human MN activity. Indeed, most results indicate
consistent EEG μ desynchronization (suppression) during both
action execution and obser vation, regardless of the type of stim-
ulus and action (e.g., object-directed and non-object-directed) ob-
served. Otherwise, it has been supposed that MN responses to
non-object-directed actions a human peculiarity denoting a depar-
ture from our common ancestors which represent a milestone in
the evolution of language (Rizzolatti & Craighero, 2004).
However, other researchers have questioned that μ suppres-
sion match MN activity. In point of fact, μ suppression studies
have been unsuccessful in providing robust evidence of the role of
the MN system due to limitations in methodology, for instance, a
few studies describe changes in power at locations other than the
central electrodes, one can therefore wonder whether observed
effects are not due to changes in power in other areas (Hobson
& Bishop, 2016). Coll, Bird, Catmur, and Press (2015) described
that μ suppression was associated with sensory mirroring but not
motor mirroring, a finding that weakens the essential connection
be twe en ac tio n and per cep t ion tha t MN s ar e th oug ht to re p r esen t.
For these reasons the legitimacy of μ suppression as a measure
of the human MN system still represents a matter of discussion.
Some authors have also emphasized that the rolandic μ rhythm
consists of two spectral peaks and that its arch-like form depends
on the contribut ion of both th e alpha a nd the beta range ac tivities
(Niedermeyer & da Silva, 2005). The ß frequency band is usually
defined as a rhythm between 13 and 35 Hz, with a typical peak
frequency of about 20 Hz (Niedermeyer & da Silva, 2005). Like μ,
ß activity is suppressed by voluntary movements, motor imager y
(MI) and action observation (Babiloni et al., 2002), so changes in ß
activity have also been considered to be an index of MN activity
(Hobson & Bishop, 2016; Pozzo et al., 2017).
Neurophysiological and fMRI data have also been correlated
during action observation tasks (e.g., see Braadbaar t, Williams, &
Waiter, 2013). These authors found that μ power modulation was
negatively associated with BOLD response in supposed MN areas:
right inferior parietal lobe, premotor cortex, and inferior frontal
gyrus. Thanks to μ suppression they have also identified a variety
of structures that control motor preparation and respond to visual
input including, but not limited to, the human analogue of the MN
system cluster (bilateral cerebellum, left medial frontal gyrus, right
temporal lobe, and thalamus) (Braadbaart et al., 2013).
Most functional studies on MNs have explored hand actions
and very few have studied how MNs respond to mouth actions
or communicative gestures. A recent study by Ferrari and col-
leagues has shown the presence of MNs in different cytoarchitec-
tonic areas and that their specific proper ties are related not only
to the type of effector involved (hand or mouth) but also to the
different anatomical pathways (Ferrari, Gerbella, Coudé, & Rozzi,
2017). In particular, this study showed that the mouth and hand
MN sectors have distinct and specific connections. Unlike hand
MNs, mouth MNs do not receive their visual input from parietal
regions. This information concerning face/communicative behav-
iors could come from the ventrolateral prefrontal cortex. Other
strong connections derive from the limbic structures involved in
coding emotional facial expressions and motivational/reward pro-
cessing (e.g., anterior cingulate cortex, anterior and mid-dorsal
insula, orbitofrontal cortex, and the basolateral amygdala). The
mirror mechanism is therefore composed and suppor ted by at
least two dif fe rent anatomi ca l pathw ays: th e first concerns sens o-
rimotor mirroring in relation to reaching and hand grasping within
the traditional parietal-premotor circuits; the second is related to
mouth/face motor control, is connected with limbic structures,
and potentially explains the function of MN system in empathy
and social interaction.
2.2.1 | MN functions in humans
Recognizing actions of others
The first function attributed to MNs in humans has been recognizing
actions per formed by other people. In a TMS study (Fadiga et al.,
1995) subject s were submitted to stimulation (with an increase of
left motor cortex excitability) during observation of grasping acts,
purposeless movement s, and static objec ts. Evoked potentials of
hand muscles were more marked during grasping observation, even
if they were also present during observation of aimless movements.
The most impor tant point is the fact that evoked potentials were
present in muscles specifically involved in the execution of the ob-
served act.
Another emblematic study was conducted with fMRI on patients
with upper limbs aplasia (Gazzola et al., 2007). The observation of
manual grasping by subjects that never used hands activated MNs
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FARINA et A l.
at the same extent than acts having the same aim and performed by
the subjects with the mouth or the foot.
Interpreting action intention
Other studies on MN function investigated whether they were
also involved in interpreting the intention embedded in the action.
Iacoboni et al. (2005) performed a fMRI study where par ticipants
observed three types of stimuli: grasping hand actions without a
context, context only (scenes containing object s), and grasping hand
actions performed in two different contexts. In the latter condition,
the context suggested the intention linked to the grabbing action
(either drinking or cleaning). Actions embedded in context s, differ-
ently than actions in the other two conditions, produced a significant
signal intensification in the posterior portion of the inferior frontal
gyrus and the adjacent subdivision of the ventral premotor cortex,
where hand actions are represented. The authors concluded that
premotor MN areas play a role in understanding the intentions of
others.
Motor imitation and motor learning
The MN system is thought to be concerned in imitational learning
of familiar elementary movements. Iacoboni et al. (1999) demon-
strated the activation of the inferior frontal cortex (pars opercu-
laris) and of the superior parietal lobule during the observation,
spontaneous execution, and imitation of a motor task in a fMRI
study. The involvement of the pars opercularis of the frontal lobe
in imit ation has been also confirmed by a TMS study in which the
cortic al area was excited using a stimulous frequency of 5 Hz
(Heiser, Iacoboni, Maeda, Marcus, & Mazziotta, 2003). Another
study suggesting the role of the MN system in imitation is the
already cited research by Molenberghs, Brander, Mattingley, and
Cunnington (2010). Buccino et al. (2004) have also suggested that
the MN system is involved in the acquisition of new motor skills. In
a fM RI st u dy, re sea rch er s recru ite d sub je c ts who had never played
a guitar. The subjects watched a video showing a music teacher
who playe d so me chords. Af ter a paus e, they had to re produce th e
chords. Control conditions were represented by: (a) obser ving the
video without reproducing chords, (b) playing accords spontane-
ously, (c) obser ving a video with a guitar alone, before imitating,
and (d) executing movements not related to the music, after chords
observation. Watching the video and then imitating was the condi-
tion which activated the MN system the most, while observation
not followed by imitation activated the MN circuit (IPL and the
posterior part of the inferior frontal gyrus plus the adja cent motor
cortex) at a lesser extent. In imitation-based motor learning, the
creation of per ma ne nt motor me morie s was consi de re d in th e p as t
to b e don e thr oug h the physic al pr a cti ce of m ovem ent s. Ac co rdi ng
to the new view, in this kind of learning the MN system enables
motor lea rning si mplifying the physica l performance of the pro per
training movements. Mattar and Gribble (2005) utilized kinematic
analyses to demonstrate that the achievement of complex motor
behaviors is eased by a previous observation of subject s mastering
the novel task.
The role of MN in higher cognitive functions
MN discovery receive d a lot of at tention from sp ecialists (not only
neuroscientists but also psychologists and philosophers) both in
scientific and public media. The MN network, besides playing a
role in action understanding and imitation, is now considered to
be involved in many other sophisticated human behaviors such
as empathy, language, and learning (Cook, Bird, Catmur, Press,
& Heyes, 2014; Corradini & Antonietti, 2013; Oz top, Kawato, &
Arbib, 2013; Rizzolatti & Fogassi, 2014). For instance, the find-
ing of MNs has given a biological complement to the simulation
theory, suggesting that actions involve both an overt and a cov-
ert stage (Jeannerod, 2001; Jeannerod & Frak, 1999). The cover t
stage is a kind of implicit cognitive representation of the future
and comprises the goal of the action, the means to get it, and its
consequences on the organism and the external world. Covert
and overt stages would represent a continuum; every overtly ex-
ecuted action indicates the existence of a covert stage, although
the cognitive covert stage of action does not necessarily turn out
into overt action (Jeannerod, 2001). In a further development of
this research line, the existence of the MN system supports the
theoretical perspective of the “embodied” or “motor” cognition.
Among the multitude of ways to explain human and animal be-
haviors, there is a growing body of experimental evidence indicat-
ing that cognition and action produc tion are mutually dependent
and that motor representations are present at each level of cog-
nitive (language, memory, spatial and temporal representations,
and social cognition) processes (Barsalou, 1999, 2008; Gallagher,
2005; Gavazzi, Bisio, & Pozzo, 2013; Noe, 2004; Wheeler, 20 05;
Wilson, 2002). More generally, the evolution of the brain and its
volume increase is associated with more complex behavior, mean-
ing more sensorimotor sophisticated response to environmental
constraints, an idea highly consensual in evolutionists (Krubitzer,
2007; Northcutt, 2002). The discovery of a category of neurons
that link s k nowledge about actions and pe rceptions has th us giv en
a possible neural motor substrate to an extensive array of high
cognitive functions, including attention, meaning, concepts, goals,
and intentions understanding, in addition to communication for
social interaction (Pulvermüller, Moseley, Egorova, Shebani, &
Boulenger, 2014).
