To move or not to move: Subthalamic deep brain stimulation effects on implicit motor simulation

brain research 1574 (2014) 14–25

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Research Report

To move or not to move: Subthalamic deep brain stimulation effects on implicit motor simulation Barbara Tomasinoa,n, Dario Marina, Roberto Eleoprac, Sara Rinaldoc, Lettieri Cristianc, Mucchiut Marcoc, Belgrado Enricoc, Monica Zanierb, Riccardo Budaic, Massimo Mondanid, Stanislao D’Auriad, Miran Skrapd, Franco Fabbroe,a a

IRCCS “E. Medea”, San Vito al Tagliamento (PN), Milan, Italy Facoltà di Medicina e Chirurgia, Università di Udine, Udine, Italy c Unità Operativa di Neurologia, Neurofisiopatologia, A.O. S. Maria della Misericordia, Udine, Italy d Unità Operativa di Neurochirurgia, A.O. S. Maria della Misericordia, Udine, Italy e Dipartimento di Filosofia, Università di Udine, Udine, Italy b

ar t ic l e in f o

abs tra ct

Article history:

We explored implicit motor simulation processes in Parkinson’s Disease (PD) patients with

Accepted 6 June 2014

ON-OFF subthalamic deep brain stimulation (DBS) of the sub-thalamic nucleus (STN).

Available online 13 June 2014

Participants made lexical decisions about hand action-related verbs, abstract verbs, and

Keywords:

pseudowords presented either within a positive (e.g., “Do …”) or a negative (e.g., “Don’t …”)

Sub-thalamic nucleus

sentence context. Healthy controls showed significantly slower responses for hand-action

Deep brain stimulation

verbs (vs. abstract verbs) in the negative (vs. positive) context, which suggests that negative

Primary motor cortex

contexts may suppress motor simulation or preparation processes. The STN-DBS improves

Motor imagery

cortical motor functions, thus patients are expected to perform at the same level as

Semantics

unimpaired subjects in the ON condition. By contrast, the 50% reduced DBS is expected to

Embodied cognition

result in a reduced activation for motor information, which in turn might cause a reduced, if not absent, context modulation. PD patients exhibited the same pattern as controls when their DBS was at 100% ON; however, reducing the DBS to 50% had a deleterious outcome on the positive faster than negative context effect, suggesting that the altered inhibition mechanism in PD could be responsible for the missed effect. In addition, our results confirm the view that implicit motor simulation mechanisms behind action-related verb processing are flexible and context-dependent. & 2014 Elsevier B.V. All rights reserved.

1.

Introduction

Motor simulation entails the rehearsal of a motor task and can occur implicitly (Jeannerod and Frak, 1999) when subjects nn

Corresponding author. Fax: þ39 434 842 797. E-mail address: [email protected] (B. Tomasino).

http://dx.doi.org/10.1016/j.brainres.2014.06.009 0006-8993/& 2014 Elsevier B.V. All rights reserved.

unsolicitedly and unconsciously simulate a movement while performing another task, e.g., during mental rotation of body parts (e.g., Kosslyn et al., 1998, 2001; Zacks et al., 1999), handedness recognition of a visually presented hand

brain research 1574 (2014) 14–25

(e.g., Parsons and Fox, 1998), judgment as to whether an action would be easy, difficult or impossible to perform (Johnson et al., 2002) or recognition and understanding of actions of other individuals (e.g., Jeannerod, 2001). Recent studies have shown that implicit triggering of motor representations might occur also during language processing of action words. Processing action-related words has been shown to activate the premotor and motor cortex, (e.g. Hauk et al., 2004; van Elk et al., 2010; Willems et al., 2010). One way to explore implicit motor representations is to present participants with action-related words either within a positive (e.g., “Do …”) or a negative (e.g., “Don’t …”) context (Tomasino et al., 2013). It is known that processing negative commands (e.g. “Don’t’ run!) causes a reduced activation in the left fronto-parietal regions (Tettamanti et al., 2008) as well as in the hand region of the primary motor and premotor cortices (Tomasino et al., 2010). See also Liuzza et al., 2011 for a TMS study on negations. In addition, positive and negative action-related imperatives cause a modulation of the participants’ RTs, namely an advantage (in terms of RTs) of positive on the negative context (Tomasino et al., 2010). Exposure to commands and contexts has been previously used as a measure of implicit motor activation (Tomasino et al., 2013). In the present study we used the same positive-negative imperative paradigm and asked patients with Parkinson’s Disease (PD) to make lexical decisions about hand actionrelated verbs, abstract verbs and pseudowords presented either within a positive (e.g., “Do can …”) or a negative (e.g., “Don’t …”) context. PD patients underwent bilateral subthalamic deep brain stimulation (DBS). Bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) is one of the most effective treatments for advanced idiopathic PD (Benabid et al., 2009; Limousin et al., 1998; Limousin and Martinez-Torres, 2008). The STN is a key structure in the socalled direct (Cortex-Striatum-internal segment of the Pallidus/substantia nigra pars reticulata-Thalamus-Cortex) and indirect (Cortex-Striatum-external segment of the PallidusSTN; STN-internal segment of the Pallidum/substantia nigra pars reticulata-Thalamus-Cortex) pathways. The direct pathway modulates the thalamo-cortical projection by means of a disinhibitory mechanism. The indirect pathway allows for irrelevant action inhibition and suppression of unwanted movement (Kropotov and Etlinger, 1999). PD alters the balance of activity in the direct and indirect pathways (see Miller and DeLong, 1987) and it is associated with altered action initiation/inhibition mechanisms. The exact mechanism behind DBS remains unknown; however, bilateral STN-DBS is thought to interfere with the integrity of the indirect pathway so that the direct pathway largely assumes control of the internal globus pallidus/substantia nigra reticulate outputs (Wichmann and DeLong, 2003). Importantly, metabolic and neurophysiological techniques have demonstrated that the STN-DBS improves cortical motor functions in several brain regions, including the prefrontal cortex (Gerschlager et al., 1999), supplementary motor area (Ceballos-Baumann et al., 1999; Limousin et al., 1997), premotor cortex and primary motor cortex (Dauper et al., 2002). Thus, patients in the fully active STN-DBS ON condition are expected to perform at the same level as unimpaired subjects to show the context effect shown in Tomasino et al. (2010)).

