Curr Neurol Neurosci Rep (2016) 16:73
DOI 10.1007/s11910-016-0676-z
BEHAVIOR (H KIRSHNER, SECTION EDITOR)
Alien Hand Syndrome
Anhar Hassan 1 & Keith A. Josephs 1
# Springer Science+Business Media New York 2016
Abstract Alien hand syndrome (AHS) is a rare disorder
of involuntary limb movement together with a sense of
loss of limb ownership. It most commonly affects the
hand, but can occur in the leg. The anterior (frontal,
callosal) and posterior variants are recognized, with
distinguishing clinical features and anatomical lesions.
Initial descriptions were attributed to stroke and neurosur-
gical operations, but neurodegenerative causes are now
recognized as most common. Structural and functional
imaging and clinical studies have implicated the supple-
mentary motor area, pre-supplementary motor area, and
their network connections in the frontal variant of AHS,
and the inferior parietal lobule and connections in the
posterior variant. Several theories are proposed to explain
the pathophysiology. Herein, we review the literature to
update advances in the understanding of the classification,
pathophysiology, etiology, and treatment of AHS.
Keywords Alien limb . Stroke . Corticobasal syndrome .
Frontal . Callosal . Parietal
This article is part of the Topical Collection on Behavior
* Anhar Hassan
hassan.anhar@mayo.edu
Keith A. Josephs
josephs.keith@mayo.edu
1
Department of Neurology, Mayo Clinic, 200 1st Street SW,
Rochester, MN 55905, USA
Historical Background
The first description of alien hand syndrome (AHS), by
Goldstein in 1908, was of a 57-year-old female who felt her
left hand had a will of its own and grabbed her throat; it took
her great effort to restrain her hand. Autopsy identified strokes
in the right hemisphere and corpus callosum [1]. Multiple
descriptions of patients with involuntary limb movements
subsequently emerged throughout the twentieth century. A
variety of nomenclatures were offered to describe their differ-
ing clinical characteristics. In the 1940s, Akelaitis reported
two patients with involuntarily left hand movements after cor-
pus callosotomy for intractable seizures, where the left hand
acted in conflict and opposition to the right hand. This was
termed Bdiagonistic dyspraxia^ [2]. In the 1950s, Denny-
Brown used the term Bmagnetic apraxia^ to describe compul-
sive unilateral hand groping and grasping of objects following
frontal lobe ablation [3]. In 1972, Brion and Jedynak first used
the term Ble signe de la main étrangère^ (Bthe sign of the
foreign hand^) for patients with corpus callosum tumors.
These patients lost recognition of their left arm when it was
held by their right arm behind their back, with inability to
transfer functions between hemispheres, but without sensory
loss or involuntary movements [4]. Bogen reported
Bintermanual conflict^ (IMC) when the non-dominant hand
(usually left) is activated by conversation or voluntary activa-
tion of the dominant (right) hand. It behaves as foreign and
performs simultaneous conflicting actions during unilateral
normal limb actions or bimanual tasks (e.g., tying shoelaces,
buttoning shirt, using a knife and fork) [5]. Bogen borrowed
Brion and Jedynak’s term and translated it to Balien hand^ to
describe a milder form of IMC in patients with surgical
callosal lesions [5].
73 Page 2 of 10
Thereafter in the literature, alien hand has remained the
preferred terminology. In the 1990s, Goldberg used the term
Balien hand^ to describe two patients with right hand grasping
and impulsive limb groping behavior against their will, de-
spite visual guidance, and recognizing the limb as their own.
Strokes were identified in the left medial frontal cortex and
callosal areas [6]. Common features were noted between
Bogen’s (callosal) and Goldberg’s (frontocallosal) AHS.
Damage to the mesial frontal cortex may have occurred during
surgical retraction for callosotomy in Bogen’s cases
explaining some similarities. Della Sala et al. proposed the
term Banarchic hand^ where the patient retained awareness
that self-conflicting limb movements were inappropriate, in
contrast to Balien hand^ if they were unaware of this [7]. In
1992, Feinberg classified the alien hand syndrome into two
anterior variants, a frontal variant (grasp reflex, groping, and
compulsive manipulation of tools) and a callosal variant (IMC
and lack of frontal features), with different anatomical features
[8].