2.2.2 | Inter-subjectivity, empathy, and
social cognition
Experimental evidence strongly suggests that the MN system
(alo ng wi th ot her cere bra l cir cu its, such as the so cia l cogni tio n net-
work), contributes to understand not only other people's actions
but also their emotions (Agnew, Bhakoo, & Puri, 2007; Gallese,
2003; Gallese, Keysers, & Rizzolatti, 2004; Pineda & Hecht, 2009;
Wicker et al., 2003). In this sense, a crucial role of MN would be
to foster empathy. Empathy is a subjective experience. It can be
viewed as the process by which a person resonates and tunes to
others’ affective and cognitive states (Levy & Feldman, 2019).
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FARINA et A l.
It plays a key role in social relations and allows humans to con-
nect and understand each other and to create social and cultural
gr oup s . Stu die s on emo t io nal st ate s demo nst rat e that a la r ge- scal e
neural network—including the ventral premotor cortex and the in-
ferior fro nt al gyrus (tw o reputed MN areas) , in additi on to classical
cerebral regions involved in feeling emotions, such as the anterior
insula and the amygdala—is active for instance during facial ex-
pression observation and imitation (Budell, Jackson, & Rainville,
2010; Carr et al., 2003; Grosbras & Paus, 2006; Iacoboni, 2009;
Rizzolatti & Craighero, 2004). In children, activity in the frontal
part of the MN system, produced by observation and imitation
of emotional expressions, correlates with measures of empathic
behavior and interpersonal skills (Pfeifer, Iacoboni, Mazziotta, &
Dapretto, 2008). Likewise, it is now proposed that the core defi-
cits of autism, which are motor, language, and social impairments,
are indicative of dysfunction of the MN system (Dapretto et al.,
2006; Fishman, Keown, Lincoln, Pineda, & Müller, 2014), and
various works suggest a role of MNs in schizophrenia (Kato et al.,
2011; Saito et al., 2017; Schilbach et al., 2016). In contrast, as sug-
ges te d by Lin kov ski, Kat zi n, and Salti (2017), caut io n in theoret ic al
generalization of exper imental procedures is needed. As an exam-
ple, res earche s on MNs and schizophrenia do not repo rt a cor rel a-
tion between social dysfunction severit y and the abnormality of
the MN network (Enticott et al., 2008; McCormick et al., 2012).
2.2.3 | Language
Some studies have shown that MNs have a main role in differ-
ent aspects of language acquisition (Theoret & Pascual-Leone,
2002), speech perception (Glenberg et al., 2008) and production
(Kühn & Brass, 20 08), and evolutionar y language development
(Arbi b, 200 8). Tett amant i et al. (20 05) demonst rated tha t liste ning
to sentences describing actions performed with the mouth, the
hand or the leg activated a left fronto-parietal-temporal network
that included the pars opercularis of the inferior frontal gyrus
(Broca's area), the intraparietal sulcus, and the posterior middle
temporal gyrus, in a somatotopic manner. Based on these stud-
ies, it has been suggested that cerebral areas establishing a cor-
respondence among performed and observed actions in monkeys
(F5Area) match to those that are appointed to language produc-
tion in humans (Broca's Area; Molnar-Szakacs, Iacoboni, Koski, &
Mazziott a , 20 05, Tet taman ti et al. , 200 5) . Howe ve r, a recent study
raised doubts about this presumed matching (Cerri et al., 2015).
Other neuroimaging studies revealed zones in the human premo-
tor cortex that activate both when participants see actions being
performed and when they read sentences concerning those ac-
tion s ( A zi z-Z ade h et al. , 2006). Fur t he r mo re, Hauk , Johnsr ude , a nd
Pulvermüller (2004) found a somatotopically organized activation
in the motor and premotor cortex when subjects passively read
action-associated words (i.e., leg-associated action words lead to
activations in medially situ ated areas while a rm or face-associated
action words lead to lateral areas activation).
More generally, the role of the MN system in evolutionary lan-
guage development is recurrently proposed (Chwilla, Virgillito, &
Vissers, 2011; Fischer & Zwaan, 20 08; Meteyard, Zokaei, Bahrami,
& Vigliocco, 2008; Rizzolatti & Arbib, 1998), even if it is still under
discussion (Caramazza, Anzellotti, Strnad, & Lingnau, 2014).
2.2.4 | Memory
Several behavioral investigations suppor t the idea of the embod-
ied nature of memor y processes, that is the idea that memory is
the re c al l of a sensa tion store d af ter an ac tio n pro du c tion ge ner at-
ing that sensation. According to this view, memory is considered
a dynamic process instead of a static storage such as a library or a
video archive and learning is influenced by sensorimotor coupling.
For instance, when normal subjects are asked to ret ain lists of
object s in memory while performing a congruent or incongruent
action with these objects, performing an incongruent action im-
paired memory performance, in comparison to congruent action.
Interestingly, the quantity of manual experience with the object
regulates the quantity of interference (Yee, Chrysikou, Hoffman,
& Thompson-Schill, 2013). Accompanying words or sentences in
a foreign language with the corresponding gestures conducts to
better learning (Macedonia, 2014); gestures activate motor neu-
rons and could activate MN, which are a subset of motor neurons.
Neurophysiological studies have indicated a direct involvement
of the MN network in the imitational learning of familiar elemen-
tary movements (Iacoboni et al., 1999) and in the acquisition of
new motor skills (Buccino et al., 20 04; Gatti et al., 2013; Mattar &
Gribble, 2005). Stefan et al. (2005) demonstrated that a specific
motor memory like the one induced by practicing movements is
formed by observation. Viewed together, these studies suggest
that MNs could affect memory by improving encoding. In con-
trast, the MN system seems to influence not only encoding, but
also retrieving; autobiographical memories in body-congruent and
body-incongruent positions relative to that of the original expe-
rience also influences performance (Dijkstra, Kaschak, & Zwaan,
2007). Gelbard-Sagiv, Mukamel, Harel, Malach, and Fried (2008)
showed, in patients with pharmacologically intractable epilepsy
implanted with depth electrodes, that neurons in the medial tem-
poral lobe are reactivated during spontaneous recall of previously
observed audiovisual sequences (episodic memory). According to
the authors, these neurons could match the vision of actions ex-
ecuted by other people with the memory of those same actions
completed by the observer. This concept is in agreement with the
idea that during action accomplishment, a memory of the per-
for me d action is formed, and this memor y trace is reac ti vated dur-
ing action observation. The same group (Mukamel et al., 2010),
by recording extracellular activity, described neurons with mirror
proper ties in the hippocampus (that is neurons which responded
to both observation and execution of actions). This important
observation suggests that in humans, multiple neuronal systems
might be endowed with mechanisms of mirroring others’ actions;
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FARINA et A l.
the functional significance of the mirror mechanism might vary ac-
cording to the position of the MN, thus supporting different func-
tions, memory included. Even if these data need to be confirmed
by further studies, it opens exciting perspectives for a novel inter-
pretation of memory mechanisms.
In conclusion, MNs represent the neuronal population which
link perception and action, cognition and motilit y. For a summar y
of the literature about MN functions in humans, see Supporting
Information Appendix A.
3 | MIRROR NEURONS AND
NEURODEGENERATIVE DISEASES
The possible role of MNs in cognition suggests a hypothetic in-
volvement of this neuronal network in neurodegenerative dis-
eases. In the last decade it has become increasingly evident that
the classic distinction between cognitive and motor neurodegen-
erative disorders is blurred and that in each neurodegenerative dis-
ease both cognitive and motor symptoms are represented in a sort
of continuum; in PD, initially classified as a movement disorder, it
is recognized that non-motor symptoms (cognitive, autonomic,
affective, and behavioral disorders) are relevant in the course of
the disease (Moustafa & Poletti, 2013). This disease has a strong
relationship with the second most common cause of neurodegen-
erative dementia, DLB (McKeith et al., 2017). In contrast, AD, the
most common cause of dementia, and MCI, which is now seen as a
pre-dementia stage of the same disease, particularly in its amnesic
form, have always been seen as “pure” cognitive disorders (Rossor,
1992). However, in the last decade, there has been a growing rec-
ognition of a connection between deficiencies in motor function
and these two clinical entities. (Bisio et al., 2012; Ghilardi et al.,
1999; Yan, Rountree, Massman, Doody, & Li, 2008). Nevertheless,
the most striking example of combining cog ni ti ve and motor symp-
toms in neurodegenerative disease is the continuum of ALS-FTD.
To investigate the possible role of MNs in neurodegenerative
diseases we performed a quasi-systematic search of sources, to
appraise the existing studies considering the MN system, the em-
bodied cognition theory, and these three main categories of neuro-
degenerative diseases.
3.1 | Empathy deficit in
neurodegenerative conditions
As previously cited, the MN network is thought to greatly contrib-
ute to social relationships. Early loss of empathy (accompanied by
reduced response to other people's needs and feelings, and dimin-
ished social interest) is one of the six core symptoms in the revised
diagnostic criteria of the behavioral variant of FTD (Rascovsky et
al., 2011) and is frequently encountered in this disease (Baez et al.,
2014; Laforce, 2013). Impaired performance at a test which is consid-
ered a measure of empathic abilities showed to better discriminate
behavioral variant of frontotemporal dementia (bvFTD) patients
from normal controls or AD patients than altered performance
in executive tests. This result highlights the impor tance of social
cognition abnormalities in bvFTD diagnosis (Schroeter et al., 2018).
Interestingly, loss of empathy (Girardi, MacPherson, & Abrahams,
2011) and altered emotional empathy attribution (Cerami et al.,
2014) have also been described in AL S patients without dementia.