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By contrast, the 50% reduced STN-DBS condition is expected to result in a lower activation for motor information, which in turn might cause slower RTs overall – as long as motor information contributes to action word identification – and a reduced, if not absent, context modulation. It has been argued that the advantage (in terms of RTs) of the positive on the negative context, which has been observed in previous studies using the positive-negative imperative paradigm, may reflect motor simulation triggered by the positive command and suppression of simulation by the negative “don’t” command mechanisms (Tomasino et al., 2010, 2013). Accordingly, since PD patients show an impaired motor inhibition mechanism, they could serve as model to further test this hypothesis. By using action-related sentences as stimuli, this DBS study will also contribute to the debate on the role of the sensorimotor areas in language processing, (e.g. Kemmerer and Gonzalez-Castillo, 2010; Willems and Hagoort, 2007). Theories of embodied cognition promote the idea that conceptual representations are modality-dependent and built upon sensory and motor experiences. Accordingly, action concepts are understood through motor simulations, that is, by re-enacting sensorimotor memories acquired through experience (Barsalou, 1999, 2008; Gallese and Lakoff, 2005). According to this view, activation of the motor networks in the brain has been held to be necessary and automatic (Pulvermuller, 2005) whenever an action-related word is encountered. According to this view, independent of whether the verb stimuli were presented as positive or negative imperatives, we should observe similar DBS effects for action-related sentences because it is the meaning of an action word per se that is represented in motor networks (Pulvermuller, 2005). Furthermore, the STN-DBS should affect the patients’ performance in deciding whether a stimulus is a real word (i.e., during the lexical decision task) because, according to the embodied cognition view, processing lexico-semantic information about words describing actions depends on the integrity of the motor system. Indeed, deficits in processing action-related stimuli have been reported in patients with PD (Boulenger et al., 2008; Ibáñez et al., 2013; Peran et al., 2003, 2009; Rodríguez-Ferreiro et al., 2009), although another study has shown that PD patients performed a semantic judgment task as accurately as controls but were significantly slower for both action and non-action verbs (Kemmerer et al., 2013). (For a review see also (Vigliocco et al., 2011 and Cardona et al., 2013)). By contrast, showing that positive or negative imperatives exert a different effect on action verbs would rather support the view that the involvement of sensorimotor areas depends on the context (van Dam et al., 2010, 2012a, 2012b) in which conceptual features are retrieved. See also Tomasino and Rumiati, 2013a.

2.

Results

Patients (see Table 1 for their neuropsychological details) made lexical decisions about hand action-related verbs, abstract verbs and pseudowords presented either within a positive (e.g., “Do …”) or a negative (e.g., “Don’t …”) context. A repeated-measure ANOVA with “condition” (ON, 50%), type

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Table 1 – Patients’ neuropsychological and clinical details. Case

S,A,E

Handedness

Years since surgery

1

M,76,5

R

5

2

F,72,13

R

3

3

F,71,13

R

3

4

M,57,13

R

3

5

M,59,13

R

3

6

M,72,5

R

2

7

M,64,13

R

2

8

M,61,13

R

2

9

F, 49,13

R

3

10

M,73,13

R

4

Cut off

–

–

–

Case

1 2 3 4 5 6 7 8 9 10 Cut off

Intelligence

Language

Mini mental

Naming

30/30 30/30 30/30 30/30 28/30 29/30 28/30 30/30 30/30 29/30 24

L L L L L L L L L L L

15/15; NL 12/15; NL 11/15; NL 15/15; NL 15/15; NL 15/15; NL 15/15; NL 15/15; NL 15/15; NL 15/15; NL 8; NL 17

DBS

Stimulation parameters

STN Bil STN Bil STN Bil STN Bil STN Bil STN Bil STN Bil STN Bil STN Bil STN Bil –

20/20 20/20 20/20 20/20 20/20 20/20 20/20 20/20 20/20 20/20

UPDRS

Int (V)

Duration (μs)

Freq (Hz)

On

50%

D (%)

3.2

90

130

30

43

30

1.4

90

130

17

34

50

3

90

130

15

35

57

3.35

60

180

8

10

20

2.6

60

185

13

15

13

3

60

180

6

9

33

2.5

60

130

20

22

9

2.2

60

130

9

11

18

3.2

60

185

8

11

27

4

60

90

8

11

27

–

–

Spatial attention

STM

Praxis

Comprehension

Albert

D span

IMA

Oral

36/36 36/36 36/36 36/36 33/36 35/36 36/36 35/36 36/36 36/36 25

⋎ ⋎ ⋎ ⋎ ⋎ ⋎ ⋎ ⋎ ⋎ ⋎ –

4 7 5 6 7 5 4 5 5 6 3.75

72/72 65/72 59/72 72/72 72/72 72/72 72/72 72/72 72/72 72/72 53

16/20 20/20 17/20 20/20 20/20 20/20 20/20 20/20 20/20 20/20 20

S¼ sex; A ¼age; E ¼ education; DBS ¼Deep brain stimulation; STN ¼ sub-thalamic nucleus; bil ¼ bilateral; Int ¼Intensity; Freq ¼frequency; UPDRS ¼ Unified Parkinson’s Disease Rating Scale (performed ON and 50% DBS); D ¼difference between UPDRS ON vs 50%DBS; L¼ living; NL ¼non living items on the naming task; STM ¼short term memory; D span¼ digit span; IMA ¼Ideomotor apraxia.

of “stimulus” (M, nM and PW) and “context” (positive and negative) as within-subject factors was performed on patients’ error rates and reaction time (RTs) data.