In 1986, Levine and Rinne described Bopticosensory atax-
ia^ for spontaneous movements of the left arm attempting to
choke and stroke the patient, following right temperoccipito-
parietal and thalamic infarcts. Although similar to Goldberg’s
AHS, there was severe ataxia, sensory loss, no grasp reflex,
and no frontal or callosal lesions [9]. Therefore, Levine and
Rinne’s cases could not be included in Feinberg’s classifica-
tion. In 1998, Ay reported a sensory variant of alien hand with
less complex involuntary limb movements and sensory defi-
cits and lacking frontal or callosal lesions [10]. This became
termed posterior variant to distinguish it from the anterior
variants [11]. Doody and Jankovic proposed a new definition
for alien hand syndrome as Bfailure to recognize ownership of
one’s own limb as well as the body part feeling foreign togeth-
er with involuntary motor activity^ [12]. However, foreign-
ness is not consistently present in all alien hand variants [6].
Aboitiz in 2003 proposed that there should be five variants
[13]. However, most consensus in the literature currently re-
fers to three variants: frontal, callosal, and posterior.
Anterior Variants
Frontal Variant
The frontal form most commonly affects the dominant (right)
hand, characterized by impulsive groping, compulsive manip-
ulation of objects, and difficulty releasing objects when
grasped. Additional features include other frontal lobe signs
(leg or arm weakness, non-fluent speech, grasp reflex) [6, 8,
14]. The patient is aware that the arm belongs to them but is
unable to voluntarily suppress movements [15]. They may try
and restrain the limb by sitting on it or holding it between their
legs [15]. It is usually due to a dominant (left) medial frontal
Curr Neurol Neurosci Rep (2016) 16:73
lobe lesion (medial prefrontal cortex, supplementary motor
area) with or without involvement of the corpus callosum
(anterior cingulate gyrus, anterior corpus callosum, or callosal
genu) [8, 12]. It is most commonly a result of stroke in the
anterior communicating artery territory, which supplies the
medial frontal cortex and anterior callosum. Historical exam-
ples are Denny-Brown’s magnetic apraxia and Goldberg’s
AHS.
Callosal Variant
The callosal form exclusively affects the non-dominant (left
hand) in right-handed patients. It is characterized by IMC,
with minimal limb weakness and absence of frontal features.
(Feinberg, Goldberg). Other clinical features of the callosal
disconnection syndrome are present (apraxia, tactile anomia,
visual anomia, agraphia, neglect, alexia) [16, 17]. It is mostly
caused by isolated corpus callosum injury [8, 18–20]. It is
most commonly due to surgical resection (callosotomy),
callosal hemorrhage or infarct, or callosal demyelination.
Historical examples include Akelatis’ diagonistic dyspraxia
and Bogen’s AHS (considered synonymous with diagonistic
dyspraxia) [21].
Mixed frontal and callosal AHS due to mesial frontal and
extensive callosal lesions have been reported [22]. They typ-
ically have more grasping behavior and compulsive manipu-
lations, with limb weakness contralateral to the affected
hemisphere.
Posterior Variant
The posterior variant more commonly affects the non-domi-
nant (left) hand [23]. It is associated with strong feelings of
estrangement from the affected limb, less complex motor ac-
tivity (e.g., limb levitation, ataxia, non-purposeful or non-
conflicting movements), and parietal sensory deficits (visual
or sensory neglect, body schema dysfunction,
hemiasomatognosia, spatial neglect, or astereognosis). The
lesion is typically in the non-dominant (right) parietal lobe
(posterior postcentral gyrus, posterior primary sensory cortex,
and tertiary somatosensory cortex in the superior parietal lob-
ule) [23]. Uncommonly, the occipital lobe and thalamus are
involved [24]. [9, 25, 26] Common etiologies are neurodegen-
eration of the parieto-occipital cortex (corticobasal syndrome
[CBS], Creutzfeldt-Jakob disease [CJD]), and stroke in the
parietal lobe or posterior cerebral artery territory [27•].
Historical examples include Levine and Rinne’s Bopticosensory
ataxia.^
Exceptions to the classification scheme do not infrequently
occur. For example, posterior AHS may affect the dominant
hand with CBS or dominant lobe stroke; or a patient may
experience anterior variant AHS due to a parietal lobe lesion
[28–31].