However, empathy loss has also been described in neurodegen-
erative diseases other than the FTD/ALS continuum; several studies
(Ariatti, Benuzzi, & Nichelli, 2008; Herrera, Cuetos, & Rodríguez-
Ferreiro, 2011; see also Péron, Dondaine, Jeune, Grandjean, & Vérin,
2012 for a review) have shown emotion recognition deficits in PD
patients when compared to matched healthy controls. Deficits in
recognizing others' emotions are reported in AD (Fernandez-Duque,
Hodges, Baird, & Black, 2009; Martinez et al., 2018) and even in MCI
(Teng, Lu, & Cummings, 2007).
These data are important for caregivers of persons with neuro-
degenerative diseases; in point of fact, this emotional impairment
can affect both sides, that is the sender and the receiver of the
emotional communication. A recent study has shown not only that
subjects with AD and PD are significantly impaired in recognizing
emotions, but also that their caregivers do not recognize these defi-
cits, and this is linked with increased caregiver burden and depres-
sion (Martinez et al., 2018). We found several studies linking the MN
network to neurodegenerative diseases in our literature revision.
Their results will be detailed in the following chapters.
3.2 | Mirror neurons and Parkinson's disease
Most available studies considering both cognition and action sys-
tems are focused on PD, the most common extrapyramidal disorder,
with controversial results. The functioning of the MN network in PD
has been studied, as in normal subjects, through neurophysiologi-
cal techniques (EEG and TMS), neuroimaging (fMRI), and kinematic
studies. Several studies suggested rehabilitative training based on
stimulating the MN network and the embodied cognition framework
in PD. An in-depth presentation of the studies on MN and PD is
shown in the Suppor ting Information Appendix B.
3.2.1 | Neurophysiological studies
Many studies on MNs in subject s with PD have used the “Action
Observation” (AO) approach. This approach includes both observation
and execution of an action (Ertelt & Binkofski, 2012) and it is based on
the core property of MN. The subthalamic nucleus is direc tly linked
with the frontal (motor and premotor) cortex through the so called “di-
rect” pathway of the motor circuit (Nambu, 2004) and by the cortico-
strio-pallido-subthalamic projection (the “indirect” circuit). The direct
pathway conveys a monosynaptic excitator y input from the frontal
areas to the subthalamic nucleus. Cortical activity triggered in the MN
network by AO could therefore easily propagate to the basal ganglia
8
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FARINA et A l.
and particularly to the subthalamic nucleus through these pathways.
This entry might modulate basal ganglia output in order to facilitate/
inhibit competing motor programs according with the expected results
of action (Alegre et al., 2010).
According to these views, Alegre et al. (2010) have shown that
the subthalamic nucleus displays variations in activity during both
movement observation and movement execution. The authors re-
corded EEG and local field potentials in 18 patients with PD through
surgically implanted electrodes for deep brain stimulation (DBS).
Oscillations in electrical activities were recorded during AO and t wo
control conditions. During AO (observing wrist extension move-
ment s of an examiner seated in fr ont), a significant bilater al decrease
of beta range activity in the subthalamic nucleus was recorded in
both on and off me dic ati on st ates (eve n if high er in the firs t one ). This
result sug gests a substantial conservation of the MN network in PD,
with a possible influence of the medication state. In line with this ev-
idence, another study regarding DBS-implanted patients (Marceglia
et al., 2009) found a change in subthalamic nucleus oscillatory activ-
ity during AO.
Other studies however showed opposite result s; in a study,
µ-rhythm desynchronization usually recorded during movement
observation was reduced in patients with early PD (Heida, Poppe,
Vos, Putten, & Vugt, 2014). Tremblay, Léonard, and Tremblay (2007)
tested 11 PD patients in the on condition and the same number of
healthy eld erly controls , by re cor ding motor evoked potentials (MEP)
amplitudes in four conditions: rest, AO (a video depic ting a hand cut-
ting a piece of paper with scissors), MI, and active action imitation.
The MEP amplitude (recorded at the first dorsal interosseous and
abductor digiti minimi) increased in PD patients during active imi-
tation but neither during AO nor during ac tion imagery. This would
indicate a failure to involve the motor system more at the covert than
at the overt phase of action execution. This would be due, according
to th e authors, to a def icit in motor ac tivation af fecting cr it ic al nodes
in the motor cor tical circuit physiologically involved in action prepa-
ration. Tremblay et al. hypothesize that these nodes could be the
supplementary motor area and the inferior parietal cortex. However,
these remarks may also be explained by the involvement of the fron-
tal-subcor tic al circu it s that link the bas al gan gl ia to th e pr em ot or cor-
tex (Alegre, Guridi, & Artieda, 2011; Alegre et al., 2010; Alexander,
Crutcher, & DeLong, 1990).
Contrasting results in PD studies could depend on several fac-
tors, namely, most importantly, the stage of the disease (not always
precised in the different studies), then the recruited population (e.g.,
a bias depending on the recruitment of very small samples cannot
be discarded), the dopaminergic state and maybe the clinical form
of the disease (tremor vs. akinetic form), an information which is sel-
dom repor ted.
3.2.2 | fMRI studies
In an interesting neuroimaging study, Anders et al. (2012) recruited
eight pre-symptomatic carriers of a single mutant Parkin gene, who
exhibited a slight but significant decrease of dopamine metabo-
lism in the basal ganglia. Indeed, it is well known that PD has a long
pre-symptomatic stage, during which the brain compensates for
dopaminergic degeneration by augmenting motor-related cortical
activity (Morrish, Sawle, & Brooks, 1996). This work aimed to study
whether comparable compensatory mechanisms were operative in
non-motor basal ganglia-cortical gating circuits. As execution and
perception of facial gestures are thought to be related to MNs in
the ventrolateral premotor cortex (Hennenlotter et al., 2005; Leslie
et al., 2004), Parkin mutation carriers first underwent fMRI while
observing neutral and affective dynamic facial expressions and then
performed a facial emotion recognition task. As expected, recruited
pa r t icip a nts sh o we d a sig nif ica ntly hi ghe r ac t ivi t y in th e rig ht vent ro-
lateral premotor cortex during execution and perception of affective
facial gestures than healthy controls. Furthermore, Parkin mutation
carriers showed a slightly reduced ability to recognize facial emo-
tions that were inversely proportional to the increase of ventrolat-
eral premotor ac tivit y. According to the authors, these findings are
consistent with the hypothesis that compensatory activity in a MN
area during processing of affective facial gestures can lessen impair-
ment in facial emotion appreciation in subclinical Parkin mutation
carriers. A failure of this compensatory mechanism could conduct to
the impairment of facial expressivity and facial emotion recognition
observed in clinically evident PD. In contrast, it is possible that the
stimulation of MNs could favor these compensation mechanisms at
least in the first phases of the disease, thus allowing PD patients to
have better social interaction.
Addit ional support to the putative link bet ween MN area impair-
ment and the well-known emotional deficit of PD patients (Péron
et al., 2012) comes from a similar recent study by the same group
(Pohl et al., 2017). In this investigation, 13 PD patients and controls
performed an emotion recognition task during fMRI measurement.
Subjects watched video clips displaying emotional, non-emotional,
and neutral facial expressions or were requested to make these fa-
cial expressions. Patients completed the emotion recognition t ask a
little worse than controls, but only for the most difficult expressions
to be interpreted. Inferior frontal and anterior inferior parietal MN
areas activated during obser vation and execution of the emotional
expressions in both groups, but at a lesser extent in PD patients;
furthermore, activation of the right anterior IPL positively correlated
with patients’ emotion recognition ability.
Péran et al. (2009) compared fMRI cortical activation during the
production of action verbs with activation during object naming,
in 14 PD patients using a common set of objects pictures. Data re-
vealed the participation of a large cortical circuit during action verb
generation, with differences from the object name production situ-
ated above all in the premotor and prefrontal cor tices. These results
suggest an important role of the frontal cortex in action verb gen-
eration. They also suggest that a motor striatal-frontal loops impair-
ment leads to the compensative enrollment of a cortical network.
Abrevaya et al. (2016) found similar results when subjects listened
to action verbs and nouns. The verb lexical category elicited con-
nectivity between primary motor areas and anterior areas (implied
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FARINA et A l.
in action observation and imitation), in normal controls, while acti-
vated posterior areas in PD patients, thus suggesting that patients
might afford alternative pathways to process words when motor
substrates are altered.
3.2.3 | Behavioral studies
Poliakoff, Galpin, Dick, Moore, and Tipper (20 07) evaluated the ef-
fect of movement-relevant visual stimuli on reaction times in mild-
to-moderate PD patients. In the first experiment, participants had
to classify visual stimuli (graspable door handles and the control
bar condition) according to shape and orientation. No difference
was detected in the overall reaction times for patients and con-
trols. However, the spatial compatibility effect (that is faster reac-
tion times when the response hand and the stimulus direction were
compatible) was larger in the handle than in the bar condition for
controls, but not for PD patients. In the second experiment, the two
groups observed video clips of finger or object movement s and had
to answer as quickly as possible if an X appeared at the end. Both
patients and normal participants reduced significantly their reaction
times after observing finger compared to objects movements, indi-
cating partial preser vation of MN network in PD. However, patients
with PD showed a spat ial compatibility effec t onl y for non-liv ing ob-
ject movements leading the authors to propose that in PD the MN
system is not completely preser ved and that external cues would act
through low-level visual processes.
