جفت شدگی زمانی به علت حرکات گمراه کننده در اقدامات با دو دست انجام یافته: شواهدی از ناتوانی در ادراک بیماری برای همی پلژی

Abstract In anosognosia for hemiplegia, patients may claim having performed willed actions with the paralyzed limb despite unambiguous evidence to the contrary. Does this false belief of having moved reflect the functioning of the same mechanisms that govern normal motor performance? Here, we examined whether anosognosics show the same temporal constraints known to exist during bimanual movements in healthy subjects. In these paradigms, when participants simultaneously reach for two targets of different difficulties, the motor programs of one hand affect the execution of the other. In detail, the movement time of the hand going to an easy target (i.e., near and large), while the other is going to a difficult target (i.e., far and small), is slowed with respect to unimanual movements (temporal coupling effect). One right-brain-damaged patient with left hemiplegia and anosognosia, six right-brain-damaged patients with left hemiplegia without anosognosia, and twenty healthy subjects were administered such a bimanual task. We recorded the movement times for easy and difficult targets, both in unimanual (one target) and bimanual (two targets) conditions. We found that, as healthy subjects, the anosognosic patient showed coupling effect. In bimanual asymmetric conditions (when one hand went to the easy target and the other went to the difficult target), the movement time of the non-paralyzed hand going to the easy target was slowed by the ‘pretended’ movement of the paralyzed hand going to the difficult target. This effect was not present in patients without anosognosia. We concluded that in anosognosic patients, the illusory movements of the paralyzed hand impose to the non-paralyzed hand the same motor constraints that emerge during the actual movements. Our data also support the view that coupling relies on central operations (i.e., activation of intention/programming system), rather than on online information from the periphery.

1. Introduction Being aware of intending, controlling, and owning voluntary actions is at the root of humans' notion of self-awareness. Studying the abnormalities of the integration among the different aspects of motor behavior due to brain damages has a crucial role in addressing questions regarding the structure and functional signature of motor consciousness (Berti and Pia, 2006). Indeed, patients' counterintuitive behavior can unmask the inadequacies of theories on human brain functioning hidden from the view in the intact brain (see Churchland, 1986, for a discussion on this point). To this respect, one of the most informative neurological disorders is anosognosia for hemiplegia (hereinafter AHP), a condition in which movement cognition is dramatically distorted (see Bottini et al., 2010; Orfei et al., 2007; Pia et al., 2004 for reviews). AHP patients, affected by a complete paresis of the side of the body opposite to the brain damage (often the left side but see also Cocchini et al., 2009) deny that there is anything wrong with their contralesional limbs. The disturbance may range from emotional indifference (i.e., patients simply minimize the severity of the paralysis) to explicit denial. In this latter case, patients claim of being able to perform any kind of action with the paralyzed limb. If asked to perform a purposeful movement with the motionless limb, they may be convinced of having accomplished the action despite unambiguous evidence to the contrary coming from different sensory channels. However, it is noteworthy that explicit and implicit awareness for motor deficits can be dissociated. In other words, patients may explicitly deny a deficit despite having some insight into it, as they correctly approach bimanual tasks according to their motor impairment (Cocchini et al., 2010). Delusional beliefs concerning the affected side of the body, such as somatoparaphrenia (i.e., the ownership of the limb is ascribed to another person as, for instance, the doctor or a relative), misoplegia (e.g., hatred toward the affected limbs), or limb personifications (e.g., the plegic limb is considered as an entity with an own identity) are usually considered as additional, thought independent, abnormal manifestations (see Bottini et al., 2010 for a discussion on this point). The interpretation of AHP is not straightforward. Theories that explain AHP either as a psychological defense against the illness (e.g., Weinstein and Kahn, 1955), a secondary consequence of sensory feedback deficits (e.g., Cutting, 1978), or a combination of sensory