2.1.

Accuracy

Their average error rates for the lexical decision task did not differ significantly when they performed the task in the DBSON and DBS-50% conditions (see Table 2).

2.2.

Reaction times

Reaction times (RTs) for action-related verbs were significantly faster for positive than negative commands in the DBS-ON condition, while they were identical in the DBS-50%

condition. This result was supported by the following statistical results. We found a significant 3-way ‘stimulation condition  stimulus  context’ interaction, F(2, 18)¼4.066, po0.05. The effect of linguistic negative vs. positive context in which a (hand) action verb occurs was dependent on the stimulation condition (see Fig. 1d). A post-hoc two-way ANOVA performed separately for the ON and 50% conditions (Bonferroni adjustment for multiple comparisons, αo.05) revealed that the effect of negative vs. positive context on hand-action related verbs affected the participants’ reaction times, with significantly slower RTs for hand-action verbs presented in a negative context than hand-action verbs presented in a positive context (po.001) in the DBS-ON condition (F(2, 18)¼15.09, po.001). However, in the DBS-50% condition (i.e. when PD-related motor

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Table 2 – Average error rates for each condition. All the main effects and interactions were not significant. Healthy controls

Patients DBS-ON

M_pos 1.66%72.22 M_neg 1.5%72.8 nM_pos 2.14%71.65 nM_neg 1.8%71.99 PW_pos 2.83%73.2 PW_neg 1.66%72.66 Stimuli, F(2, 28) ¼.51, p4.05, n.s. Context, F(1, 14) ¼.69, p40.05, n.s. Stimuli  context, F(2, 28) ¼ .57, p4.05, n.s.

DBS-50%

0.68%71.22 1.02%71.15 0.88%71.81 0.4%71.13 0.28%70.38 0.56%70.94 0.72%71.34 0.6%71.35 0.94%71.14 0.4%70.42 0.72%70.96 0.64%70.82 Stimuli, F(2, 18) ¼ 1.607 context, F(1, 9)¼ .29 Stimuli  context, F(2, 18) ¼ .016 Condition, F(1, 9) ¼1.033 Condition  stimuli, F(2, 18)¼ 3.59 Condition  context, F(1, 9) ¼ 1.24 Condition  stimuli  context, F(2, 18) ¼2.301

Fig. 1 – The target area, the subthalamic nucleus, is shown on one representative patient’s (P1) anatomical MR scan. (a) The four channel micro-guide system (Bengun) used for the four microelectrode signal recording. (b) Mean RTs for the lexical decision task on action-related (M), non-motor (nM) related verbs and pseudowords (PW) presented in a positive (pos) and negative (neg) context for healthy controls (c) and for the patients’ group (d) in the DBS-ON and the DBS-50% conditions. Error bars indicate standard errors (SEM). Asterisks denote a significant difference between pos and neg M verbs. symptoms were strongest), the ‘stimulus  context’ interaction (F(2, 18)¼ 1.38, p4.05, n.s.) was not significant and accordingly RTs for hand-action verbs were not significantly

affected by the linguistic context (p ¼.15, n.s.). The context effect was absent for non-motor (nM) verbs in both stimulation conditions (p¼ .148 and p ¼.688 for the DBS-ON and

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DBS-50% conditions respectively, all n.s.) as well as for pseudowords (PW) (p¼ .434 and p ¼.521 for the DBS-ON and DBS-50% conditions respectively, all n.s.). We further analyzed this pattern of results in an item analysis too, since the analysis above is a repeated measure within-subject ANOVA and thus all the Fs we reported always referred to a subject analysis (and the patient group includes 10 participants). Thus we carried out a repeated-measure ANOVA on the patients’ mean RTs with type of “stimulation condition” (DBS ON, DBS 50%) and “context” (positive and negative) as within-subject factors, plus a between-item variable “stimulus type” (motor and non motor verbs) and we controlled for the effects of frequency and imageability by inserting two more regressors coding such variables. The analysis confirmed that the three way “stimulation condition  stimulus  context” interaction was significant [F(1, 74)¼ 5.79, p¼.019] and that the effect of linguistic negative vs. positive context in which action verbs occur was dependent on the stimulation condition. In addition we found the following significant main effects and interactions: context (F(1, 74)¼ 9.31, p¼ .003) and its interaction with imageability for positive contexts (F(1, 74)¼4.64, p¼ .034); the stimulation condition (F(1, 74)¼ 49.37, p¼ .001). none of the other main effects or interactions were significant. As a further confirmation of the finding that the 100% stimulation condition is similar to controls, we carried out a repeated-measure ANOVA on the subjects’ error rates and RTs with “group” (patients and controls) as between-subject factor and type of “stimulus” (M, nM and PW) and “context” (positive and negative) as within-subject factors. All post-hoc comparisons between single factors were based on LSD Fisher’s test (αr .05). We found a significant effect of group (F(1, 18)¼ 16.61, p¼ .001, with patients slower than controls), context (F(1, 22)¼ 6.8, p ¼ .018, with negatives slower than positives), stimuli (F(2, 44)¼ 10.08, p¼ .000, with both M and nM slower than PW, p¼ .002 and p ¼.001 respectively, and no significant difference between M and nM, p¼ .36) and of the ‘stimuli  context’ interaction (F(2, 36)¼ 29.79, p¼ .000, motor verbs: negative (neg)4positive (pos), p¼ .000 and non-motor verbs: neg¼ pos, p¼ .08, n.s.). The ‘group  stimuli’ (F(2, 36)¼.62, p¼ .53), the ‘group  context’ (F(1, 22)¼ 4.25, p¼ .06) and the ‘group  stimuli  context’ (F(2, 36)¼ 2.37, p¼ .108) interactions confirmed that the effect of context for motor verbs (and the lack of effect for non-motor verbs) is not different across groups.