However, other findings sugges t a no rmal co up ling be twee n per-
ception and action systems in PD. In an interference task, healthy
controls and PD patients, (tested in off period) completed hori-
zontal and ver tical arm movements, while watching a person, or a
moving dot, performing similar movements in the same-congruent
or orthogonal-incongruent plane (Alber t, Peiris, Cohen, Miall, &
Praamstra, 2010, see also Alegre et al., 2011). No dif ference was
found bet ween patients and controls.
Castiello, Ansuini, Bulgheroni, Scaravilli, and Nicoletti (2009),
examining PD patients’ motor imitation ability, showed kinematic fa-
cilitation ef fects only when the model was a patient with PD—who
performed slower and less fluid movements—in contrast to a healthy
model. Therefore, differently than normal controls, patients could
re-enact their motor representations only when the visual model be-
longed to the patient's motor repertoire. In line with this, the authors
have proposed that basal ganglia play a role in setting frontal and
parietal cortices; this role is important not only for the execution of
actions but also for the internal simulation of observed behaviors,
given that the internal state of the simulated action is available.
Reaserchers have also studied the ability of PD patients to per-
ceive and recognize human action. Precisely, when displayed with
limited visual attributes (a point-light walker) persons with PD
showed reduced visual sensitivit y to biological motion (Jaywant,
Shiffrar, Roy, & Cronin-Golomb, 2016). Likewise, when observing
point-light human figures that carried communicative and non-com-
municative gestures, patients were impaired, relatively to normal
controls, in describing the meaning of non-communicative gestures,
while they normally perceived communicative gestures. However,
men were more compromised than women and their ability to rec-
ognize both t ypes of gestures was reduced.
3.2.4 | Neuropsychological studies
Action naming is an ability that depends on the inferior frontal gyrus,
a “classical” MN area (see Kemmerer, Rudrauf, Manzel, & Tranel,
2012). Action verb impairment (with relative preservation of noun
processing) has been repetitively described in PD. In the same vein,
it has been reported that motor-language coupling (i.e., the influ-
ence between verbal processes and voluntary body movement s, see
García & Ibáñez, 2014) is altered in PD. For a detailed list of pub-
lications on these topics one can refer to the reviews by Cardona
et al. (2013), Silva, Machado, Cravo, Parente, and Carthery-Goular t
(2014), and Birba et al. (2017).
Neuropsychological studies (Jacobs, Shuren, Bowers, &
Heilman, 1995; Livingstone, Vezer, McGarr y, Lang, & Russo, 2016;
Marneweck, Palermo, & Hammond, 2014; Ricciardi et al., 2017), sim-
ilar to the already cited study of Pohl et al. (2017), have also reported
the existence of a significant relationship between voluntar y control
of facial muscles and emotion recognition deficits in PD patients, an
interesting finding at the light of the embodied cognition framework.
If the MN system is implicated in both production and perception
of facial emotional expression, one can really expect an alteration
of MN in PD, even if the MN net work is not the only neuronal sys-
tem involved in emotion perception (Wang, Larson, Bowen, & van
Belle, 2006). A possible involvement of the MN network in PD em-
pathy deficits is also suggested by a study of Nobis et al. (2017).
This research shows a relationship between the performance on the
reading the mind in the eyes test (RME, Baron-Cohen, Wheelwright,
Hill, Raste, & Plumb, 2001), a test measuring empathic abilities, and
the severity of motor symptoms, along with disease duration, in PD
patients. It is also interesting to mention that similar data to those
reported in PD have been obtained in Huntington disease (Clark,
Neargarder, & Cronin-Golomb, 2008; Sprengelmeyer et al., 1996;
Trinkler et al., 2017).
Overall, fMRI data (Anders et al., 2012; Pohl et al., 2017) and
neuropsychological studies listed above considerably support the
contention that empathy deficits in PD are linked to an impairment
of the MN network.
3.2.5 | Action observation training for PD
rehabilitation
Several works found that action observation training (AOT), which
includes observation and execution of an action (Ertelt & Binkofski,
2012) and is evidently based on the stimulation of the MN system
(Shih et al., 2017), has a positive effect on PD rehabilitation. During
a typical rehabilitation session, patients must obser ve a specific
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FARINA et A l.
daily action presented through a video clip on the computer screen
and then perform what they have observed. Typically, 20 daily ac-
tions are performed and chosen based on their ecological value
(e.g., drinking coffee, reading the newspaper) during a rehabilitation
treatment that lasts 4 weeks (5 days a week; see Buccino, 2014).
This supplementary top-down therapeutic tool was first developed
for patients with stroke, with the aim to improve brain plasticity
and functional outcomes (Carvalho et al., 2013) but subsequently it
has also been used in motor deficits of children with cerebral palsy
(Bassolino, Sandini, & Pozzo, 2015; Buccino et al., 2012; Sgandurra
et al., 2011) and in PD (Buccino, 2014). Most of the studies in PD
have focused on walking disturbances.
Efficacy of AOT in motor rehabilitation
A pioneering study by Buccino et al. (2011), in a randomized con-
trolled trial, explored the efficacy of AOT as an added therapy to
standard pharmacological and rehabilitative treatments. After treat-
ment, the experimental group reported better scores in the Unified
Parkinson Disease Rating Scale and the Functional Independence
Measure, while there was no objective variance in gait performance.
Jaywant, Ellis, et al. (2016) found similar results—no difference in gait
performance was observed; however, the AOT group obtained a re-
ported signific antly improved mobility measured through a subscale
of self-perceived mobilit y. Santamato et al. (2015) performed a study
on the efficacy of AOT in balance and walking of PD patients. They
obtained negative results, but a limitation of this study was the ab-
sence of a control group.
In contrast, a supplementary effect of AOT on regaining of
walking ability in PD patients with freezing of gait (FoG) was ob-
served by Pelosin et al. (2010). The patients, while performing a
standard physical therapy treatment, were randomly attributed to
an “action group” or to a control group. Patient s in the action group
watched video clips showing specific movement s and strategies to
avoid freezing events, while patients in control group watched video
clips of static pictures showing different landscapes. Another study
(Agosta et al., 2016) confirmed the positive effect of AOT on FoG,
showing that this improvement was associated with brain functional
changes. The protocol reproduced the one developed by Pelosin et
al. (2010). Af ter 4 weeks, both AOT and standard therapy groups
showed lessening of FoG and enhanced walking speed and quality of
life. Only in the AOT group motor disability was additionally reduced
and balance ameliorated. After 8 weeks, only the AOT group still
exhibited a positive effect on motor disability, walking speed, bal-
ance, and quality of life. Patients were then scanned while execut-
ing foot movement s, a MI task related to FoG, and during AOT. The
AOT group displayed amplified recruitment of frontoparietal mirror
areas during fMRI tasks. In the same group, functional brain changes
were mirrored by clinical progresses. It was concluded that AOT may
enhance motor learning and facilitate the construction of a motor
memory in PD to circumvent FoG through MN net work ac tivation.
Pelosin, Bove, Ruggeri, Avanzino, and Abbruzzese (2013) have
also shown that watching video clips showing repetitive finger
movements paced at 3 Hz increased the spontaneous rate of finger
movements. AOT significantly affected movement rate in both the
on and off conditions, but 45 min later the effect was still evident
only in the on condition. The authors conclude that AOT could be a
pos sible method for the reha bilit ation of bradykine sia, even if the do-
paminergic state participates in the ef fect s of AOT. In another work
focusing on arm bradykinesia, Bieńkiewicz, Rodger, Young, and Craig
(2013) demonstrated that it was possible to improve motor perfor-
mances in PD patients by a LED display simulating biological motion.
Among rehabilitative approaches thought to be based on MN stim-
ulation and aimed to reduce hand bradykinesia in PD (Bonassi et al.,
2016) we must cite the use of “mirror box.” In this approach a motor
training is per formed with the non-affected limb, while the patient
receives visual feedback from the affected limb. This procedure has
been used above all for stroke patients (Ramachandran & Altschuler,
20 09). Among it s possi bl e neura l su bst rates , it has been pro posed the
involvement of the MN system or at least some areas strictly linked to
it (such as the superior temporal g yrus; Deconinck et al., 2014).
A recent review about the efficacy of AOT and MI in PD
(Caligiore, Mustile, Spalletta, & Baldassarre, 2017) concluded that
AOT facilitates motor behavior at least in the earlier stages while
there is less agreement about MI efficiency. Another recent review
(Patel, 2017) has taken into account AOT studies in PD rehabilitation
as a mean to modify postural way and gait. As in the case of Caligiore
et al ., the gen er al con cl usion of the author was tha t AOT could be ef-
fective if used in conjunction with traditional treatment in rehabilita-
tion, by exploiting the MN network and its ability to understand the
motor planning of others, which could favor anticipatory postural
responses and reactive reflexes.