deficits and higher-order cognitive impairments (e.g., Levine et al., 1991) are not thought to be exhaustive explanations. Indeed, double dissociations have been shown between AHP and each of the aforementioned impairments (Adair et al., 1995; Berti et al., 2005; Bisiach et al., 1986; Coslett, 2005; Heilman et al., 1998; Marcel, 2004; Starkstein et al., 1992). Recently, it has been proposed that AHP might be explained as a domain specific disorder of motor control (Berti and Pia, 2006; Berti et al., 2007; Gold et al., 1994; Jenkinson and Fotopoulou, 2010; Spinazzola et al., 2008). In line with several findings on intact brain showing that the conscious awareness of action and movement control shares several cortical areas (e.g., Desmurget and Sirigu, 2009), it has been demonstrated that AHP follows a brain damage located within the same cortical network that is responsible for motor monitoring in the lateral premotor and insular cortex (Berti et al., 2005; Fotopoulou et al., 2010; Garbarini et al., 2012; Karnath et al., 2005; Moro et al., 2011; Vocat et al., 2010). Consequently, the well-established framework of a forward model of normal motor control (Blakemore and Frith, 2003; Wolpert et al., 1995) has been employed to predict the pattern of intact and impaired neurocognitive mechanisms pinpointing the distorted motor awareness of AHP patients. The model posits that when a subject has the intention to move and the appropriate motor commands are selected and sent to the appropriate motor areas, a prediction (forward model) of the sensory consequences of the movement itself is formed on the efference copy of the programmed motor act. This would be subsequently matched (by a comparator system) to the actual sensory feedback (see also Gold et al., 1994), and constitutes the signal on which motor awareness is constructed. This model has two important implications. First, motor awareness would, counter-intuitively, precede movement execution, instead of following it. This entails that whenever a sensory prediction is formed, motor awareness emerges before the availability of any sensory feedback. Second, motor awareness is evaluated against the sensory feedback by the operation of the comparator system that, among other functions, can differentiate between movement/no-movement conditions. Within this framework, it has been proposed that, in AHP patients, a damage to the comparator processes would alter the monitoring of voluntary actions, thus preventing them from distinguishing between movement and no-movement states. Moreover, the (non-veridical) feeling of movement would arise from an intact motor intentionality assisted by the normal activity of the brain structures that implement the intention-programming system (Berti and Pia, 2006; Berti et al., 2007; Garbarini et al., 2012; Spinazzola et al., 2008). Evidence of preserved movement intentionality in AHP patients comes from the fact that they may show normal proximal muscle electrical activity in the affected side when they believe they are moving the plegic limb (Berti et al., 2007; Hildebrandt and Zieger, 1995). Interestingly, such an intentional stance dominates their subjective experience of willed actions because patients falsely detect the movement of their plegic arm when they intend to move it, versus when they do not (Fotopoulou et al., 2008). To the best of our knowledge, however, only one study has directly analyzed the existence in AHP patients of the same motor programs for the affected limbs that govern normal movement execution. Garbarini et al. (2012), capitalized on evidence showing that the spatial constraints known to exist in healthy subjects during a classical bimanual movement paradigm (i.e., when people have to draw circles with one hand while drawing lines with the other tend to produce curved lines and line-like circles) arise also in amputee patients with vivid subjective experience of moving their ‘phantom’ limb (Franz and Ramachandran, 1998). Indeed, Franz and Ramachandran (1998) found that when amputees with vivid sensation of phantom limb movement have to draw linear segments in a continuous fashion with the intact arm while performing either lines or circles with the phantom arm produced spatial coupling. As clearly pointed out by the authors, those results suggest, for the first time, that spatial coupling strongly relies on internal motor program rather than on the online feedback coming from movement execution. Starting from this findings, Garbarini and coworkers reasoned that the circles–lines drawing task would have been the ideal paradigm to examine whether, despite the paralysis, the motor