3.

Discussion

This study was designed to investigate the impact of STNDBS on implicit motor simulation processes in PD patients. We addressed this issue by presenting hand action- and nonaction-related verbs either within a positive or a negative sentence context. Processing action-related words has been shown to activate the premotor and motor cortex, (e.g. Hauk et al., 2004; van Elk et al., 2010; Willems et al., 2010). Importantly, positive and negative action-related imperatives caused a modulation of the participants’ RTs, namely an advantage (in terms of Rts) of positive on the negative context

(Tomasino et al., 2010). This effect may reflect motor simulation and motor simulation inhibition mechanisms, which in turn can be pathological in PD patients. Similarly to healthy controls, PD patients exhibited a linguistic context effect on reaction times, with increased RTs for the negative context vs. the positive context in the DBS-ON condition. However, in the DBS-50% condition (that is when the inhibition mechanism was altered) their RTs for hand-action verbs were not significantly affected by the linguistic context. A modulatory effect of context on RTs causing slower RTs for negative than positive commands evidenced that in a negative context we act as if we received a command and refrain from performing the corresponding action (Tomasino et al., 2010). Consistent with this, our data revealed that the negative context led to a relative increase in RTs. Similarly, a TMS study has shown that excitatory cortico-spinal excitability is suppressed during negative motor simulation (i.e., the mental simulation of suppressing a movement) (Sohn et al., 2003). Negations, indeed, have also been shown to decrease activation in the premotor and motor cortex when compared to affirmatives (Tettamanti et al., 2008, 2010). The notion that areas involved in motor act preparation (i.e., premotor cortex) are underactivated in PD patients (Jahanshahi et al., 1992; Playford et al., 1992; Rascol et al., 1992) might explain why PD patients did not show a context-dependent modulation in RTs in the DBS-50% condition. This pattern of performance indicates that STN-DBS has a positive effect both clinically, in that it reduces PD-related motor disability such as rigidity and tremor, and cognitively, as it restores the RT pattern shown by controls during action word lexical decisions. There is a rich literature on how negation is processed. According to one account, negation could imply simulating the mentioned entity and later deleting it, as some embodied theories of negation assume (e.g., Kaup et al., 2007, 2010; Kaup and Zwaan, 2003). According to the two-step simulation hypothesis of negation processing (Kaup et al., 2007, 2010; Kaup and Zwaan, 2003) a subject first simulates the negated action (e.g. “John has not left”) and then the actual state of affairs (e.g., “John has left”). Negation is implicitly encoded in the deviation between both simulations (Ludtke et al., 2008). In line with this view, activation of the premotor cortex by negations was documented in a study involving a sentencepicture verification task (Hasegawa et al., 2002). Another view assumes that negations could inhibit the simulation of the meaning expressed by the sentence. In line with this view, negations have been found to limit access to mental representations of the negated information (Tettamanti et al., 2008). Accordingly, the activation in the left fronto-parietal regions and the effective connectivity in concept-specific embodied systems is reduced, too (Tettamanti et al., 2008). Similarly, activations in the hand region of the primary motor and premotor cortices were found to be reduced for negative hand action-related imperatives such as “Don’t grasp!” compared to “Grasp!” (Tomasino et al., 2010). These contradictory results has been reconciled (Tomasino and Rumiati, 2013a) by proposing that negations can activate the sensorimotor cortex depending on whether the strategy of simulating the corresponding movement has or has not been blocked. Stimuli used in previous studies (e.g. Kaup et al., 2007, 2010; Kaup and Zwaan, 2003), e.g. “Johns has not left”, differ in two ways from the studies

brain research 1574 (2014) 14–25

evidencing a reduced motor system activation, e.g. “Now I don’t push the button” (Tettamanti et al., 2008) and “Don’t grasp!” (Tomasino et al., 2010). Meaning, the perspective in which verbs are presented might have influenced the modulation of the sensorimotor activation. While in the former studies verbs are presented in a third person perspective, the latter studies used the first person perspective. Second, in Tomasino et al. (2010), simulation was blocked by means of an experimental manipulation involving the use of imperatives. Negative imperatives are known, if heard, to refrain participants from performing the corresponding action. By contrast, in a sentence–picture verification paradigm (Hasegawa et al., 2002) participants might have been free to use a two-step simulation strategy leading to an activation of the sensorimotor areas.

3.1.