The mechanism through which AOT improves motor per for-
mances in PD needs, however, to be further elucidated. AOT does
not directly stimulate basal ganglia but might activate MN prefron-
tal areas that rely on the basal ganglia through frontal-subcortical
circuits. Such a kind of connections has been proposed by several
authors (Alegre et al., 2011; Bonini, 2016) and claimed to explain re-
sults of several studies (see previous paragraphs). Recent anatomical
data (Gerbella, Borra, Mangiaracina, Rozzi, & Luppino, 2015) have
in fact revealed that most of the regions forming the cortical MN
system for hand actions such as the inferior pariet al areas, the ven-
tral premotor cortex, and the ventrolateral prefrontal cortex (which,
according to some authors -Borra, Gerbella, Rozzi, & Luppino, 2011;
Gerbella, Borra, Tonelli, Rozzi, & Luppino, 2012; Nelissen et al., 2011
could also have MN like properties) send convergent projections to
specific sectors of the putamen. In birds, imitation learning would
develop, assuming a Hebbian model, using pathways bet ween basal
ganglia and MN areas (Giret, Kornfeld, Ganguli, & Hahnloser, 2014).
Music in PD rehabilitation
We now know that MN are multimodal cells, which can be stimu-
lated not only by action observation and execution but also by the
acoustic perception of action-related sounds (e.g., breaking a peanut,
paper ripping) (Aziz-Zadeh, Iacobon, Zaidel, Wilson, & Mazziotta,
2004; Fadiga et al., 1995; Gazzola, Aziz-Zadeh, & Keysers, 2006;
Kohler et al., 2002). Using fMRI, Gazzola and colleagues searched
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FARINA et A l.
for brain areas that respond both during motor execution and when
individuals listened to the sound of an action performed by the same
effector. In the study, the authors tested the auditory and motor
proper ties in the same subjects on two separate days. For auditory
activity, the subjects listened to the sounds of five categories: mouth
action sounds (for example kissing, gurgling), hand action sounds
(e.g., opening of a hinge, crushing a soft- drink can), ambient sounds
(e.g., train passing by), scrambled mouth actions, and scrambled
hand actions. During the motor execution task, subject s had to per-
form actions similar to those used in auditory stimuli. The authors
showed that in both cases a left-sided temporo-parieto-premotor
hemispheric circuit is activated, providing evidence for a human au-
ditory mirror system (Gazzola et al., 2006). Moreover, the cortical
facilitation due to AO is at its maximum for both acoustic and visual
stimuli linked to the action ( Alaer ts, Swinnen, & Wenderoth, 20 09).
This result agrees with the idea that daily life activities are t ypically
sustained by multiple sensorial experiences and that action produc-
tion is always multimodal. These MN proper ties suggest the fasci-
nating possibility to combine the visual information with the action
sound to maximize the positive effect of AOT in subject s with PD.
Schiavio and Altenmüller (2015) have suggested the use of music in
the rehabilitation of PD. It is well known that periodicity, such as
the fact of matching walking to a musical beat or to a metronome,
improve velocity, cadence, and stride length of parkinsonian gait (del
Olmo & Cudeiro, 20 05). Indeed, as Schiavio and Altenmüller under-
line, “timing and periodicity are fundamental aspects of human gait
and because basal ganglia-cortical circuitry is typically involved in
time-related processes,” musical stimulation could of fer a way to ob-
tain a better sensorimotor coupling (Schiavio & Altenmüller, 2015).
Bacigalupe and Pujol (2014) propose that the external auditory and
visual cues (often used in PD rehabi litat ion) repre sent the main stim-
ulus for the paradoxical kinesia, the phenomenon according to which
PD patients improve their motor per formance thanks to external
stimuli relevant for movement (e.g., bradykinetic PD patients begin,
suddenly and for a while, to run). Provoking this phenomenon would
be po ssibl e by exploiting the two main stream s of the perceptua l-a c-
tion coupling (but above all the dorsal stream, more linked to action)
and the MN system. Exploiting paradoxical kinesia could be useful
in rehabilitation and it could be done by using motor affordances in
recreational and artistic activities.
Efficacy of AOT on cognitive functions
Two recent studies have further examined the role of AOT in PD
rehabilitation, showing significant results in terms of improvement
not only from the motor but also from the cognitive point of view.
In a study by Di Iorio et al. (2018) in cognitively conserved patients
with PD, the improvement in cognitive and motor performance (in-
cluding FoG) thanks to AOT was correlated with a reduction in P300
latency duration (finding which points to changes in cortical activity).
Another study (Caligiore et al., 2019) showed that long-term AOT
could also lead to cognitive improvement in PD patients if utilized
within a dual task framework. In fact, participants significantly pro-
gressed in both shor t-term and long-term verbal memory tasks, in
long-term visuospatial memory, and in some attentional/focusing
aspects (Stroop Test) after the intervention. Interestingly, the im-
provement in both short and long-term memory tests persisted at
follow-up, one month later.
3.2.6 | Motor imagery
Motor imager y is a cognitive process in which subjects imagine
performing a movement without actually doing it (Jeannerod,
2001; Jeannerod & Frak, 1999). MI would mirror the result of con-
scious access to the intention to move (Jeannerod & Decety, 1995).
Since the last decade of the 20th century, many studies have shown
that this process involves many areas also recruited during action
execution (e.g., Abbruzzese, Trompetto, & Schieppati, 1996; Decety,
1996). Among these areas, there are regions thought to be part of
the MN network in humans, such as the premotor cortex and the
IPL. Differently than AOT, which is an implicit and automatic online
process, MI can only be performed offline that is when one is dis-
connected from other potential interactions with other subject s or
object s. It is also clear that there are obvious behavioral differences
among AO, MI, and action execution; they are linked, for example
to motivation, attentional processes, the recollection of a sensitive
initial state to be able to recall kinesthetic sensation for MI—which is
not present in AO—,and the absence of a risk linked to a real execu-
tion in AO and MI. Recently, a review has recapitulated data from
neuroimaging experiments examining MI, AO, and related control
tasks implicating movement execution (Hardwick, Caspers, Eickhoff,
& Swinnen, 2018). These behavioral and neural differences should
be taken into account when planning a rehabilitative training in dif-
ferent neurodegenerative diseases.
Several studies investigated MI in PD with different approaches
(electrophysiological, neuroimaging, and neuropsychological ones)—
results are once again controversial. A TMS research (with an increase
of cortic al excitability; Tremblay et al., 2007) and a neurophysiologi-
cal study (Cunnington et al., 2001) recording movement-related po-
tentials (usually associated with volunt ary movements preparation
and execution) reported an impaired facilitation by MI in PD. Conson
et al. (2014) tested whether the most affected body side influenced
PD patients' ability to mentally manipulate images. PD patients were
specifically compromised in judging laterality of the hand corre-
sponding to their own affected side when presented with back-fac-
ing human figures, in comparison with normal subjects. However, no
difference was found for front-facing figures. Authors hypothesized
that two kinds of whole-body transformation could exist, namely an
“embodied” one, for back-facing figures, and a “perspective” one,
activated for front-facing bodies. However, their interpretation is
questionable and their results could be also interpreted in another
way—a defective “embodied” mechanism could succeed in judging
front-facing figures, but not back-facing ones, because this kind of
judgment is less frequently requested (and therefore exerted) in ev-
eryday life. It must be also kept in mind that aging affects MI abil-
ities, particularly for the non-dominant side of the body (Saimpont,
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FARINA et A l.
Mourey, Manckoundia, Pfitzenmeyer, & Pozzo, 2010; Saimpont,
Pozzo, & Papaxanthis, 2009); this could exert a confounding effec t
in studies focusing on MI, PD, and laterality.
Recent investigations testing MI through ad hoc assessment
batteries did not found differences between PD patients and nor-
mal controls (Heremans et al., 2011; Maillet et al., 2015) both during
the on and off phases (Peterson, Pickett, & Earhart, 2012, see
Abb ru zzese , Ava nzino, March ese, & Pe losin , 2015 for a complete re-
view). A position emission tomography investigation showed that MI
in PD was associated with a normal activation in the supplementary
motor area and a significant activation of the ipsilateral inferior pa-
rietal cortex (both in the “off” and the “on” state) and the ipsilateral
premotor cortex (when “off” only). Inferior parietal cortex hyperac-
tivation could compensate the reduced activation of other areas in
comparison with controls, including the right dorsolateral prefrontal
area, which deals with the working memor y component of the im-
agery task (Cunnington et al., 2001). Other studies (Helmich, Lange,
Bloem, & Toni, 2007; Maillet et al., 2015) hypothesized that neural
compensation mech anism s ca n help pati ents to mai ntain a good per-
formance in MI tasks.
3.3 | Mirror neurons and amyotrophic lateral
sclerosis-frontotemporal degeneration continuum
3.3.1 | MRI studies
Most of the research into MN and ALS (a form of motoneuron dis-
ease [MotND] in which both central and spinal motor neurons de-
generate) or FTD (a common presenile dementia which can display a
spectrum of clinical syndromes, ranging from behavioral impairment
to language or motor deficit, tightly linked to ALS both from the
clinical and genetic point of view) were conducted using magnetic
resonance imaging (MRI). For a summary of the literature searching
about MN and FTD/ALS, see Supporting Information Appendix C.
Li et al. (2015) conducted a study on 30 patients with ALS and 30
matched healthy controls. The participants per formed fMRI while
observing a video of repetitive flexion-extension of the fingers at
three frequencies or difficulties. AO activated brain areas belonging
to the MN system in both ALS and healthy subjects. In ALS patients,
however, the dorsal lateral premotor cortex, inferior parietal gyrus,
and supplementary motor area were more activated in comparison
with controls. Augmented ac tivation within the primary motor cor-
tex, the dorsal lateral premotor cortex, the inferior frontal gyrus, and
superior parietal gyrus was linked with hand movement frequency/
complexity in patients. This finding indicates a constant compen-
satory process happening within the motor-processing network of
ALS patients, in order to compensate the loss of function. However,
a limitation of this study is the fact that it was restricted to action
observation.
