بهبود انتخابی از ناتوانی در ادراک بیماری برای همی پلژی در طول تحریک جریان مستقیم کرانیال: گزارش یک مورد

Abstract Right brain damage patients may not complain of a left sided paralysis up to the point of denying it or even claiming of having just moved an otherwise paralyzed limb. This condition is known as anosognosia for hemiplegia (AHP). Recent behavioural experiments suggest that some residual intentionality might be preserved in patients with anosognosia and that the false belief of having moved originates from a failure to notice discrepancies between movement expectancies and the actual state of the motor system. This failure may be caused by a lack of afferent sensory information concerning the movement or alternatively by a direct dysfunction of the brain regions involved in actions' motor monitoring (i.e., the comparator system). Here we examined the effect of anodal transcranial direct current stimulation (tDCS) of the right premotor cortex in a patient with a bilateral lesion, involving predominantly the right hemisphere, and a dense unawareness for his left hemiplegia. During sham or anodal tDCS the patient was requested to judge his ability to perform simple motor actions (i) without actually executing the movement itself (“offline” condition) and after having performed a series of verbally cued finger opposition movements (“online” condition) with (i) eyes-closed or (ii) eyes-open. We found that anodal tDCS induces a significant remission of the false experience of movement only when the patient is requested to actually perform the movement with eyes open. Conversely, the patient's awareness does not improve in both the “offline” condition (in which the patient does not attempt to perform the movement) and in the “online” condition, when vision is precluded (“online” condition, eyes-closed). We conclude that the stimulation of the premotor cortex by tDCS activates brain regions involved in motor monitoring, temporary restoring the ability of the motor comparator system to correctly appreciate afferent information and build up a veridical motor awareness.

1. Introduction We are normally able to judge whether we have performed or not a movement even if many aspects of motor control occur without conscious awareness (Blakemore & Frith, 2003). However, there are neurological diseases, such as anosognosia for hemiplegia (AHP), in which patients are unaware of their motor inabilities (Babinski, 1914). Patients with AHP do not spontaneously complain about their contralesional motor deficit and in most severe cases they continue to deny their hemiplegia even after clear demonstration of it through the neurological examination. These patients have such a strong false experience (false beliefs of movement; Fotopoulou, 2012) that they claim to have performed the actions requested by the examiner, typically clapping hands or raising arms, although no movement actually occurred with the paretic arm (Ramachandran, 1996). The clinical observation of patients with AHP clearly reveals that motor unawareness is a heterogeneous phenomenon rather than a unitary entity and that diverse levels of motor awareness may be differently affected, even in the same patient (Marcel, Tegner, & Nimmo-Smith, 2004). A first distinction between different forms of AHP has been introduced by Bisiach and collaborators (Bisiach, Vallar, Perani, Papagno, & Berti, 1986). They differentiate between “moderate” anosognosia, when the patient recognizes the inability after its demonstration through the neurological examination (score: 2/3), and severe anosognosia, when the patient remains anosognosic after the demonstration of the failure (score: 3/3). A further distinction has been recently proposed by Moro, Pernigo, Zapparoli, Cordioli, and Aglioti (2011) that used the term “emergent awareness” to indicate a condition in which the patient denies the deficit but becomes declarative aware of it when invited to execute the action with the affected limb. Moreover, double dissociations between verbal (explicit) and non-verbal behaviour have been described (Berti et al., 1996 and Bisiach and Geminiani, 1991). Some patients, although explicitly able to recognize the presence of the motor impairment, do not refrain from performing infeasible actions (e.g., a patient with a complete lower limb left hemiplegia may attempt to walk; Bisiach & Geminiani, 1991). By contrast, other patients verbally deny their motor deficit but act coherently with the presence of the paralysis: implicit awareness or tacit knowledge (Ramachandran, 1996; for example a patient with a complete lower limb hemiplegia remains in bed, without trying to walk; Bisiach & Geminiani, 1991). Further, even if AHP is frequently associated with unilateral spatial neglect and sensory impairments (tactile imperception and loss of position sense), double dissociations have been described in literature (see review in Vallar & Ronchi, 2006), suggesting the independence of AHP