Abstract

Imitation of tool-use gestures (transitive; e.g., hammering) and communicative emblems (intransitive; e.g., waving goodbye) is frequently impaired after left-hemispheric lesions. We aimed 1) to identify lesions related to deficient transitive or intransitive gestures, 2) to delineate regions associated with distinct error types (e.g., hand configuration, kinematics), and 3) to compare imitation to previous data on pantomimed and actual tool use. Of note, 156 patients (64.3 ± 14.6 years; 56 female) with first-ever left-hemispheric ischemic stroke were prospectively examined 4.8 ± 2.0 days after symptom onset. Lesions were delineated on magnetic resonance imaging scans for voxel-based lesion-symptom mapping. First, while inferior-parietal lesions affected both gesture types, specific associations emerged between intransitive gesture deficits and anterior temporal damage and between transitive gesture deficits and premotor and occipito-parietal lesions. Second, impaired hand configurations were related to anterior intraparietal damage, hand/wrist-orientation errors to premotor lesions, and kinematic errors to inferior-parietal/occipito-temporal lesions. Third, premotor lesions impacted more on transitive imitation compared with actual tool use, pantomimed and actual tool use were more susceptible to lesioned insular cortex and subjacent white matter. In summary, transitive and intransitive gestures differentially rely on ventro-dorsal and ventral streams due to higher demands on temporo-spatial processing (transitive) or stronger reliance on semantic information (intransitive), respectively.

Introduction

Meaningful gestures are considered one of the earliest methods of communication in primate evolution (Hewes 1973) and have remained a powerful way of expression until today (Varney and Benton 1982; Andric and Small 2012). Since meaningful gestures may be used as a substitute for speech (Andric and Small 2012), they are particularly relevant in situations where language is unavailable, for example, when compensating for aphasic deficits (Hogrefe et al. 2012), or when communicating with someone speaking another language. Two basic categories of meaningful gestures can be distinguished (Ekman and Friesen 1969; Haaland et al. 2000; Goldenberg 2013): transitive gestures depict skilled actions associated with tools or objects (e.g., hammering a nail or smoking a cigarette); conversely, intransitive gestures convey messages by means of emblematic movements and postures (e.g., the “hush” sign or “thumbs up”).

The ability to produce meaningful gestures is frequently impaired in patients with left-hemispheric lesions who suffer from apraxia, a cognitive motor disorder characterized by the inability to perform skilled movements despite intact basic sensorimotor functions such as strength or coordination (Heilman and Rothi 1993; Leiguarda and Marsden 2000; Donkervoort et al. 2006; Goldenberg and Spatt 2009). Given the high frequency of coexisting language comprehension deficits, meaningful gesture performance is usually probed by imitation tasks, that is, by instructing the patient to reproduce an observed gesture (De Renzi 1985; Bartolo et al. 2008; Goldenberg 2008).

An influential neuropsychological model of cognitive motor functions proposed that gesture imitation may be realized via 2 alternative “routes,” see Figure 1 (Rothi et al. 1991; Tessari and Rumiati 2004; Rumiati et al. 2005; Tessari et al. 2007). Meaningful gesture imitation relies on the indirect (or semantic) route which involves the retrieval of knowledge about characteristic spatio-temporal action features (Heilman et al. 1982; Rijntjes et al. 1999; Hermsdörfer et al. 2013), as well as access to the semantic system to decode gestural meanings, for example, “you are crazy!” for tapping one's temple (Rothi et al. 1991; Rumiati and Tessari 2002; Rumiati et al. 2009). By contrast, meaningless gestures are imitated via the direct (or non-semantic) route that facilitates the mapping of visually perceived movements onto the observer's motor system without contacting stored action representations or conceptual knowledge (Tessari et al. 2007; Tessari and Cubelli 2014; although see Goldenberg 2001 for a contrary proposal).

Figure 1.