program of the affected hand is normally available in AHP patients. The results showed that when AHP patients are requested to simultaneously and continuously draw lines with the right (intact) hand and circles with the left (affected) hand the lines assume an oval shape. This effect, comparable to that of healthy subjects, indicated that voluntary actions performed by the moving hand can be spatially constrained by the intended (but not executed) movements of the paralyzed hand. It is also noteworthy that other constraints in the production of bimanual movements can be observed on purely temporal measures. For instance, whereas in unimanual reaching movements exists a reliable temporal relationship between distance and time, when movements are combined in a bimanual task with different target distances, the two hands initiated and (approximately) terminated in a more coupled fashion (Kelso et al., 1979). Interestingly, temporal coupling is dissociable from spatial coupling on both functional and anatomical grounds (e.g., Franz et al., 1996; Heuer, 1993). Therefore, if AHP patients' motor behavior is driven by the same motor computations that govern normal movement execution, the temporal aspects of motor preparation of the paralyzed hand should be also preserved. One of the most employed paradigm to study temporal coupling has been proposed by Kelso et al. (1979). The authors developed a bimanual version of the classical Fitt's task, which originally showed that in unimanual movements the time required for reaching a target is a function of the task difficulty, that is distance and target width (Fitt's law, Fitts, 1954). Accordingly, these authors found that when people have to reach for an easy target (i.e., near-large), the movement times (hereinafter MTs) are shorter than when they have to reach for difficult (i.e., far-small) targets, both in unimanual (one hand at a time reaches for the target), and in bimanual symmetric conditions (both hands go either to the easy or to the difficult targets). However, Kelso and coworkers found a violation of Fitt's law in the bimanual asymmetric condition (one hand goes to the easy target and the other goes to the difficult target). Here, the movements of the two hands were coupled so that they were initiated and terminated synchronously, mainly because the hand moving to the easy target slowed. In other words, the temporal aspect of the motor programming/execution of one hand was affected by the simultaneous motor programming/execution of the other hand (temporal coupling effect). We capitalized on this evidence to test whether in AHP patients the illusory movements of the plegic arm impose on the healthy arm the same temporal constraints that are observed in healthy subjects during the actual movements in the asymmetric condition. If so, any effects on the motor parameters of the healthy hand would be the consequence of normally activated motor representations of the plegic hand. Kelso's paradigm (Kelso et al., 1979) was administered to right-brain-damaged patients with complete left upper limb hemiplegia (with and without anosognosia) and to healthy subjects. We predicted that when AHP patients are asked to move one hand to the easy target and the other to the difficult target (i.e., bimanual asymmetric condition), the non-paralyzed arm going to the easy target would show a normal interference effect (slowing down of the MT) from the paralyzed arm requested to go to the difficult target. In hemiplegic patients without anosognosia (hereinafter HP), we predicted that, being these patients perfectly aware of their deficit, they should not attempt any movement with the plegic hand. Therefore, no temporal coupling effect should be observed (Garbarini et al., 2012).

3. Results While both the C and HP groups, and the AHPpost patient were 100% correct in judging whether they achieved a given movement, the AHPpre patient always misjudged his performance in the self-evaluation test: in bimanual conditions, he always claimed having performed the bimanual action. This result suggests that the patient experienced a vivid subjective sensation of the movements that he did not actually perform. 