Curr Neurol Neurosci Rep (2016) 16:73 Page 3 of 10 73

Clinical Symptoms/Signs Table 1 Causes of alien hand syndrome

Etiology Examples
AHS most commonly affects the non-dominant (left) hand
[32•]. It may also affect the leg so findings are not always Neurodegeneration Corticobasal syndrome (CBS) [12, 27•]
confined to the upper limb [12, 22, 27•, 33]. The location, Corticobasal clinical overlap syndromes (with
progressive supranuclear palsy (PSP), posterior
onset, temporal progression, and associated clinical fea- cortical atrophy, primary progressive aphasia,
tures can be explained by the etiology. It is mostly multiple system atrophy, dementia with Lewy
unilateral but can become bilateral with neurodegenera- bodies) [27•]
tive disorders or bilateral strokes [12, 27•, 34]. Subacute CBS with PSP pathology [79]
Alzheimer’s disease [27•]
onset is most common, seen with neurodegenerative dis- Progressive dementia, not otherwise specified [27•]
orders [12]. Sudden onset AHS may occur with a stroke Thalamic dementia [27•]
[35, 36]. It may be the first presenting sign of CJD Stroke Frontal lobe infarct (contralateral medial) [80]
followed by other classical findings [32•]. Alien hand Anterior communicating artery stroke/rupture [15,
typically progresses in neurodegenerative causes with 20, 81]
Corpus callosal infarct, hematoma [41, 74, 82]
spread to ipsilateral or contralateral limb(s) over months Intracranial hemorrhage [27•, 73]
to years [27•]. In comparison, it commonly improves Subdural hematoma [27•]
weeks to months following a stroke [15, 30, 37]. It may Parietal infarct [68]
also be short-lived or intermittent in metabolic causes, Thalamic infarct [25]
Occipital infarct [10]
multiple sclerosis or stroke [38, 39]. While it mainly af-
Prion disease Sporadic Creutzfeldt-Jakob disease [32•]
fects middle-aged to older adults, a pediatric case has
Familial Creutzfeldt-Jakob disease [43]
been reported associated with Parry-Romberg syndrome
Tumors Midline tumors [83]
[40]. The patient may have an emotional response to the Astrocytoma [27•]
AHS. They may express self-criticism, frustration, and Oligodendroglioma [27•]
annoyance with the limb. They may hit it, admonish it, Demyelination Unspecified demyelinating disease [27•]
or personify it as Bmischievous.^ They may not perceive it Multiple sclerosis [38]
Marchiafava-Bignami disease [84]
not as their own, thus truly alien [14]. Rarely, they may be
Progressive multifocal leukoencephalopathy [27•]
frightened by it [35, 36]. Hereditary diffuse leukoencephalopathy with
spheroids [27•]
Etiologies Iatrogenic Corpus callosotomy [5]
Electrical cortical stimulation [72]
Radiation treatment of oligodendrioglioma [85]
The most commonly reported causes in the early literature
Resection of frontal lobe tumor [86]
were stroke and iatrogenic. However, with the decline of sur-
Seizures Epilepsia partialis continua [87]
gery and increased recognition of AHS, the most common Ictal event [72]
causes now are CBS, stroke, and CJD. In the last 5 years, Developmental Parry-Romberg syndrome [40, 88]
single case reports of many other etiologies have been de- Miscellaneous Migraine aura [89]
scribed (See Table 1). Posterior reversible encephalopathy syndrome [27•]
The largest AHS case series to date (n = 150) con- Spontaneous pneumocephalus [90]
firmed CBS (n = 108) as the most common cause, Diabetic hyperosmolar non-ketotic state with
leukoariosis [91]
followed by stroke (n = 14), CJD (n = 9), hereditary dif-
fuse leukoencephalopathy with spheroids (n = 5), tumor
(n = 4), progressive multifocal leukoencephalopathy
(n = 2), demyelinating disease (n = 2), progressive de- are more likely to produce AHS than left-sided infarcts, pre-
mentia not otherwise specified (n = 2), posterior revers- senting as a subacute posterior AHS, or acute hemiparesis and
ible encephalopathy syndrome (n = 1), corpus dysarthria followed months later by AHS. Strokes due to an-
callosotomy (n = 1), intracerebral hemorrhage (n = 1), terior cerebral artery infarcts typically cause contralateral leg
and thalamic dementia (n = 1) [27•]. plegia and aphasia (which resolves) followed by AHS [8, 21].