Modified Rothi-model. A modified version of the cognitive model of gesture imitation suggested by Rothi et al. (1991). According to the model, imitation of meaningful gestures is exerted via the indirect route (solid lines), encompassing stored spatio-temporal action representations (“visuo-kinesthetic engrams”) (Heilman et al. 1982) or “action-blueprints” (Rijntjes et al. 1999), as well as additional semantic information. Contrary, imitation via the non-semantic, direct route (dotted line) directly leads from visual decoding to the innervatory pattern for motor output.

Figure 1.

Modified Rothi-model. A modified version of the cognitive model of gesture imitation suggested by Rothi et al. (1991). According to the model, imitation of meaningful gestures is exerted via the indirect route (solid lines), encompassing stored spatio-temporal action representations (“visuo-kinesthetic engrams”) (Heilman et al. 1982) or “action-blueprints” (Rijntjes et al. 1999), as well as additional semantic information. Contrary, imitation via the non-semantic, direct route (dotted line) directly leads from visual decoding to the innervatory pattern for motor output.

Based on primate research as well as studies using functional imaging or lesion analysis in humans, several authors proposed that direct and indirect routes for imitation map onto distinct subdivisions of the dorsal “where” or “how” stream, originally proposed to mediate “vision for action” (Ungerleider and Mishkin 1982; Goodale and Milner 1992; Rizzolatti and Matelli 2003; Buxbaum and Kalenine 2010; Binkofski and Buxbaum 2013). Processes related to the direct route for meaningless gesture imitation may primarily rely on the dorsal subdivision of the dorsal stream (i.e., the dorso-dorsal stream) which projects from visual areas (e.g., V3a) to the intraparietal sulcus and the superior parietal lobe, and from there, via the superior longitudinal fascicle II, to premotor cortex (PMC) (Binkofski and Buxbaum 2013; Hoeren et al. 2014; Vry et al. 2015; Martin et al. 2016a, 2016b, 2016c). Conversely, the indirect route is thought to correspond to the ventro-dorsal stream (Kalenine et al. 2010) which, via arcuate and superior longitudinal fascicle III, traverses from higher order visual areas in the lateral temporal cortex to inferior-parietal and ventral premotor areas (Kalenine et al. 2010; Binkofski and Buxbaum 2013; Vingerhoets 2014). Dissociations between impairments of different spatio-temporal action features, such as functional hand shapes or movement kinematics (Sirigu et al. 1995; Buxbaum et al. 2007), indicated that the ventro-dorsal stream may store action “engrams” in a distributed fashion; however, given contradictory results (Buxbaum et al. 2003, 2014), establishing precise relations between different ventro-dorsal regions and distinct spatio-temporal movement aspects has remained elusive (Vingerhoets 2014). Moreover, it is unclear if skilled motor acts differentially rely on ventro-dorsal regions depending on the modality of execution (e.g., pantomimed vs. imitated tool-use gestures vs. actual tool use), but see Buxbaum et al. (2014).

However, in addition to ventro-dorsal and dorso-dorsal streams, recent voxel-based lesion-symptom mapping (VLSM) and functional magnetic resonance imaging (fMRI) studies with patients suffering from stroke (Hoeren et al. 2014; Martin et al. 2016a, 2016b, 2016c) or semantic dementia (Hodges et al. 1999; Bozeat et al. 2002) highlighted the anterior temporal lobe (ATL) for conceptual or semantic aspects of skilled actions. These results support the concept of a domain-general ventral stream which, expanding on the original definition of a visual “ventral stream for perception” or the “what” pathway (Goodale and Milner 1992; Ungerleider and Mishkin 1982), was proposed to involve not only inferior but also middle and superior temporal regions, as well as the anterior inferior frontal gyrus and association fibers running through the extreme capsule (Saur et al. 2008; Makris and Pandya 2009; Weiller et al. 2009, 2011, 2015a; Rijntjes et al. 2012; Vry et al. 2012; Hamzei et al. 2016). This more broadly defined ventral stream was proposed to process categorical relationships between perceptual and semantic elements, for example, words, musical chords, objects, numbers, etc. (Rijntjes et al. 2012; Klein et al. 2013; Musso et al. 2015; Weiller et al. 2015a), and the formation of transmodal concepts (Patterson et al. 2007; Lambon Ralph 2014).