Another study suggesting a compensator y response of the MN
system during AO processing in ALS was performed by Jelsone-
Swain, Persad, Burkard, and Welsh (2015). Using fMRI, while subjects
observed an actor's hand rhythmically squeezing a ball or squeezed
themselves a ball, the authors recorded greater activit y in ALS pa-
tients than in controls in MN regions, particularly the right frontal
inferior operculum and the right frontal and left parietal lobes. In
the second part of this same study, Jelsone-Swain et al. (2015) in-
vestigated ALS patients’ ability to recognize actions of other peo-
ple. Participants watched a short video of an actor pantomiming an
action with his hands; they had either to passively observe it or to
“actively recognize” the action by choosing the correct action from
two ph rases dis pl ay ed on the scr ee n. Th e co nt ras t an alysis of the ce-
rebral activity during active recognition versus passive observation
displayed greater activity in various anterior and posterior regions in
the normal group; on the contrary, only in the ALS group the right
occipital activity increased. Patients were then separated into two
groups according to their performance at the recognition task—only
the best performers showed activation in bilateral frontal superior
gyrus. Their performance was also proportional to performance at
the RME test. Thus, social cognition would be affected in some ALS
patients, an impairment which may be related to a MN system dys-
function (Jelsone-Swain et al., 2015).
Jastorff et al. (2016) investigated brain areas which process
emotional stimuli in patients diagnosed with bvFTD. They used both
behavioral testing and structural and resting state imaging. bvFTD
patients performed worse than controls in emotion detection and in
emotion categorization tasks. Their per for mance in emotion catego-
rization inversely correlated with atrophy of the left inferior frontal
gyrus (IFG), a MN area. Functional connectivity analysis also found
lessened connectivity of this area. An explanatory hypothesis could
be that, due to the atrophy of the IFG, the absence of motor mirror-
ing could prevent the recognition of emotions. Similarly, Brioschi-
Guevara et al. (2015) discovered that the atrophy of prefrontal and
premotor regions at structural MRI inversely correlated with the
ability of bvFTD patients to infer intention and emotional beliefs
of others. Marshall et al. (2016) found that grey matter correlates
between impaired emotion recognition and automatic imitation
depended on the dif ferent clinical form of FTD. The brain regions
involved delineated a distributed neural network previously asso-
ciated with embodied cognition. We can conclude that data from
bvFTD patients highly support the role of the MN system in emotion
recognition.
Finally, another study in AL S deserves to be repor ted. Verstraete,
Veldink, van den Berg, and van den Heuvel (2013) investigated the
longitudinal effects of the disease on brain networks using diffusion
tensor imaging. Their analyses revealed an expanding sub-network of
impa ir ed br ai n conne cti on s over time, with a centr al role of the pr im ary
motor cortex and loss of struc tural connectivity mainly propagating to
frontal and parietal brain areas (regions also belonging to the MN net-
wor k). In fa ct, some aut ho rs suggest a po ssible ro le of the MN net wo rk
alteration in the pathogenesis of ALS and FTD. According to Eisen,
Turner, and Lemon (2013), the ALS/FTD complex might be associated
with a disruption of MN. In particular, the damage would involve MN
projecting to the pyramidal tract, along with their sophisticated brak-
ing mechanism, which allows a subject to obser ve an actor and use his
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FARINA et A l.
own motor rep er toire to recognize and categorize the observed move-
ment, without activating his own movements (Kraskov, Dancause,
Quallo, Shep he rd , & Lemo n, 2009) . In ALS/F TD the MN damage woul d
lead to an impairment of different evolutionarily interlinked functions,
associated with the different clinical forms of the disease, in particu-
lar: (a) hand function specialization and the associated development
of bipedalism (associated with the “classical” form beginning from the
upper limbs or to the pseudo-polineuritic form, beginning from the
lower limbs), (b) sound production, swallowing, and breathing (which
the authors designate as “the brainstem functional complex”; this im-
pairment would be associated with the “bulbar” ALS variant), and (c)
cognitive functions linked to social behavior and communication abil-
ity, through gestures and language (associated with FTD). Previously,
Bak and Chandran (2012) had already proposed that dementia associ-
ated with MotND could be interpreted as the fifth major clinical form
of the disease, toget her with bulbar, thoracic and upper and lower limb
presentation. Accordingly, the authors underline that in AL S the most
impaired cognitive functions are those with the tightest functional re-
lations to the motor system, such as verb and action processing (see
also Bak, 2013).
3.3.2 | Neuropsychological studies
A series of neuropsychological researches showed an impairment
of action rather than object naming in ALS (Bak & Hodges, 1997;
Bak, O’Donovan, Xuereb, Boniface, & Hodges, 2001; Grossman et
al., 2008; York et al., 2014) and FTD (Cappa et al., 1998; Hillis, Oh,
& Ken, 20 04). Combining neuropsychological assessment with mor-
phological MRI, York et al. (2014) showed that performance in action
verb judgment was related to gray matter atrophy in bilateral frontal
regions, including motor association cortex and pre-frontal regions.
Similarly, Grossman et al. (2008) had shown that cortical atrophy in
premotor areas associated with the representation of the face, arm,
and leg correlated with performance on measures requiring action
knowledge. This supports the hypothesis that the difficulty shown
by ALS patients in naming actions is partly related to the degradation
of action-related conceptual knowledge represented in the motor-
associated cortex.
Fiori et al. (2013) investigated controls and ALS patient s’ re-
sponses during a task testing the effects of biomechanical con-
straints on MI. Effects present in normal subjects (slower responses
and lower accuracy when participants judged the laterality of a hand
displayed in a position dif ficult to reach with a real movement awk-
ward positions) were compromised in AL S, at least for the proximal
muscles.
Vannuscorps, Dricot, and Pillon (2016), longitudinally examined a
patient with basal cortical degeneration, a clinical picture related to
FTD, and found contra-indicative data compared to previously cited
studies. Throughout 4 years, the patient exhibited worsening action
production disorders with associated growing bilateral atrophy in
cortical and subcortical regions linked to sensorimotor control (tsu-
perior parietal cortex, primary motor and premotor cortices, inferior
frontal gyrus, mostly on the right side, and basal ganglia). Differently,
the patient's performance in processing action-related concepts
(e.g., action naming and action comprehension) was spared during
the same period. These data would defy the idea that action concept
processing is based on the same cognitive and neural networks un-
derlying the sensorimotor control of actions (Meteyard, Cuadrado,
Bahrami, & Vigliocco, 2012). However, the moderate involvement of
MN areas on the left side could have allowed the maintenance of
behavioral performances.
3.4 | Mirror neurons and mild cognitive impairment/
Alzheimer's disease continuum
Over the years, many studies have investigated the neurophysiologi-
cal and neuroimaging correlates of AD, the most frequent cause of
dementia, and MCI—a category characterized by cognitive decline
greater than expected for an individual's age and education level
without loss of independence in ever yday life, at high risk of de-
veloping dementia (Busse, Bischkopf, Riedel-Heller, & Angermeyer,
2003; Petersen et al., 1999, 20 01). Among these works, only a few
studies have focused on the link between MCI/ AD and MN. For
a summary of the literature investigating MN and AD/MCI, see
Suppor ting Information Appendix D.
3.4.1 | EEG spectral analysis
Recently, 74 adult subjects with MCI undertook EEG recording and
high-resolution MRI by Moretti (2016). Alpha3/alpha2 frequency
power ratio and cortical thickness were computed for each sub-
ject. This ratio represents the increase in high alpha frequencies
relatively to low alpha power; it has been demonstrated as a reli-
able EEG marker of hippocampal atrophy and its increase has been
found in MCI subjects who will convert in AD (Moret ti et al., 2011).
High EEG alpha3/alpha2 frequency power ratio was correlated with
atrophy of cortical regions pertaining to the posterior MN network
(IPL) areas in MCI subjects. Thus, a possible pathological uncoupling
of the MN system would justify the cognitive deficits in prodromal
AD. The location of the IPL at the junction of the parietal, temporal,
and occipital lobes makes it ideally situated to perform cross-modal
integration (hearing/vision/proprioceptive); its impairment would
induce both praxis, language, calculation, and topographical deficits
charac te ri zi ng AD, a hypothe sis wh ic h ag re es wit h traditi on al neu ro -
logical views (Greene, Killiany, & Alzheimer's Disease Neuroimaging
Initiative, 2010).
3.4.2 | TMS studies
In a study by Cotelli et al. (2006), TMS of both left and right dorsolat-
era l prefrontal areas—w ith a frequenc y of 20 Hz lea ding to an increase
of cortical excitability—ameliorated action naming but not object
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naming in 15 AD patients. Similar results were obtained for a mild AD
group (Cotelli, Manenti, Cappa, Zanetti, & Miniussi, 2008), while an
improved naming accuracy for both action and objects was found in
the moderate to severe group. These results raise the interesting pos-
sibility of improving language performance in AD via magnetic stimu-
lations of the motor system, but are dif ficult to interpret. The role of
the dorsolateral prefrontal cortex in action naming must be further
elucidated. A possibility might be the fact that this cerebral area can
intervene by selecting and combining motor representations in the
MN system (Vogt et al., 20 07); therefore, stimulation of dorsolateral
prefrontal cortex might facilitate MN activation and consequently
naming of action (if we accept the embodied nature of language). In
contrast, according to a recent study (Lanzilot to, Gerbella, Perciavalle,
& Lucchetti, 2017) in the dorsolateral prefrontal cortex there are also
neurons with mirror-like propert ies, which re ac t to bot h self and othe r
people head rotation.