Stroke subtypes reported include infarcts, hematoma, intra- In a large series of 100 cases of anterior cerebral artery stroke
cranial and subdural hemorrhages. The typical locations are in (with infarcts in corpus callosum, cingulate gyrus, or supple-
the contralateral anterior communicating artery territory, cor- mentary motor area [SMA]), alien limb occurred in 10 %.
pus callosum, parietal lobe, or posterior cerebral artery terri- There was not a specific infarct location associated with
tory [10, 26, 27•, 37, 41]. Although frontal and callosal strokes AHS however [42]. Strokes of the corpus callosum are rare
were first associated with AHS, parietal infarcts are more and can produce mixed callosal and posterior variant AHS
commonly reported now [27•]. Right-sided parietal strokes [16, 37].
73 Page 4 of 10
Corticobasal syndrome may manifest in some patients
with AHS accompanied by other typical features (parkin-
sonism, myoclonus, cortical sensory, or language deficits).
If the right hemisphere is affected in CBS, there is a
strong association with development of left AHS [27•].
Other neurodegenerative causes include CBS spectrum
disorders and Alzheimer’s disease [27•]. Both the sporad-
ic and familial variants of CJD may manifest alien limb
[32•, 43]. Similar to parietal stroke, AHS is most common
in the non-dominant (left) hand in CBS and other neuro-
degenerative disorders.
Differential Diagnosis
A number of disorders may present with complex involuntary
limb movements or a sense of loss of ownership of limb control,
but the characteristics are different from the alien limb variants
(See Table 2). It is critical to keep in mind the clinical features of
alien hand, and the company it keeps, when diagnosing AHS.
Pathophysiology
Clinicopathologic studies provided the initial insights to AHS.
Over the past 30 years, structural and functional imaging and
other investigative modalities have contributed to understand-
ing AHS.
Supplementary Motor Area Lesioning
The SMA, located on the mesial surface of the frontal lobe, is
involved in motor planning and initiation, as well as inhibi-
tion. It has direct projections to the primary motor cortex,
reciprocal connections with the contralateral SMA, and pri-
mary motor cortex, plus extensive cortical and subcortical
Table 2 Differential diagnosis of
alien hand syndrome Disorder
Grasp reflex
Utilization behavior
Hemineglect
Mirror movements
Pseudoathetosis
Task-specific limb dystonia
Focal dystonia
Hemiballismus
Hemiataxia
Curr Neurol Neurosci Rep (2016) 16:73
connections [44]. Early frontal lobe ablation studies produced
unilateral limb compulsive tactile exploration or Bmagnetic
apraxia,^ which was a more elaborate behavior than the grasp
reflex [3, 45, 46]. Damage to the cingulate gyrus, area 8, and
the SMA was proposed to result in these exaggerated positive
exploratory behaviors [3]. Lhermitte extended this theory for
bilateral magnetic apraxia, observed in patients with left or
right unilateral or bilateral frontal lesions, which he termed
Butilization behavior.^ He speculated that the inhibitory func-
tion of the frontal lobes on the parietal lobes was impaired.
This resulted in a release of parietal lobe activity, driven by
external visual and tactile inputs. Thus, presentation of objects
within reach of the hands or the visual field compels the pa-
tient to grasp and use the object [47].
Asymmetry of hemisphere function was proposed to explain
why frontal AHS predominantly affects the right hand [8]. It
depends on whether the SMA lesion is ipsilateral or contralat-
eral to the dominant hand. The right SMA is dominant for
inhibition and inhibits both right and left cortex, whereas the
left SMA inhibits only the right limb [28]. The characteristics of
AHS may also depend on whether hypokinesia is present, in
addition to the side of the lesion [21]. If the lesion is in the left
hemisphere, the AHS usually manifests as a right frontal AHS,
with or without IMC. If the lesion is in the right hemisphere,
hypokinesia can alter the presentation. When hypokinesia is
prolonged and severe enough to mask frontal release behavior
(frontal AHS), the symptoms tend to resemble a pure callosal
AHS. As hypokinesia resolves, the frontal AHS appears, thus
explaining its relative rarity [21].