In light of these findings, the suggestion that “at least some interaction between semantics and the action-lexicons must be specified” for meaningful gesture production (Fig. 1) may point to a role of the ventral stream (in its broader definition) for decoding gestural meaning (e.g., “good job” for “thumbs up”); however, the available evidence is contradictory. Few fMRI and positron emission tomography studies reported activity in the ATL when healthy participants imitated tool-use gestures (Rumiati et al. 2005) or viewed communicative emblems (Lotze et al. 2006; Andric et al. 2013). Conversely, the majority of functional imaging experiments, as well as the available lesion studies linked the processing of meaningful gestures to ventro-dorsal stream regions (Haaland et al. 2000; Johnson-Frey et al. 2005; Montgomery et al. 2007; Tessari et al. 2007; Pazzaglia et al. 2008; Villarreal et al. 2008; Bohlhalter et al. 2009; Kroliczak and Frey 2009; Mengotti et al. 2013b; Bonivento et al. 2014; Weiss et al. 2016).

Further controversy concerns the overlap and dissociations between the areas involved in tool-use gestures versus communicative emblems. According to some authors, the lower performance frequently observed for transitive compared with intransitive gesture production not only in apraxic patients (Haaland and Flaherty 1984; Rothi et al. 1988; Foundas et al. 1999; Haaland et al. 2000; Buxbaum et al. 2005b, 2007) but also in healthy subjects (Mozaz et al. 2002; Carmo and Rumiati 2009) simply reflects the greater spatio-temporal complexity (and hence, greater difficulty) of transitive gestures, rather than distinct neuroanatomical representations of the 2 meaningful gesture categories (the “complexity hypothesis”) (Carmo and Rumiati 2009). In line with this suggestion, fMRI studies showed largely congruent activity during tasks involving the production of tool-use or communicative gestures (Bohlhalter et al. 2009; Kroliczak and Frey 2009). However, reports of patients with selectively impaired production of communicative emblems (Stamenova et al. 2012) may indicate that transitive and intransitive gestures are mediated by at least partly different regions (the “representational hypothesis”) (Mozaz et al. 2002).

Several methodological challenges may have contributed to these unresolved issues. The disparity between the neuropsychological evidence for the role of the ATL semantic system in object use (semantic dementia) and the lack of fMRI data is probably, at least in part, due to a set of methodological problems with imaging the ATL (Du et al. 2007; Visser et al. 2010a, 2010b; Lambon Ralph 2014; Martin et al. 2016c). Visser et al. (2010b) described 3 methodological factors that influence the likelihood of observing ATL semantically related activations—the magnetic field distortion, the depth of the field of view, and the nature of the baseline task (see also Humphreys et al. 2015). Furthermore, fMRI cannot distinguish between areas that are critical versus simply co-activated during a task (Rorden and Karnath 2004); for example, the greater temporal activity during the observation of emblems compared with grasping movements (Andric et al. 2013), or during meaningful compared with meaningless gesture imitation (Rumiati et al. 2005) may relate to accessory processes such as covert verbalization. In lesion studies, premotor and parietal regions are more frequently affected by stroke than the temporal lobe (Visser et al. 2010b; Karnath et al. 2011; Buxbaum et al. 2014; Hoeren et al. 2014; Martin et al. 2016a, 2016b), so that studies with smaller cohorts may be underpowered to detect associations between gesture imitation deficits and temporal damage (Kimberg et al. 2007). Moreover, the identification of areas differentially relevant for tool-use gestures versus communicative emblems may have been hampered by the lack of investigations directly comparing transitive and intransitive gesture imitation in brain lesioned patients (but see e.g., Bonivento et al. 2014). Finally, so far, there is no statistical tool to analyze dissociations, that is, areas of differential relevance for distinct behavioral tasks (e.g., transitive vs. intransitive gesture imitation) in VLSM. Therefore, we introduced a newly developed toolbox that enables a voxel-wise nonparametric test for interaction effects in VLSM studies, the “Nonparametric Interaction Effects” (NIX) toolbox (Nitschke et al. forthcoming).