Neurophysiological interpretation

Theories of subcortical involvement in language processing recently included the STN (Whelan et al., 2003). Bilateral STNDBS produces significant changes in high-level linguistic and semantic processing (Whelan et al., 2003). In the present study, we concentrated on the effects of STN-DBS on action verb processing, especially because the target for STN stimulation is the dorsolateral (sensorimotor) portion of the STN. The DBS in the basal ganglia changes activity and modulates information processing in the premotor cortex, primary motor cortex (Dauper et al., 2002), SMA (Ceballos-Baumann et al., 1999; Limousin et al., 1997) and PFC (Gerschlager et al., 1999). This might explain how the pattern of action verb processing in our lexical decision task was comparable to that of control subjects in the DBS-ON condition. Furthermore, it is know that the STN is a key structure in the so-called direct (Cortex-Striatum-internal segment of the Pallidus/substantia nigra pars reticulata-Thalamus-Cortex) and indirect (Cortex-Striatum-external segment of the Pallidus-STN; STN-internal segment of the Pallidum/substantia nigra pars reticulata-Thalamus-Cortex) pathways. The direct pathway modulates the thalamo-cortical projection by means of a disinhibitory mechanism. In PD, nigral dopaminergic degeneration causes altered action initiation and a reduced thalamus inhibition, which therefore amplifies cortical activity. This is why it has been claimed that the thalamus “…functions similarly to a searchlight that highlights, intensifies the selected program in the cortex” (Crick, 1984). The altered action inhibition effect seen in PD could well explain why patients showed an altered pattern of performance in the DBS-50% condition. The indirect pathway, on the contrary, allows for irrelevant action inhibition and suppression of unwanted movement (Kropotov and Etlinger, 1999). Motor program suppression is allowed by the indirect pathway through the basal ganglia to the thalamus towards the premotor cortex. The altered irrelevant action inhibition and suppression of unwanted movement mechanism in PD could also be responsible for the missed effect of the negative context “Don’t” on action verb processing which is thought to prevent and inhibit action preparation and motor simulation. We argue that the absence of context-dependent modulation found in the 50% STN-DBS condition might be related to the alterated functioning of direct and indirect pathways in the reduced STN-DBS condition. Importantly, the direct pathway

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has been shown to be associated with the registration of contexts, while the indirect pathway has been associated with context negation (Lawrence et al., 1998). According to these authors (Lawrence et al., 1998), context-relevant information processing would allow the striatum to instruct cortical areas as to which sensory inputs or patterns of motor output are behaviorally significant in a given context. In healthy controls, even pseudowords showed a linguistic context effect, albeit in the opposite direction to motorrelated verbs. PWs were used simply to accomplish the requirements of the lexical decision task. We could interpret the unexpected pattern only within the stimulus-response compatibility. In Tomasino et al. (2010) the context had an effect also on PW, albeit in the opposite direction. The important result is that we replicated the effect on actionrelated words, which was our main condition of interest, whereas we can conclude that PWs show a very inconsistent pattern. One might also argue that reading verbs in a negative or positive context and making a lexical decision (yes to words, no to pseudowords) creates compatible and incompatible conditions, where a negative context induces a response tendency for “no” (conflicting with the required “yes” response for words, motor and non-motor related items), whereas the opposite is true for pseudowords. Participants were equally accurate in all conditions, ruling out any possible tendency causing errors. Furthermore, the pattern of compatibility-incompatibility should be seen for all words (motor and non-motor), and not only for action-related words and pseudoverbs as found in our study. Data on pseudowords, albeit producing unexpected pattern of results, served as a further control condition (a sort of low-level baseline) in addition to nM related words. Motor activity has been observed not only during action-related word processing, but also when reading imaginable concrete words with no motor content (D’Esposito et al., 1997; Mellet et al., 1998; Postle et al., 2008; Pulvermuller and Hauk, 2006). Abstract words have been shown to activate the sensorimotor system in a similar manner as motor related words, (e.g. Borghi and Cimatti, 2009; Moseley et al., 2012; Papeo et al., 2012). It has been suggested that abstract and action-related word processing reflects a continuum rather than a dichotomy (Scorolli et al., 2011). A recent fMRI study (Papeo et al., 2012) found that reading (both abstract and motor related verbs) following a motor simulation task versus to reading following a visuospatial simulation task determined an increased activity in the left primary motor cortex, bilateral premotor cortex and right somatosensory cortex. Similarly, in a recent TMS study of the left M1 cortex (Scorolli et al., 2012), abstract words (verbs) also activated the motor system related to manual action. Lastly, patients were slower in the DBS-ON compared to the DBS-50% condition. For practical reasons, the DBS-ON and the DBS-50% conditions were not counterbalanced between subjects (as they were not in (Boulenger et al., 2008) in which patients were also slower in the OFF_Levodopa than in the ON_levodopa intake). All our patients performed the experiment first in the DBS-ON and then in the DBS-50% condition. Learning effect thus could be a very basic explanation for a faster performance under the 50%. There are previous indications of slowed RTs during DBS (Dujardin et al., 2001; Gerschlager et al., 1999; Whelan et al., 2003) relative to

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preoperative testing. The STN-DBS may facilitate a generalized mental slowness (Trepanier et al., 2000). We ruled out the possibility that the context effect modulation was due to this overall facilitation observed in the DBS-50% condition. Facilitatory effects are smaller for faster/easier conditions. However, if results were due to this, then the context effect should have been found for nM-related words, too.

3.2.