Object Affordance Theory
BAffordances^ are properties of objects which prime an ob-
server to act [48]. For example, a teapot with the handle to the
Definition/distinguishing features
Simple frontal release sign
Bilateral coordinated use of hands to respond to an object within the visual
field or within grasp: e.g., putting on glasses, smoking, eating, drinking
No abnormal movement, with loss of awareness of limb as one’s own
One hand involuntarily mimics the other, without intermanual conflict or
groping
Involuntary distal movement following loss of proprioception and visual
input and resolves with restoration of visual input
Abnormal limb posturing provoked by specific task. Preserved sense of limb
ownership.
Abnormal limb posturing, fixed or variable, that may increase with
contralateral limb movement. Preserved sense of limb ownership.
High amplitude limb choreiform movements. Limb does not feel foreign.
Clumsy ataxic limb, but has sense of limb ownership and does not feel
foreign.
Curr Neurol Neurosci Rep (2016) 16:73
right might prime the observer to reach out the right hand to
grasp the handle. Object affordance has been studied in
healthy adults and suggests that through experience, objects
are associated with particular actions. These actions can be
evoked by perceptual processing of the object even when
irrelevant to the subject’s task [49•]. In healthy subjects, these
primed responses to the environment can be automatically
suppressed [50, 51]. This automatic suppression may be cru-
cial for goal-directed behavior; freeing the subject from the
stimulus response and allowing alternative actions [52]. Thus,
AHS may represent an exaggerated form of automatic priming
[53]. This could explain grasping behavior in AHS following
disruption of automatic inhibitory mechanisms.
Experimental work from Riddoch and colleagues
instructed a patient with bilateral AHS to reach out and grasp
a cup with either hand [53]. The patient could do this correctly
as long as the cup handle was on the same side as the hand
ordered to move. If the handle was on the opposite side,
Binterference^ errors occurred where the patient reached with
the hand on the same side as the handle. Fewer errors occurred
if the patient was asked to point, or respond, to LEDs instead
of cups. This suggested that the problem is not with perception
or attention, but that observing a graspable object elicited a
motor plan to interact with that object, even when it conflicted
with motor goals. The SMA in medial frontal lobes is associ-
ated with viewing graspable objects without reaching for them
and with successful automatic inhibition of primed responses
[54, 55]. Therefore, medial frontal lesions could explain the
grasping behavior in frontal AHS.
Volitional Movement and Motor Control Theories
The pre-SMA, in the medial prefrontal cortex, has a role in
voluntary action, especially during the decision and prepara-
tion to act [56]. The conscious experience of voluntary actions
is also linked to the pre-SMA. Stimulation here elicits an urge
to move a specific body part, and neuronal activity in the pre-
SMA is related to awareness of the intention to act [57, 58].
The pre-SMA has many cortical and subcortical connections
important for volitional movement [44]. It connects to the
dorsolateral prefrontal cortex, with increased functional con-
nectivity during conscious intention; the basal ganglia to in-
fluence behavior according to desired goals; the insular cortex
associated with the sense of self-agency; and possibly the
premotor-posterior parietal network linked to the experience
of conscious intent to act [59–62].
One study used fMRI to assess volitional movement in a
patient with left AHS and involuntary hand grasping, follow-
ing a right parietal stroke [23]. The left hand was assessed by
fMRI at rest, during alien hand movements and voluntary
movements. The alien hand movements were associated with
selective isolated activation of the contralateral primary motor
cortex. In contrast, voluntary movements activated extensive
Page 5 of 10 73
bilateral neural networks beyond the primary motor cortex,
including inferior frontal gyrus, dorsolateral prefrontal cortex
(especially left), and bilateral SMA, anterior cingulate and
parietal areas. Interestingly, fMRI activity in the primary mo-
tor cortex was identical for both AHS and voluntary move-
ments. Thus, the alien hand experience of motor action
showed absent motor planning. Activating the primary motor
cortex alone did not correlate with subjective ownership of
limb movement and could have reflected release from inten-
tional planning secondary to the parietal lesion. In addition,
the left prefrontal areas were preferentially activated during
movements of either hand, more so for voluntary than alien
movements. This supported prior theories that the left
(dominant) hemisphere is critical for guiding willed action
[23].