from these deficits. The presence of such a complex semiology has important implications at both the clinical and theoretical level and clear consequences for the treatment of AHP. The development of instruments to assess all these different forms should rely on different theoretical frameworks taking into account this heterogeneity. In this view, focused rehabilitation treatments might allow to better target the multifaceted clinical manifestations of AHP. More recently, it has been suggested that various forms of unawareness do not correspond to a mere different degree of severity of the same symptom (see for example Bisiach et al., 1986), rather they represent different clinical phenomena with discrete underlying mechanisms and anatomical substrates (Fotopoulou et al., 2010, Moro et al., 2011 and Vocat et al., 2010). Despite the presence of AHP being a negative prognostic factor for motor recovery (Gialanella, Monguzzi, Santoro, & Rocchi, 2005), evidence concerning the efficacy of rehabilitative treatments is scarce (see review in Besharati et al., 2014 and Kortte and Hillis, 2011). Seminal studies demonstrate a recovery of AHP after caloric vestibular stimulation (Cappa, Sterzi, Vallar, & Bisiach, 1987; case 5 and 3 in Geminiani and Bottini, 1992, Rode et al., 1998, Vallar et al., 2003 and Vallar et al., 1990). In most of these studies the remission of AHP during CVS is generally transient (see review in Bottini et al., 2010), although in two cases described by Cappa and colleagues the remission outlasted the period of vestibular stimulation (Cappa et al., 1987). Beschin and collaborators (Beschin, Cocchini, Allen, & Della Sala, 2012) have recently tested the efficacy of a number of treatments including prism adaptation, optokinetic stimulation and transcutaneous electrical stimulation. All these manipulations were transiently effective (within 48 h) although with different responses by patients (Beschin et al., 2012). More recently, a case of permanent recovery of motor unawareness has been described in a patient (case LM) when she was observing her motor performance in a video replay (e.g., in a 3rd person perspective) and in a time subsequent to the attempt to execute the movement (e.g., off-line; Fotopoulou, Rudd, Holmes, & Kopelman, 2009). Two alternative explanations have been proposed by the authors to explain this remission: the first argues that body observation from a 1st or 3rd perspective involves distinct brain regions ( Corradi-Dell'acqua et al., 2008 and Saxe et al., 2006) that might be differently damaged in anosognosic patients. The second interpretation is that when the patient is observing himself in an off-line condition (e.g., when the action is observed after the request to try to execute the movement), the judgement does not require the attempt to perform the movement and thus the role of motor intention became irrelevant ( Fotopoulou et al., 2009). In summary, different techniques might transiently ameliorate AHP although the cognitive and functional mechanisms underlying this effect are still ambiguous and more systematic studies are needed for further clarifications (see reviews in Besharati et al., 2014 and Jenkinson et al., 2011). Transcranial magnetic stimulation (TMS) and trascranial direct current stimulation (tDCS) are two non-invasive and promising techniques recently used to modulate different cognitive and neurological dysfunctions in stroke patients. Neglect and tactile extinction may ameliorate after TMS applied to the contralesional unaffected hemisphere (Brighina et al., 2003, Oliveri et al., 2001, Oliveri et al., 1999 and Shindo et al., 2006), suggesting a possible use of this technique as complementary procedure for the rehabilitation of spatial attention disorders and associated symptoms. Among these manipulations, tDCS is a simple and non-invasive method, which can be used to modulate cortical excitability at low intensity electric currents (Nitsche and Paulus, 2000 and Priori, 2003), whose effects are comparable, if not even more persistent, to those of TMS.1 Cathodal tDCS stimulation causes a decrease in cortical activity (i.e., inhibition or neuronal hyper-polarization), while anodal stimulation determines a depolarization of the transmembrane potentials with an increased cortical activity (review in Bolognini, Pascual-Leone, & Fregni, 2009). Different cognitive and neurological dysfunctions have been proven to be modulated by tDCS mainly in patients with stroke (Boggio et al., 2007, Fregni et al., 2005 and Hummel and Cohen, 2005). Further, this stimulation enhances the effects of the canonical motor rehabilitation procedures (review in Bolognini et al., 2009). To date, only a few studies have investigated the effects of tDCS on spatial neglect and associated symptoms (Harza et al., 2007, Ko et al., 2008, Sparing et al., 2009 and Sunwoo et al., 2013) and it is still unknown whether it can also mitigate other disorders, such as AHP. The possibility