Action-related verb processing in PD

If premotor and motor regions that are involved in motor preparation/simulation mechanisms also play a role in action-related word processing (Barsalou, 1999, 2008; Barsalou et al., 2003; Fischer and Zwaan, 2008; Gallese and Lakoff, 2005; Glenberg, 1997; Rizzolatti and Arbib, 1998; Zwaan, 2004; Zwaan and Taylor, 2006), our results shed light also on the relationship between language and motor processes. The context effect was specific for action words, suggesting that the neurophysiological mechanisms of PD affect this specific class, as compared to non-motor related verbs and pseudoverbs. However, our results are not consistent with the view that action words automatically trigger neural activity in motor areas because it is the meaning of an action word per se that is represented in overlapping networks (Pulvermuller, 2005). Embodied cognition theorists argued that imagination is necessary to understand actionrelated sentences such as “Harry picked up the glass” and write that “if you cannot imagine picking up a glass or seeing someone picking up a glass, then you cannot understand that sentence” (Gallese and Lakoff, 2005). If this prediction were correct, we should have found similar effects of DBS for action-related verbs independent of whether the verb stimuli were presented as positive or negative imperatives, because the linguistic context should not have an effect on the automatic activation of the motor system. If this prediction were correct, we should have found a reduced ability to process action verbs when the STN-DBS is decreased. In particular, the embodied cognition view predicts that the ability to process lexico-semantic information about words describing actions depends on the integrity of the motor system. However, the STN-DBS did not affect the patients’ accuracy in a task requiring to decide whether an item is a real word, i.e. the lexical decision task. In our study, patients were proficient at deciding whether an item is a real word in the DBS-50% condition just as they were in the DBS-ON condition. Our results diverge from previous studies on PD patients showing deficits in action-related verb processing (Boulenger et al., 2008; Ibáñez et al., 2013; Peran et al., 2003, 2009; Rodríguez-Ferreiro et al., 2009). For instance, Fernandino et al. (2013a) administered a semantic similarity judgment task on action and abstract verbs to PD patients. They found that RTs did not differ between patients and controls and observed significant differences in accuracy. PD patients were significantly less accurate at judging action verbs than abstract verbs, while controls were equally accurate at judging action verbs and abstract verbs. It was however pointed out (Kemmerer et al., 2013) that it is unclear whether this difference was due to a minimal deficit in action verb comprehension (PD mean: 95.5%, control mean: 96.7%) or facilitation in abstract verb comprehension (PD mean:

97.5%, control mean: 96.9%). In addition, another aspect involves RTs and it has been proposed that the use of alternative between-group tests might have led to different results, since PD patients were slower than controls for both action (PD: 2451 ms, controls: 2022 ms) and abstract (PD: 2332 ms, controls: 1890 ms) verbs. However, in another study (Fernandino et al., 2013b) significant differences were found in RTs but not in accuracy, similarly to our results. The authors asked PD patients and controls to perform a sentence comprehension task. The same hand/arm action related verbs were presented within a literal, non-idiomatic metaphoric and idiomatic context in addition to abstract verbs. Unlike controls, PD patients showed slower RTs to literal and idiomatic action sentences than to abstract sentences, and the authors argued that the sensory-motor system plays a functional role in semantic processing, including processing of figurative action language (Fernandino et al., 2013b). Taken together, our results are consistent with Kemmerer and colleagues’ study (Kemmerer et al., 2013) in which no effect on accuracy was found: PD patients performed a semantic judgment task as accurately as controls but were significantly slower for both action and non-action verbs (Kemmerer et al., 2013). In addition, independent of whether the verb stimuli were presented as positive or negative imperatives, we should have found similar effects of DBS for action-related verbs because the linguistic context should not have an effect on the motor system if it is the action concept that is represented in sensorimotor networks (Pulvermuller, 2005). Again, our results do not confirm this assumption. We did not find any significant main effect of stimulus or of ‘stimulation condition  stimulus’ interaction, and the STN-DBS did not affect the general ability to process action verbs (both in positive and negative contexts) but evidenced a contextdependent selective impairment. The effect of the DBS reduction was similar for all conditions. The only significant effect was found for action verbs presented in a negative context. Taken together, these results support the view that sensorimotor activation is not automatically triggered by the type of stimulus and it is accessory to linguistic processing, as shown by the fact that PD patients were as accurate as controls both in the DBS-ON and in the DBS-50% conditions (Mahon and Caramazza, 2005, 2008; Papeo et al., 2009; Postle et al., 2008; Raposo et al., 2009; Tomasino et al., 2010; Tomasino and Rumiati, 2013b; Willems et al., 2010).

4.

Conclusion

Our results showed that when STN-DBS settings are reduced, that is when the motor network is altered, the RT pattern which reflects implicit motor simulation is altered as well. The STN-DBS has a positive effect both clinically, in that it reduces PD-related motor disability such as rigidity and tremor, and cognitively, as it restores the RT pattern shown by controls during action word lexical decisions. In addition, our results confirm the view that implicit motor simulation mechanisms behind action-related verb processing are flexible and context-dependent.

brain research 1574 (2014) 14–25

5.

Experimental procedures

5.1.

Participants

The present study included 10 right-handed (Oldfield, 1971) patients diagnosed with non-demented Parkinson’s Disease (PD) (mean age 65.4 years 76.7, mean education 11.4 years 73.37) who had been implanted with permanent deep brain stimulation (DBS) electrodes bilaterally into the subthalamic nucleus (STN) (Fig. 1a and b). The target for STN stimulation is the dorsolateral (sensorimotor) portion of the STN. They all gave their informed consent to participate in the study, which was approved by the local Ethics Committee. All were native Italian speakers and had normal or correctedto-normal vision. They fulfilled the neuroradiological, neurological and neuropsychological criteria (Defer et al., 1999; Lang and Widner, 2002) for PD and DBS of the STN which has become a common treatment for medically intractable PD since it is associated with improvements in PD motor symptoms (Rodriguez-Oroz et al., 2005). At the time of testing patients were considered to have stable stimulator settings by their neurologist. Cognitive performance was assessed using a neuropsychological battery of tests tapping language, attention, praxis and memory (see Table 1) as well as the Mini Mental State Examination (Folstein et al., 1975). The strict inclusion criteria for being a candidate to STN-DBS include lack of dementia in the patients (Defer et al., 1999; Lang and Widner, 2002). All performed well at the neuropsychological screening (see Table 1 for the description of the clinical characteristics). Participants were tested whilst taking their usual medication (Levodopa). Since a one-h break separated the two stimulation conditions, the medication status of the PD patients during the DBS-ON and DBS-50% sessions was the same. Motor disability was evaluated using Part III of the Unified Parkinson’s Disease Rating Scale (UPDRS Part III, Fahn et al., 2004) in OFF- and ON-states (Table 1).