Motor control theory is the concept that awareness and
control of action are tightly linked. They both have internal
representation models [63, 64]. An intention to act produces
motor commands to achieve the desired goal. An Befference
copy^ of motor commands provides a prediction model of the
sensory effect of a movement, and this is compared with ac-
tual sensory feedback. If the feedback matches the prediction,
the sensory event is experienced as self-caused, but otherwise
it is perceived as external and independent of one’s own voli-
tion. The pre-SMA is linked to this network to provide input to
drive voluntary action, the efference copy signals and sensory
predictions [65]. Changes in the pre-SMA network can there-
fore cause disorders of both awareness and volition.
Interhemispheric Disconnection Theory
The corpus callosum connects both hemispheres and relays
information between them. The genu and anterior body con-
tain connection fibers between the prefrontal areas; the poste-
rior body connects the premotor areas; and the isthmus con-
nects both primary motor cortices [66]. Therefore, the major-
ity of the corpus callosum contains frontal cortical intercon-
nection fibers. They help mediate interhemispheric guidance
of unilateral movements; coordinate bilateral coordination of
synchronous movements; and allow orderly dissociation dur-
ing bilateral actions that require coordinated but different
movements on each side (e.g., tying shoelaces). A lesion in
the corpus callosum may thus disconnect the two hemispheres
and explain the frontal and callosal variants of AHS. In cases
of frontal callosal disconnection, patients are unable to learn
movement patterns that require simultaneous, mutually ad-
justed movements in the upper limbs [66]. It has been ob-
served in patients with IMC performing bimanual tasks, the
alien hand performs a task before the healthy hand can. It may
snatch an object before the other hand reaches properly for it,
and this abnormal motor behavior of the non-dominant hand
appears to be elicited by voluntary actions of the dominant
hand [14, 20]. The loss of bimanual coordination can be
73 Page 6 of 10
explained by loss of inhibition after hemisphere disconnec-
tion, allowing the hand to interact inappropriately with ob-
jects. A pure callosal disconnection syndrome can be seen in
surgical section of the corpus callosum, following tumor or
cyst resection via a transcallosal approach, or callosal stroke.
However, not all injury to the corpus callosum results in AHS
or IMC. This is evidenced by Machiafava-Bignami disease, a
rare disorder of corpus callosum demyelination and necrosis
in alcoholics and malnourished patients. It may cause split-
brain dissociation syndrome in one-third of cases, but AHS
appears uncommon. [67] Therefore, the mechanism of the
callosal lesion may be important in addition to the location.
Interhemispheric disconnection can also offer insight
into posterior variant AHS. It was proposed that in
healthy persons, the hemisphere controlling the active
limb (e.g., right hemisphere controlling left arm) simulta-
neously suppresses the contralateral (left) hemisphere
through corpus callosal connections. If those connections
are damaged, then the right hemisphere is unable to in-
hibit the left, resulting in unwanted motor activity in the
right arm [39]. Posterior variant AHS was also suggested
to be a variant of a neglect syndrome, where the patient
ignores the contralateral limb actions only, with preserved
awareness of the remainder contralateral hemibody [68].
The parietal cortex is important to generate a conscious
image of actions and maintain internal motor representa-
tions, allowing a sense of agency [23]. Lack of proprio-
ceptive feedback or neglect of a limb may result in spon-
taneous activity due to absent goal-directed movements.
Disruption to the inferior parietal lobule, a multimodal
association area that coordinates motor output, may there-
fore also cause AHS [6, 68].
A number of posterior variants are reported due to thalamic
infarcts [10, 25, 26, 28, 69]. It was suggested that a discon-
nection syndrome could be produced by a remote effect or
Bdiaschisis^ of thalamic stroke. This was illustrated by PET
imaging in a patient with left hemineglect and AHS after a
right thalamic stroke. There was hypometabolism in the right
frontotemperoparietal region (maximal in the sensorimotor
cortex) suggesting the thalamic lesion produced a distant ef-
fect [26].
Recent Advances in Pathophysiology
Recent advances in Object Affordance Theory McBride
et al. studied object affordance in a right-handed patient with
right AHS [49•]. The alien hand responded significantly faster
to images which afforded an action with the right hand versus
the left hand, suggesting that involuntary grasping behaviors
in AHS may be exaggerated automatic motor activation.
There was normal automatic inhibition of primed responses
in the unaffected hand, but no inhibition in the alien hand. The
findings concluded that grasping behaviors in AHS may result
Curr Neurol Neurosci Rep (2016) 16:73
from exaggerated object affordance effects, which might arise
from disrupted inhibition of automatically evoked responses.