The first and foremost goal of this study was to clarify the relevance of dorsal and ventral streams for transitive and intransitive gesture imitation. To that end, we used VLSM in a large cohort of acute stroke patients (n = 156). Voxels where lesions differentially affected tool-use gestures versus communicative emblems were indicated by significant tests for interactions between the factors lesion status (lesioned/not-lesioned) and behavioral performance (transitive/intransitive gestures), using the above-mentioned open-source NIX toolbox (Nitschke et al. forthcoming; see Material and Methods for details). Second, we intended to identify regions tuned to the processing of particular spatio-temporal action features during meaningful gesture imitation (e.g., incorrect hand configurations or deviant kinematics). Third, to elucidate potential correlates of modality-specific deficits, we compared the current results on meaningful gesture imitation with in part previously published data on pantomimed and actual tool use obtained in the same patients.

In line with the proposed function of dorsal and ventral streams, we, first, hypothesized that transitive and intransitive gestures would differentially rely on ventro-dorsal and ventral streams due to their higher spatio-temporal complexity and their stronger association with communicative content, respectively. Second, based on previous results, we expected an association between posterior temporal lesions and hand-configuration and -orientation errors, as well as between kinematic errors and inferior-parietal damage (Buxbaum et al. 2014; Martin et al. 2016a; though, see e.g., Sirigu et al. 1995; Buxbaum et al. 2003, 2005a for studies reporting a specific relation between hand configurations and the inferior-parietal lobule, IPL). Third, we postulated that meaningful gesture imitation compared with actual tool use may be more susceptible to damage in regions involved in the decoding of observed motor acts, whereas pantomimed and actual tool use may be more reliant on areas related to the retrieval of suitable actions in response to a given tool.

Material and Methods

Patients

All patients admitted to the Stroke Unit, Department of Neurology and Clinical Neurosciences, University Medical Center Freiburg, Germany over a period of 3.75 years (February 2011– October 2014) with left-hemispheric territorial stroke were consecutively screened for eligibility (n = 752). The etiology of the infarctions was thrombotic or embolic. Exclusion criteria, reported previously comprised (1) age > 90 years; (2) reduced general health status; (3) previous infarcts; (4) pre-existing structural brain changes (e.g., severe brain atrophy, extensive white matter changes, previous brain injury); (5) major cognitive impairment or dementia; (6) hemodynamic alterations (e.g., carotid occlusion with insufficient collateralization); (7) severe visual impairments including hemianopia; (8) lacunar infarcts; (9) other reasons, for example, contraindications for magnetic resonance imaging (MRI), compliance or technical issues. Based on these criteria, 160 patients underwent neuropsychological testing and structural MRI. Four patients were not able to complete the testing due to excessive sleepiness and were excluded retrospectively (n = 4); thus, we here report data from 156 patients. Testing was carried out within 4.8 ± 2.0 days (mean ± SD) after symptom onset to avoid effects of brain reorganization (see Table 1 for a detailed overview over patient data). Of note, 102 patients also participated in a VLSM study investigating imitation of meaningless postures and pantomime tasks (Hoeren et al. 2014), 136 patients participated in an analysis concerning tool use (Martin et al. 2016a), and 98 patients in a study on action recognition (Martin et al. 2016b). Provisional normative data for the imitation tasks were obtained from a sample of 29 healthy elderly volunteers (mean ± SD, 72.0 ± 7.2 years; 15 male, 29 right-handed) who had also provided normative data for other studies (Hoeren et al. 2014; Martin et al. 2016a). Full written informed consent according to the declaration of Helsinki was obtained from all patients or their legal guardian, as well as from all controls. The study was approved by local ethics authorities.