5.2.

Procedure

5.2.1.

Stimuli

For the generation of the stimulus phrases (N¼160), 80 Italian action verbs related to hand movements [M], e.g., “grasp” and 80 non-motor related verbs [nM], e.g., “think” were selected. In addition, our design included 160 meaningless pseudoverbs [PW] to accomplish the requirements of the lexical decision task, consisting of 160 real words and 160 pseudo verbs. Two different linguistic contexts were used. Half of the stimuli were presented in a negative context ([neg], e.g., “non scrivere!”, “Don’t write!”) and half in a positive one ([pos], e.g., “puoi martellare”, “Hammer/you can hammer!”) resulting in a total of 40M_pos, 40M_neg, 40N_pos, 40N_neg, 80PW_pos and 80PW_neg stimuli. This stimulus form allowed us to keep the phrase structure as similar as possible across all experimental conditions, with both positive and negative linguistic contexts including the infinitive form of the verb preceded by a negation (“Non”) or the modal verb “Puoi” (i.e., “Don’t” or “You can”). Thus, the stimuli in the positive and negative contexts differed visually by 1 letter only, i.e., “non”, 3 letters vs. “puoi”, 4 characters. This ensured that the stimulus length

21

did not account for the variance induced by the experimental factor context (“non” vs. “puoi”) as stimuli of identical lengths occurred in both context conditions (e.g., “Non scrivere”, i.e., “Don’t write” and “Puoi firmare”, i.e., “You can sign”, both with a length of 11 characters). To avoid any potential priming effect, the same verb was not used in both contexts (positive vs. negative) and two different lists of verbs were created. Three pseudo-randomized stimulus sequences were alternated between participants. Furthermore, trial sequences were shuffled, so that the same condition did not appear more than three times sequentially (e.g., M_pos repeated more than 3 times) or the same context did not appear more than three times sequentially (e.g., M_pos, N_pos, PW_pos). PWs were generated by substituting or exchanging letters of the corresponding action verbs, e.g., “gralp”, and were thus in agreement with the phonological and orthographic rules of Italian. They were preceded by the “Puoi” (positive) and “Non” (negative), as well as the real words. PWs did not occur just before their corresponding verbs. The final choice of the stimuli was based on a pilot study where 12 right-handed (Oldfield, 1971) healthy participants (mean age, 29.3375.33), all being native speakers of Italian with comparable levels of education (mean, 15.772.63), all monolinguals, with normal or corrected-to-normal vision, with no history of neurological illness, psychiatric disease, or drug abuse, judged each verb stimulus. Following the instructions of (Barca et al., 2002), they rated the stimuli on several dimensions. Participants judged word familiarity (i.e. how well a word is known) on a scale ranging from 1 to 7, where “1”¼ very little known and “7” ¼very well known, and word imageability (i.e. how quickly and easily a word arouses mental images) on a scale ranging from 1 to 7, where “1”¼ hardly imageable and “7”¼ highly imageable.1 In addition, they estimated whether the word referred to a movement or not (i.e., M/nM stimulus). Accordingly, motorrelatedness significantly differed according to stimuli (F(1, 117)¼1183.64, po.001), with M characterized by higher ratings (M_pos vs nM_pos, po.001; M_neg vs nM_neg, po.001) as compared to nM verbs. Importantly, M_pos and M-neg (p¼ .99) as well as nM_pos and nM_neg (.114) did not differ significantly (see Table 3). We found a significant effect of familiarity (F(1, 117)¼4.9, po.05) which was not driven by a difference between the selected action verbs presented as negative vs positive (M_pos vs M-neg, p¼ .899) or between the selected non-action verbs presented as negative vs positive (nM_pos vs nM_neg, p ¼.99), which were therefore matched for familiarity, but by a significant difference between negative action verbs and non-action verbs (M_neg vs nM_neg, po.001). Not surprisingly, stimuli differed in imageability (F(1, 117) ¼314.21, po.001), since M verbs have a rich and elaborate set of associated perceptual and motor features and nM verbs are relatively impoverished in their associated perceptual features (Grossman et al., 2002). Importantly,

1 For imageability we performed within-subjects normalisation of participants’ ratings since it is quite typical that different participants make use of different parts of the scale and also use the scale differently. This uninteresting variance would all disappear through within-subjects normalisation.

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brain research 1574 (2014) 14–25

Table 3 – Stimuli details. M_pos¼motor-related verbs presented as positive commands; M_neg¼ motor-related verbs presented as negative commands; nM_pos and nM_neg¼ non motor-related verbs presented as positive and negative commands respectively.

M_pos M_neg nM_pos nM _neg a

Motor-relatedness

Familiarity

Imageabilitya

Frequency (occurrences per million words)

Length

0.9870.03 0.9870.04 0.1670.16 0.0970.1

6.6170.49 6.7070.31 6.3570.69 6.3070.57

0.5270.20 0.5570.11  0.4770.47  0.6170.52

131.577250.16 112.677389.64 244.657395.43 254.577358.94

8.771.7 8.871.8 8.571.7 8.771.5

We performed within-subjects normalization.