Recent Advances in Volitional Movement and Motor
Control Theories Schaefer et al. used fMRI to study invol-
untary (alien) and voluntary movements in a patient with left
AHS and CBS [70]. Alien hand movements activated a brain
network including primary motor cortex, premotor cortex,
precuneus, and right inferior frontal gyrus. Conscious and
voluntary movements of the alien hand elicited a similar net-
work response, with the exception of the inferior frontal gyrus
activation. Thus, alien and unwanted movements involve the
same network as voluntary movements, with different func-
tional contribution of prefrontal areas. The inferior frontal gy-
rus was activated only with alien limb movements, suggesting
it has a specific role in inhibition over involuntary movements.
These findings differ to those reported by Assal et al., which
noted isolated activation of primary motor cortex with alien
movements, and widespread network activation only with vol-
untary movement [23]. A recent study by Onofj et al. supports
Assal’s findings. They used fMRI to assess four patients with
CBS and AHS. Their affected and non-affected limbs were
studied at rest, during levitation and finger writhing move-
ments, and with voluntary movements [71]. During levitation,
there was significant increase of contralateral primary motor
cortex activation. During voluntary movements of the unaf-
fected and affected hands, there was normal activation of the
known network of frontal, supplementary, sensorimotor cor-
tex, and cerebellum. However, voluntary movements of the
affected limb showed increased activation of the contralateral
motor cortex versus the unaffected limb. This isolated activa-
tion of the primary motor cortex suggested cortical disinhibi-
tion, and excitability of the cortex produced the AHS, not
network dysfunction [71].
Wolpe et al. investigated the mechanism by which vol-
untary actions are impaired in AHS [61]. Healthy controls
and CBS patients were compared for Bintentional binding.^
This marker of awareness of voluntary action measures the
perception of timing of an action and its sensory effect. The
interval volitional signals provide a mechanism for perceiv-
ing one’s own actions. Intentional binding was abnormal in
CBS patients compared to healthy adults, which correlated
with the severity of alien limb, suggesting reduced precision
of internal voluntary action signals. Structural neuroimag-
ing showing behavioral variability in patients was related to
changes in gray matter volume in pre-SMA and in white
matter tracts to prefrontal cortex. Changes in functional
connectivity at rest between the pre-SMA and prefrontal
cortex were proportional to changes in binding. The behav-
ioral and imaging results together proposed this frontal net-
work is implicated in impaired altered awareness and voli-
tion control in CBS.
Curr Neurol Neurosci Rep (2016) 16:73
Fig. 1 Algorithm for Involuntary uncontrollable limb movement?
classification of clinical alien
hand syndromes Yes
Limb levitation/ clumsy/ non-complex movements? Yes
No
Limb conflicts with opposite unaffected limb?
(e.g. Tying shoelaces, buttoning shirt,
using knife and fork)
No
Limb gropes and grabs at objects presented
in visual or tactile field?
Recent Advances in Interhemispheric Disconnection
Theory In a study of patients with AHS due to epileptic sei-
zures or cortical stimulation, a common lesion area identified
was the primary sensory cortex and primary motor cortex and
secondary sensory association areas. Two theories were pro-
posed for AHS: functional dissociation of the primary and
supplemental association area and simultaneous inhibition of
the primary sensory cortex and primary motor cortex [72].
One neurophysiology study reported reduced amplitude by
single pulse motor evoked potential and lack of intracortical
inhibition by paired pulse TMS, in two patients with AHS
following contralateral hemisphere stroke [74]. Other recent
researchers endorse theories of contrateral hemisphere disin-
hibition or dissociation after parietal lobe stroke or CBS, either
due to loss of parietal sensory integration and feedback inter-
fering with motor function or disconnection of the parietal
lobe from other cortical centers, resulting in loss of awareness
of movement leading to AHS [27•, 32•, 39].