3.4.3 | fMRI studies
Rattanachayoto, Tritanon, Laothamatas, and Sungkarat (2012) ex-
amined the MN system abnormalities in MCI and AD through a
fMRI study. Ninety-two subjects (five MCI, seven mild AD, and 80
cognitively normal) were studied. Participants had to obser ve a
video showing the movement of a hand (tearing a piece of paper)
or a control condition (observing a fixation point). Observing
the hand movement elicited significant activations of the infe-
rior bilateral frontal lobule and the IPL, but brain activations of
controls were significantly higher than those in the MCI and mild
AD groups (with no significant difference between these last two
groups). Similar to Moret ti's study (2016), this study suggests that
a dysfunction of the MN system might play a role in cognitive im-
pairment due to MCI/AD, even if we must be cautious in this con-
clusion because the number of MCI and AD subjects examined
was l ow.
Recently, another study investigated the MN network func-
tioning in people with MCI and AD, alongside with its relationship
to cognitive performance (Farina et al., 2017). In this study, three
matched groups of 16 subjects each (normal elderly, amnesic MCI
with hippocampal atrophy, and AD) were assessed with a fMRI
task specifically created to test MN and a focused neuropsycho-
logical batter y. The MN network appeared largely conserved in
aging, while it seemed involved according to an anterior–poste-
rior gradient in neurodegenerative cognitive deterioration. In AD
the MN net work appeared clearly deficient. The authors specu-
late that the conser vation of t he anterior part of the MN net work,
found in MCI, could possibly compensate the initial decay of the
posterior part, preserving cognitive performance, particularly in
task (such as RME) related to abilities thought to be linked to MN
(see Fi gur e 2 for a gra phi c al re p re s ent ati on of th e res ult s of st udy ).
It is interesting to note that an fMRI study focusing on mindread-
ing (or theory of mind; Baglio et al., 2012) similarly found a pre-
served per forma nce at RM E in peopl e wit h MCI , des pi te a re duced
activation of some posterior regions of the mind reading network.
In the study of Farina et al. (2017) an increased activation of the
lef t Broca area (B 44), thou ght to be a node of the MN system, was
observed. This result suggests that the preservation and maybe
hype r act i vat io n of MN pr efr ont a l are as co uld pl ay a co mpe nsa tor y
role.
Another study, conducted by Peelle, Powers, Cook, Smith, and
Grossman (2014), tested a semantic judgment task, involving shape
and color of natural kinds or manufactured items. AD patients were
impaired in this task, exhibiting significantly reduced activation in
the left tem poral-occipit al cor tex than hea lt hy eld er ly peop le and di-
minished activity in the left inferior frontal cortex. According to the
authors, these results agree with a sensor y-motor approach of se-
mantic memor y; knowledge associated with objec t concepts would
be stored in brain regions that are responsible for perceptual and
motor functions of a certain material (Barsalou, Simmons, Barbey, &
Wilson, 2003).
FIGURE 2 Graphical representation of the functioning of the mirror neurons network (Farina et al., 2017): (a) normal elderly controls, (b)
subjects with MCI, (c) subjects with AD. Areas belonging to the mirror neurons network activated at the specific fMRI task are represented
in blue. The intensit y of the blue color is proportional to the intensity of activation. Areas in white are the less activated. Areas in pale green
are represented to show the connections of the mirror neurons network. AD, Alzheimer's disease; CBL, cerebellum; IPL, inferior parietal
lobule; IFG, inferior frontal gyrus; MCI, mild cognitive impairment; SMC, sensorimotor cortex; STS, superior temporal sulcus
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FARINA et A l.
Fin al ly, an fMR I st ud y by Lee, Sun, Leun g, Chu , an d Key se rs (2013)
aimed at evaluating neural activities during the processing of facial
expressions in AD patients. The patient s showed weaker activations
in left cerebral regions associated with MN or empathic simulation
(ventral premotor co rtex, ante rior insula, and fro ntal operc ulu m) com-
pared to matched controls. Notably, levels of brain activation in those
regions forecasted the level of affect in the AD group. Thus, neural
changes in areas associated with motor and emotional simulation
(co mpr ise d MN regi ons) coul d be rele van t in the pr og res s of AD sym p-
toms and explain affective impairment associated with this disease.
3.4.4 | Behavioral studies
In a first study Bisio et al. (2012) tested if the implicit imitation is
preser ved in mild to moderate AD patients. AD patient s and healthy
elderly controls had to obser ve a dot moving on a screen and to
point to its final position when it stopped. The dot speed similarly
influenced the actions of AD patients and of healthy elderly partici-
pants, suggesting that perception-action matching is not precluded
by the disease. In contrast, only patients had an anticipator y motor
response, that is they began to move before the end of the stimulus
motion, in contrast to the request by the examiner. The imitation of
the stimulus speed suggests a conserved ability to match the internal
motor representations with that of the visual model; however, the
uncontrolled motion initiation would indicate AD patients’ inabilit y
to voluntarily inhibit response production. The authors hypothesize
that the first part of their results would point to the relative preser-
vation of the MN network (responsible of perception-action match-
ing). However, MN parietal areas such as IPL would be more affected
than frontal ones, leading to impaired movement inhibition.
In th e seco nd exp e rim e nt (B isi o et al., 2016), th e auth o rs te ste d
voluntary imitation in AD and how this ability was influenced by
the nature of the observed stimulus. To this end they compared
the capability to reproduce the kinematic features of a human
model with that of a dot moving on a screen. The dot's motion
(at three different velocities) reproduced the characteristics of a
human vertical movement. Participants had to observe the move-
ment of the dot until it reached its final position. When the dot
stopped, the subjec ts were asked to replicate its movement. The
human model was a young person previously trained to make ver-
tical simple arm movement s at three different velocities. Results
showed that, when asked to imit ate the velocity of the stimulus,
AD patients presented an intact capacity to reproduce it. This ca-
pa cit y impr ove d w hen th e s ti m ulu s was a hu man ag ent . Thes e data
sug gest that hig h-l eve l cogniti ve processes lin ked to vo luntar y im-
itation could be conserved in mild-moderate stages AD and that
voluntary imitation capacities could profit from the implicit in-
terpersonal communication existing between the patient and the
human model. These findings make available new clinical views
and innovative method s in training programs for people with early
dementia. The conservation of the motor resonance mechanisms,
not reliant on conscious awareness, finds an intac t basis upon
which clinicians could model both physical and cognitive interven-
tions for healthy elderly, MCI, or early AD patients. Furthermore,
by stimulating the voluntary imitation of ever yday activities, the
caregivers might help the patients to maintain intact, as long as
possible, the ability to easily move in their familiar environment
and to feel that they are still part of their family community.
3.4.5 | Neuropsychological studies
Some studies pointed out a more severe loss in action than in object
naming in AD patients (Druks et al., 20 06; Kim & Thompson, 2004;
Robinson, Grossman, White-Devine, & D'Esposito, 1996), even if at
a minor extent than in FTD (Cappa et al., 1998). In contrast, other
researchers reported that nouns were more impaired than verbs
in AD patients (Williamson, Adair, Raymer, & Heilman, 1998) or did
not report any difference bet ween nouns and verbs (Masterson et
al., 2007; Rodríguez-Ferreiro, Davies, González-Nosti, Barbón, &
Cuetos, 20 09).
Other studies have shown deficits among individuals with AD in
recognizing facial emotions (Bediou et al., 2009; Guaita et al., 2009;
McLellan, Johnston, Dalrymple-Alford, & Porter, 2008), mainly in
the recognition of happy, sad, and fearful expressions (Kohler et al.,
2005). These data, alongside with the fMRI study by Lee et al. (2013),
appear coherent with a putative impairment of the MN network in
AD, since this network (and particularly the inferior frontal gyrus and
the ventral premotor cortex) is involved in recognizing other people
emotions. However, we must recognize that data about the relatio n-
ship between emotion recognition and the MN system in AD are
scarce in comparison with PD and FTD.
De Scalzi, Rusted, and Oakhill (2015) found a conservation of
the action compatibility ef fect in people with AD; when patients are
requested to make judgments on sentences that designate a trans-
fer of an object toward or away from their body, they are faster to
answer when the response needs a movement in the same direction
as the transfer defined in the sentence. This raises the possibilit y
to exploit the motor systems to improve language comprehension
of AD (e.g., by requiring per forming the action while listening to a
sentence).
3.4.6 | Rehabilitative studies
AOT, which is a mean to stimulate the MN network, has been pro-
posed as a rehabilitative motor tool (see Bassolino et al., 2015 for
a review). However, AOT could also play a role in maint aining cog-
nitive func tions, if one accepts the indissociable nature of cogni-
tion from the motor system. So far, the only published research
about AOT with AD is from Eggermont, Swaab, Hol, and Scherder
(2009). Nursing home residents with dementia observed either
videos showing hand movements (19 subjects) or a documentar y
(25 subject s) for 30 min, 5 days a week, for 6 weeks. At the end of
treatment, patient s showed improvements in attention and facial
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FARINA et A l.
recognition (which depends on the superior temporal sulcus, a re-
gion tightly linked to the MN system). A preliminar y research in
progress, performed on small groups (nine each) of patients di-
agnosed with mild-to-moderate AD, compared AOT with multidi-
mensional stimulation (Spada, 2012). The data analysis showed a
significant improvement bet ween test and retest in a naming ac-
tion task. However, rece ntly an intervention focused on MN in AD
patients showed negative results (Caffarra et al., 2016, oral com-
munication at XI Sindem National Congress, Florence, Italy). If the
MN network is already disturbed in the pre-dementia phase, as
suggested by Moretti’s (2016) and Farina et al.'s (2017) studies,
AOT would result ineffective as a rehabilitation technique in mod-
erate AD, and it should be rather performed in the MCI or at least
in the early phase to achieve positive results.