M_pos and M-neg (p¼ .44) as well as nM_pos and nM_neg (.15) did not differ significantly (see Table 3). Lastly, to exclude the possibility that PWs were processed as motor stimuli, we asked the 12 healthy controls who judged the stimulus list (see above) to rate each PW according to whether it resembled a motor-related, a non-motor related verb or none of them. PWs were not judged as real verbs (70% 720.68; action-related: 28.47718.13; non-motor related: 29.26717.59). The verbs were matched for word length [M_pos vs. M_neg, t(39) ¼  .27, p4.05, n.s; N_pos vs. N_neg, t(39)¼ .52, p4.05, n.s; PW_pos vs. PW_neg, t(79)¼ .50, p4.05, n.s]. Verb frequency (occurrences per million words) was balanced across conditions [M_pos vs. M_neg, t(39)¼ .24; M_pos vs. N_pos, t(39)¼ 1.5; M_pos vs. N_neg, t(39)¼ 1.8; M_neg vs. N_pos, t(39) ¼  1.9; M_neg vs. N_ neg, t(39)¼  1.6; N_pos vs. N_ neg, t(39)¼ .11, All Ps4.05, n.s] according to the frequency norms available for Italian (CoLFIS, Laudanna et al., 1995).

5.2.2.

Task and procedure

Similarly to previous studies (e.g., Pulvermuller et al., 2001), we administered our participants a lexical decision task. The experiment started with an instruction (6 s) requesting subjects to silently read the phrases and decide whether or not a letter sequence was a real word. Subjects gave a verbal response (yes/no answer for each stimulus). All experimental trials lasted 3 s and were followed by a variable inter-trial interval with a duration that was jittered between 1750 and 3250 ms, with incremental steps of 500 ms. 48 null events (i.e., blank screens), perceived as a prolongation of the intertrial period, were randomly interspersed among the event trials in order to decrease expectation. Patients performed the experiment twice in the same day in two stimulation conditions: once on stimulation (DBS_ON, see stimulation parameters in Table 1), and the second time, with a 1-h break, with a 50% reduction in intensity stimulation (DBS-50%). Although it reactivated PD symptoms, a 1-h break between stimulation conditions was tolerated by the patients and ensured that there were no after-discharge stimulatory effects and no rebound-exaggerated impairment after terminating stimulation (Castner et al., 2008). Stimulus presentation and response collection were carried out by the Presentations software (Version 9.9, Neurobehavioral Systems Inc., CA, USA). Verbal responses were recorded via a voice key. Patients were instructed to keep their hands still in a relaxed manner and respond verbally (“yes” or “no”) as quickly as possible. Verbal responses were

chosen to minimize interference between response preparation and execution and the predicted task-related activity in M1 and Pm hand area since patients, especially in the DBS50% condition, experienced tremor, slow movement and bradykinesia, which might affect the RTs. This is a frequently adopted procedure in action verb processing studies, in which subjects may be instructed to respond by a brisk lip movement during a lexical decision task of hand and legrelated verbs (Pulvermuller et al., 2005) or by foot pedal presses while processing hand-related verbs (Tomasino et al., 2010). Furthermore, the RT pattern found in the task norming study, in which healthy controls performed the lexical decision task by responding verbally (see below), is the same as that found in Tomasino et al. (2010), with slower responses for negative action-related verbs. In addition, this procedure enabled the subjects to focus their attention on the experimental tasks (lexical decisions) with minimal distraction by the response mode. Prior to the experiment, all participants practiced the experimental task on 20 verbs which were not included in the experiment.

5.2.3.

Task norming study

Task norms were collected from 14 right-handed (Edinburgh Inventory Test (Oldfield, 1971) healthy participants (mean age 7SD: 58.377.4 years; six females) -all native speakers of Italian having comparable levels of education (mean7SD: 1174 years, vs. patients: 11.473.37 years, F(1, 23)¼ .066, p ¼.79)- who performed the lexical decision task by responding verbally. All had normal or corrected-to-normal vision and reported no history of neurological illness, psychiatric disease, or drug abuse. All gave their informed consent to participate in the task norming study, which was approved by the local Ethics Committee. A repeated-measure ANOVA with “context” (positive and negative) and “stimulus” (M, N, PW) as within-subject factors was performed on accuracy and reaction time (RT) data using SPSS software for Windows (version 12.0). For the RT data, outliers were removed by excluding any trials in which the participants’ RTs were two standard deviations above or below the participants’ mean RTs for the condition in which the trial occurred (4.2% of the data) (Ratcliff, 1993). The RT analysis (see Fig. 1c) showed a significant stimulus  context interaction (F(2, 28)¼7.7, po.005), with significantly longer RTs for the negative vs. the positive context for M words (mean and SD: 1252.447163.16 ms, 1212.987 145.56 ms, t(14) ¼  3.26, po.01), no context effect for N words (1235.997155.78 ms vs. 1227.727151.47 ms, t(14) ¼  1.23,

brain research 1574 (2014) 14–25

p4.05, n.s.) and significantly longer RTs for the positive vs. the negative context for PWs (1279.727200.32 ms vs. 1341.837189.84 ms, t(14)¼ 3.011, po.01.; see Fig. 1d). In addition, we found a significant main effect of type of stimulus (F(2, 28)¼12.07, po.001), with significantly longer RTs for PWs (1301.787199.96 ms) than M words (1235.127151.05 ms, t(14) ¼  3.55, po.005) and N words (1239.677162.33 ms, t(14) ¼  3.79, po.001), whereas no significant difference was found between M and N words (t(14)¼  .62, p4.05, n.s.). Average error rates for the lexical decision task did not differ significantly between conditions (see Table 2).

5.3.

Statistical analyses

Statistics were carried out by SPSS for Windows (version 12.0). We analyzed the mean RTs of the correct responses across conditions and the mean error rates using a repeatedmeasure analysis of variance (ANOVA).

Acknowledgments We would like to thank all the patients and volunteers for their participation in this study.

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