3.1. RTs In the C group, a repeated measures ANOVA with ‘movement’ (unimanual/bimanual asymmetric/bimanual symmetric), ‘difficulty level’ (easy/difficult), and ‘hand’ (left/right) was performed. Neither the main factors nor the interactions were significant (p > .05). In the HP group, a repeated measures ANOVA with the ‘movement’ (unimanual/bimanual asymmetric/bimanual symmetric) and ‘difficulty level’ (easy/difficult) was performed. Neither the main factors nor the interactions were significant (p > .05). Single case analysis in each HP patient replicated the group results (p > .05). In the AHP patient, a repeated measures ANOVA with the ‘movement’ (unimanual/bimanual asymmetric/bimanual symmetric), ‘difficulty level’ (easy/difficult), and ‘session’ (pre/post) was performed. Neither the main factors nor the interactions were significant (p > .05). These data show that the different conditions of the experiment did not affect movement initiation. In particular, for the bimanual movement of healthy subjects these results indicate that right and left hand movements were initiated simultaneously. 3.2. MTs In the C group, a repeated measures ANOVA with the ‘movement’ (unimanual/bimanual asymmetric/bimanual symmetric), ‘difficulty level’ (easy/difficult), and ‘hand’ (left/right) was performed. There was a significant effect of the ‘movement’ [F (2, 34) = 57.65, p < .00001], ‘difficulty level’ [F (1, 17) = 317.49, p < .00001], and ‘movement’ × ‘difficulty level’ interaction [F (2, 34) = 55.33, p < .00001]. MTs were shorter (Duncan's two tailed t-test p < .0005) in unimanual (mean = 392, standard error – SE = 19) than bimanual symmetric (mean = 463, SE = 27) and in the bimanual asymmetric (mean = 535, SE = 29) conditions. In addition, MTs were shorter in easy (mean = 410, SE = 24) than in difficult (mean = 516, SE = 25) conditions. However, this difference disappeared in the bimanual asymmetric condition (Duncan's two tailed t-test p = .74) when one hand went to the easy target (mean = 533, SE = 31) and the other to the difficult one (mean = 537, SE = 29) mainly because the hand moving to the easy target slowed (see Fig. 3). This data in healthy subjects replicated the Kelso and coworkers results ( Kelso et al., 1979). Mean MTs and SE (ms) of the C group. ∗ = significant (p < .05); n.s. = non ... Fig. 3. Mean MTs and SE (ms) of the C group. ∗ = significant (p < .05); n.s. = non significant (p > .05). Figure options In the HP group, a repeated measures ANOVA with the ‘movement’ (unimanual/bimanual asymmetric/bimanual symmetric) and ‘difficulty level’ (easy/difficult) was performed. There was a significant effect of the ‘difficulty level’ [F (1, 4) = 226.85, p < .001] but no ‘movement’ × difficulty level’ interaction. MTs were shorter in easy (mean = 374.31, SE = 28.01) versus difficult (mean = 548.99, SE = 34.07). Single case analysis in each patient replicated the group results (see Fig. 4). Mean MTs and SE (ms) of the HP group. ∗ = significant (p < .05). Fig. 4. Mean MTs and SE (ms) of the HP group. ∗ = significant (p < .05). Figure options In the AHP patient, a repeated measures ANOVA with the ‘movement’ (unimanual/bimanual asymmetric/bimanual symmetric), ‘difficulty level’ (easy/difficult), and ‘session’ (pre/post) was performed. The patient showed a significant effect of the main factors ‘session’ [F (1, 13) = 12.52, p = .004] and ‘difficulty level’ [F (1, 13) = 41.41, p < .0001], and of the interactions ‘movement’ × ‘session’ [F (2, 26) = 8.04, p = .002] and ‘movement’ × ‘difficulty level’ × ‘session’[F (2, 26) = 3.65, p = .04]. MTs were shorter in pre (mean = 1043, SE = 25) versus post (mean = 913, SE = 27) sessions and, in the pre-session, in unimanual (mean = 936, SE = 50) than in bimanual symmetric (mean = 1059, SE = 35) and bimanual asymmetric (mean = 1135, SE = 34) conditions. MTs were also shorter in easy (mean = 861, SE = 29) versus difficult (mean = 1096, SE = 22) conditions. However, in the pre-session, the difference disappeared in the bimanual asymmetric condition (Duncan's two tailed t-test p = .669) when the right hand went to the easy target (mean = 1160, SE = 63) and the left had to go to the difficult target (mean = 1109, SE = 52) but did not accomplish the task due to the paralysis. Again, this effect was due to the slowing of the right hand ( Fig. 5). It is noteworthy that despite the AHP patient in the pre-session being overall slower than the C group, their MTs pattern was not significantly different (p > .05). The AHP patient comparisons were performed with a modified t-test for individual scores versus a control sample ( Crawford and Howell, 1998; Cavallo et al., 2011). Mean MTs and SE (ms) of the AHP patient in the pre and post-session. ... Fig. 5. Mean MTs and SE (ms) of the AHP patient in the pre and post-session. ∗ = significant (p < .05); n.s. = non significant (p > .05). Figure options Summing up, these results show that, in the bimanual asymmetric condition, a coupling effect was found for both the C group, where the subjects actually moved both hands, and for the AHP patient, who could only move their right hand.