Two recent studies on callosal lesions with AHS proved
further insight into callosal disconnection. Kim et al. reported
a right-handed patient with right AHS after an anterior com-
municating artery rupture [73]. Brain MRI showed lesions in
the genu and body of corpus callosum and hemorrhage in the
interhemispheric fissure. Diffusion tensor tractography identi-
fied extensive disruption of corpus callosal fibers in the upper
genu and trunk, and FDG-PET showed severe
hypometabolism in the left hemisphere (including basal gan-
glia and thalamus), and hypermetabolism in the right cerebral
hemisphere. These findings supported that the callosal
Page 7 of 10 73
Posterior variant AHS
(plus other parietal signs, e.g “foreign”; hemineglect)
Acute onset? (Stroke)
Improves/resolves? (Stroke)
Progressive? (CBS, CJD)
Yes Callosal variant AHS
(plus other callosal disconnection signs)
Corpus callosal lesion: stroke, midline tumor,
iatrogenic, demyelination
Yes Frontal variant AHS
(plus grasp reflex, other frontal signs)
Stroke, likely contralateral medial frontal lobe
disconnection syndrome may result from loss of transcallosal
inhibition in the contralateral hemisphere. In another report, a
patient with corpus callosum hemorrhage developed AHS
which resolved after 7 weeks [74]. Tractography performed
months after onset showed extensive disruption of the callosal
fibers passing through the anterior genu and body and connec-
tions of ipsilateral temporal lobe fibers to ipsilateral inferior
fronto-occipital fasciculus via the anterior commissure. These
findings were not seen in a gender and age-matched normal
subject. They hypothesized that the unusual neural connec-
tions provided a compensatory mechanism for recovery after
callosal injury disrupted callosal fibers.
Treatments
A number of treatments for AHS are reported of variable
efficacy. These include medications, botulinum toxin, mirror
box therapy, visuospatial coaching techniques, distracting the
affected hand, and other physical and cognitive therapies [75•,
76]. Abnormal activity may be reduced by occupying the limb
(e.g., holding a cane), placing it in a glove or mitt, progressive
muscle relaxation, bringing it into the contralateral visual
field, and giving it verbal commands [39]. Stroke-related
AHS has the best prognosis, and patient-tailored rehabilitation
is often successful with AHS resolving within weeks to
months, up to 24 months [15, 30, 68]. Mirror box therapy is
an established rehabilitation modality, where the patient
moves their normal limb in front of a mirror and hides the
alien hand from view. The moving reflection, where their alien
73 Page 8 of 10
hand should be, is perceived as their arm, and they can attri-
bute sensorimotor features of the intact arm to their alien one.
It significantly improves motor behavior and increased motor
speed [77]. Mirror box therapy can improve motor learning in
corpus callosal lesions [78].
Discussion
In reviewing the literature, particularly over the last 5 years,
several features should be highlighted. The list of clinical as-
sociations of AHS has expanded. A limited number of very
small studies have used structural and functional imaging,
tractography, or neurophysiology to build on existing patho-
physiologic theories. The most common theories support dis-
inhibition or disconnection syndromes or contralateral in-
creased primary motor cortex activity. The three current vari-
ants (frontal, callosal, posterior) are clinically useful, and there
is no necessity to extend the classification system. However,
the definition of AHS should be clarified regarding inclusion
of limb foreignness together with involuntary movement. We
propose the definition Binvoluntary limb movements (either
purposeful [grasping, groping] or non-purposeful [levitation])
associated with a sense of loss of ownership or control of the
limb, accompanied by other frontal/callosal/parietal signs^.
BForeignness^ is not universal in AHS. Patients experience
it with the posterior variant (explained by coexistent
hemineglect). It is frequently absent in the frontal variant
where patients recognize the limb as their own but acknowl-
edge loss of ownership of control.
There are many factors that appear to influence the presen-
tation of AHS in a patient: hand dominance, lesion location,
temporal onset (acute, subacute, progressive), etiology and
natural history (e.g., stroke, neurodegeneration), presence/
absence of other neurological symptoms and signs, and pres-
ence of preexisting neurological lesions. An algorithm to help
differentiate the clinical variants of AHS is presented in Fig. 1.
However, imaging remains necessary to confirm lesion
location.
There remain many unanswered questions about the
etiopathology of alien hand syndrome. Studies are limited to
interpretation by a lack of uniform study criteria, small subject
numbers (n = 1 or 2), lack of longitudinal data, and lack of
variety of pathology (stroke or CBS are mostly studied).
Future larger studies utilizing structural plus functional imag-
ing (PET, SPECT, tractography) and research for better treat-
ment options for AHS are important.
Compliance with Ethical Standards
Conflict of Interest Anhar Hassan and Keith A. Josephs declare that
they have no conflict of interest.
Curr Neurol Neurosci Rep (2016) 16:73
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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