4 | CONCLUSION AND PERSPECTIVES:
FUTURE DIRECTIONS FOR CLINICAL
APPLICATION RELYING ON THE
RELATIONSHIP BETWEEN THE MN SYSTEM
AND NEURODEGENERATIVE DISEASES
The traditional model, according to which almost all studies on neu-
rodegenerative diseases have been conducted, considers cognitive
abilities as high-level supervisor functions, which utilize perception
and action as separated low-level systems. Reinterpreting neuro-
degenerative diseases at the light of the new views about brain or-
ganization stemming from the discovery of MN and the embodied
cognition hypothesis could help a better comprehension of clinical
manifestations and open new pathways to rehabilitation. According
to Vallet (2015), exploring embodiment (supported by the MN sys-
tem) in normal and abnormal aging would be of interest from a the o-
retical point of view, as becoming older is accompanied by changes
in all cerebral, sensory, and bodily functions. It could also be useful
in clinical practice, because it would possibly allow to develop inter-
ventions to help patients.
Data about the status and role of the MN network in neurode-
generative diseases are poor with the partial exception of PD. A
hypothetic conclusion of existing studies in PD could be that the
MN network is in some way altere d in this diseas e (the rationale in
this case could be the degeneration of cortical-subcortical loops
linking the basal ganglia to the frontal cortex); an hyperactivation
of this system might support motor and cognitive per formances,
at least in early stages, while in later stages the more severe im-
pairment of the MN network could prevent compensation at least
in a part of patients (see Figure 3). The dopaminergic state and
DBS could have a role in compensating the functional deficit s of
circuits linked to motor cognition, too. The compensation mecha-
nism could explain why studies on AOT as a rehabilitative method
for people with PD report positive results. Interestingly, a very
recent study on mild-to-moderate PD patients showed that they
can be highly influenced by motor contagion induced by AOT also
in a negative sense (Pelosin et al., 2018). Most studies in the field
of PD rehabilitation have recruited very small samples. In contrast,
it must not be forgot ten that, in rehabilitative studies, studying
large samples of people does not allow to individualize the treat-
ment according to the clinical picture that, as we have seen, can
be ver y various along the course of the disease in each patient.
Therefore, in the field of rehabilitation, the ideal situation would
be often to characterize each patient to follow him/her as a single
case experiment.
In the ALS/FTD continuum, preliminary evidence points out an
involvement of the MN net work, a possibility which is not unex-
pected, as MN are primarily motor neurons. The MN system decay
could explain language and inter-subjectivity deficits shown in these
patients. In the MCI/AD spectrum, data are very scarce. Most re-
cent studies suggest a possible progressive involvement from pos-
terior to anterior areas of the MN network, with the brain putting in
place compensatory mechanisms for this decay (Farina et al., 2017;
Moretti, 2016; Moretti et al., 2011). However, more researches are
needed to confirm this hypothesis, also because previous behav-
ioral researches partly pointed in the opposite direction. In general,
FIGURE 3 Graphical representation of the functioning of the mirror neurons network in PD: (a) normal elderly controls, (b) subjects with
mild PD, (c) subjects with severe PD. Areas belonging to the mirror neurons net work are represented in blue. The intensity of the blue color
is propor tional to the intensity of activation according to literature. Areas in white are the less activated. Areas in pale green are represented
to show the connections of the mirror neurons network: the intensit y of the color is proportional to degeneration. CBL, cerebellum; IPL,
inferior parietal lobule; IFG, inferior frontal gyrus; PD, Parkinson's disease; SMC , sensorimotor cortex; STN, subthalamic nucleus; STR,
striatum; STS, superior temporal sulcus
|
17
FARINA et A l.
it could be very stimulating to study MNs with neurophysiological
techniques (maybe easier to perform with cognitively compromised
people) or fMRI and correlating data with neuropsychological tests
exploring functions traditionally linked to MN, behavioral measures,
and motor scales.
AOT, which stimulates the MN network, might be a power ful
tool to improve motor, language, and/or social cognition deficits in
people with PD or FTD. Based on the supposed role of the motor
system in memory building-up, it may also be hypothesized that MN
stimulation through AOT could maintain and speed up the execu-
tion of complex motor sequences needed to perform activities of
daily living. It could also facilitate the formation of memory traces of
actions executed during a normal day in people with AD or at least
with MCI. The possibility to exploit the motor resonance to stimulate
cognitive function in the frame of rehabilitation of neurodegener-
ative pathologies appears fascinating because it could represent a
therapeutic solution that does not exist yet. Specific drugs have still
not been approved for the MCI phase and pharmacotherapy effects
are extremely limited in AD (Petersen et al., 2017; Raina et al., 2008);
cognitive stimulation and serious game trainings have positive but
limited effects (Hill et al., 2017; Manera et al., 2017; Woods, Aguirre,
Spector, & Orrell, 2012) probably because of training performed in
artificial environment and developing specific skills not transfer-
able to daily normal life activities. No substantial pharmacological
therapy is available for ALS/FTD. Even in PD, where various drugs
are available, they have only symptomatic effects and do not avoid
progression of the motor and cognitive impairment. Other advan-
tages of a rehabilitative treatment based on motor cognition are the
fact that it promotes an active involvement of the patient in her/his
recovery process instead of rendering him/her a passive medicine
consumer, and the large possibility to easily personalize the training.
Finally, protocols based on motor cognition, which is easy and
cheap to implement and less risky than pharmacotherapy, might
have a strong impac t on prevention of neurodegenerative diseases
in the growing elderly population, a very interesting perspective
from the public health point of view. As usual in neurodegeneration,
a preventive intervention could in fact be far more effective than an
intervention applied in the overt phase of the disease. This view is
supported both by data coming from PD studies (Anders et al., 2012)
and by recent data on the MCI/AD spec trum (Farina et. al., 2017;
Moretti, 2016; Vallet et al., 2017).
ACKNOWLEDGMENTS
The authors are very grateful to professor Leonardo Fogazzi for his
precious suggestions and revisions. They are also grateful to Angelo
G. Gaillet and Shaun Stratford for English revision.
CONFLICT OF INTEREST
The authors have no competing interest to declare.
AUTHOR CONTRIBUTIONS
Conceptualization, E.F. and T.P.; Data Curation, E.F. and F.B.; Formal
Analysis, E.F.; Funding Acquisition, E.F.; Investigation, E.F.; Methodology,
E. F.; Writing – Original Draft, E.F. and T.P.; Writing – Review & Editing,
E.F., F.B., and T.P.; Project Administration, T.P.; Supervision, T.P.;
Validation, T.P.
ORCID
Elisabetta Farina https://orcid.org/0000-0002-9160-0356
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SUPPORTING INFORMATION
Additional supporting information may be found online in the
Supporting Information section.
Appendix A: Table 1
Appendix B: Table 2a. Summary of experimental studies investigat-
ing embodied cognition and/or mirror neurons in Parkinson disease –
neurophysiological studies
Appendix B: Table 2b. Summary of experimental studies investigat-
ing embodied cognition and/or mirror neurons in Parkinson disease –
fMRI studies
Appendix B: Table 2c. Summary of studies investigating embodied
cognition and/or mirror neurons in Parkinson disease – behavioral
studies
Appendix B: Table 2d. Summary of experimental studies investigat-
ing embodied cognition and/or mirror neurons in Parkinson disease –
action observation training for PD rehabilitation
Appendix C: Table 3a. Summary of experimental studies investigat-
ing mirror neurons in F TD or ALS – MRI studies (or behavioral/neu-
ropsychological and MRI studies)
Appendix D: Table 4a. Summary of experimental studies investigat-
ing embodied cognition and/or mirror neurons in AD/MCI – correla-
tion between morphological MRI data and EEG spectral analysis
Appendix D: Table 4b. Summary of experimental studies investigat-
ing embodied cognition and/or mirror neurons in AD/MCI – TMS
studies
Appendix D: Table 4c. Summary of experimental studies investigat-
ing embodied cognition and/or mirror neurons in AD/MCI – fMRI
studies
Appendix C: Table 3d. Summary of experimental studies investigat-
ing embodied cognition and/or mirror neurons in AD/MCI – behav-
ioral studies
Appendix D: Table 4e. Summar y of experimental studies investigat-
ing embodied cognition and/or mirror neurons in AD/MCI – neuro-
psychological studies
Appendix D: Table 4f. Summary of experimental studies investigat-
ing embodied cognition and/or mirror neurons in AD/MCI – rehabil-
itative studies
Transparent Peer Review Report
How to cite this article: Farina E, Borgnis F, Pozzo T. Mirror
neurons and their relationship with neurodegenerative
disorders. J Neuro Res. 2020;00:1–25. h t t p s : / / d o i .
org/10.1002/jnr.24579