to increase cortical activity through anodal stimulation makes this instrument an appealing technique to test current models of AHP.2 Recent interpretation framed AHP in the contest of the computation models of motor control (Wolpert and Ghahramani, 2000 and Wolpert et al., 1995) and focused the attention on the comparison between top-down representations (motor intention/prediction or forward model) and bottom-up afferent information, i.e., sensory feedback (Berti and Pia, 2006, Berti et al., 2007, Frith et al., 2000, Heilman, 1991 and Heilman et al., 1998). Following these models AHP might occur because: (i) a lesion of the intentional system might cause a lack of intention to move the paralyzed limb (feedforward hypothesis; Adair et al., 1997, Gold et al., 1994, Heilman, 1991 and Heilman et al., 1998); (ii) in patients with AHP the intention to move is preserved3 and they are still able to formulate predictions about actions' sensory consequences (see also Blakemore and Frith, 2003 and Frith et al., 2000). According to this interpretation, the delusion of having moved derives from a failure to register the mismatch between these expectancies of movement and the actual execution, because sensory information about the actual state of the system ‘is not available’ or ‘is neglected’ (feedback hypothesis; Frith et al., 2000, p. 1781); (iii) the lesion of the frontal premotor cortex (Brodmann areas 6 and 44; Berti et al., 2005) would directly affect the motor monitoring system (i.e., the comparator system) causing a failure in detecting mismatches between sensory prediction and the failure of movement, while the sparing of some premotor regions (such as the supplementary motor cortex, SMA) would allow the ‘construction of a normal conscious intention’ (Berti et al., 2007, p. 163). Following this last hypothesis we can speculate that an appropriate brain stimulation, targeting brain regions involved in motor monitoring, typically damaged in patients with AHP (Berti et al., 2005), and adjacent spared regions, could restore the functioning of the comparator system and ameliorate AHP. We had the opportunity to widely explore this prediction applying anodal tDCS to the right premotor cortex in a patient with a bilateral lesion, more extensive in the right hemispere,4 presenting with a dense, chronic AHP.

. Results 5.1. AHP: categorical yes/no answer AHP was assessed during sham tDCS, during anodal tDCS and 2 h after the active tDCS session. Fig. 5 shows the number of anosognosic responses (“yes” answers) in the different sessions. In the offline judgement task without visual feedback, sham tDCS, anodal tDCS and Post tDCS sessions did not show significant differences in the percentage of anosognosic responses (all the three comparisons ns, Fisher's exact test). Similarly, in the online judgement task without visual feedback, e.g., eyes-closed condition, the treatment with tDCS did not modulate anosognosic responses (all the three comparisons ns, Fisher's exact test). Effect of tDCS on AHP. Number of anosognosic answers (“yes” response) in each ... Fig. 5. Effect of tDCS on AHP. Number of anosognosic answers (“yes” response) in each experimental condition: sham tDCS (tDCSsham; baseline), anodal tDCS and post tDCS. Figure options Conversely, in the online condition with visual feedback (eyes open), tDCS induced a temporary remission of AHP, with a significant difference between the sham tDCS and anodal tDCS level of AHP (p < .001, Fisher's exact test). Differences between sham tDCS and Post tDCS did not survive to the statistical correction (p > .017). To better investigate the role of visual feedback we also directly compared the number of anosognosic responses during the anodal tDCS in the eyes-closed versus the eyes-open condition. We found a significant difference between conditions (p = .009; Fisher's exact test). 5.2. Tactile perception and proprioception Finally, the severity of proprioceptive and tactile deficits was not affected by tDCS and remained unchanged in all conditions (100% incorrect responses, i.e., complete proprioceptive and sensory loss). 5.3. Line cancellation test To assess the effect of tDCS on line cancellation test we performed a Chi-Square Test. No significant changes in performance were detected among the three conditions (ns, Chi-Square Test; Fig. 6). The patient presented a severe neglect and cancelled only targets located on the right part of the sheet in all the three conditions (sham: left target omissions = 18/18; central target omissions: 4/4; right target omissions: 9; tDCS: left target omissions = 18/18; central target omissions: 4/4; right target omissions: 5; post-tDCS: left target omissions = 18/18; central target omissions: 4/4; right target omissions: 4). Target stimuli omissions in the line cancellation test (Albert test) performed ... Fig. 6. Target stimuli omissions in the line cancellation test (Albert test) performed in the sham tDCS, anodal tDCS and Post tDCS.