Table 1

Overview of demographical data and behavioral test scores

Score Mean SD Min Max 
Demographic and clinical data     
Age 64.3 14.6 21.9 85.6 
Sex (female/male) 56/100 
Lesion size (cc) 26.8 34.9 0.3 244.9 
Thrombolytic treatment (none/intravenous/mechanical) 85/54/17 
Symptom onset−test delay (d) 4.9 2.0 10 
Imitation test scores     
Complete (max. 20 points) 17.0 3.7 20 
Trans (max. 10 points, n = 156) 7.7 2.6 10 
Intrans (max. 10 points, n = 155) 9.2 1.6 10 
Other apraxia test scores     
Pantomime (max. 14 points, n = 145)a 10.32 3.98 14 
ToolUse (max. 10 points, n = 154) 8.12 2.78 10 
ToolSelect (max. 10 points, n = 154) 9.24 1.75 10 
Clinical scores and other test scores     
NIHSS on admission (max. 32 points) 7.4 6.1 24 
Right arm motor NIHSS at testing 0.6 1.1 
NIHSS on discharge (max. 32 points) 2.9 2.9 15 
Modified ranking scale on discharge (max. 5 points) 2.0 1.3 
Barthel Index on discharge 79.3 26.4 100 
Corsi block-tapping test forward 4.5 1.2 
Corsi block-tapping test backwards 4.3 1.5 
Token Test Score (max. 50 points, n = 144) 36.2 18.3 50 
Aphasia yes/nob 81/75 
Score Mean SD Min Max 
Demographic and clinical data     
Age 64.3 14.6 21.9 85.6 
Sex (female/male) 56/100 
Lesion size (cc) 26.8 34.9 0.3 244.9 
Thrombolytic treatment (none/intravenous/mechanical) 85/54/17 
Symptom onset−test delay (d) 4.9 2.0 10 
Imitation test scores     
Complete (max. 20 points) 17.0 3.7 20 
Trans (max. 10 points, n = 156) 7.7 2.6 10 
Intrans (max. 10 points, n = 155) 9.2 1.6 10 
Other apraxia test scores     
Pantomime (max. 14 points, n = 145)a 10.32 3.98 14 
ToolUse (max. 10 points, n = 154) 8.12 2.78 10 
ToolSelect (max. 10 points, n = 154) 9.24 1.75 10 
Clinical scores and other test scores     
NIHSS on admission (max. 32 points) 7.4 6.1 24 
Right arm motor NIHSS at testing 0.6 1.1 
NIHSS on discharge (max. 32 points) 2.9 2.9 15 
Modified ranking scale on discharge (max. 5 points) 2.0 1.3 
Barthel Index on discharge 79.3 26.4 100 
Corsi block-tapping test forward 4.5 1.2 
Corsi block-tapping test backwards 4.3 1.5 
Token Test Score (max. 50 points, n = 144) 36.2 18.3 50 
Aphasia yes/nob 81/75 

NIHSS, National Institute of Health Stroke Scale.

aOnly patients above 26 points in subtest 11 of the Birmingham Object Recognition Battery (max. 32 points).

bToken Test Score or clinical assessment by speech therapists.

Behavioral Testing

Imitation of Meaningful Gestures

Imitation of meaningful gestures was examined according to a modified version of the testing procedure established by Bartolo et al. (2008). Patients were instructed to observe and imitate 10 object-associated gestures, for example, hammering a nail, writing with a pen (Trans), and, subsequently, a set of 10 communicative gestures, for example, waving goodbye, pointing at someone (Intrans; see

for a specification of test items). Imitation was performed without the presence of an object. Gestures comprised different hand configurations, movement dynamics, and semantic categories. The task was trained with 2 example items in each subtest. Performances of 145/156 patients were videotaped for scoring procedures. The examiner demonstrated the gestures once with the right hand. Patients with paresis or fine motor deficit (tested beforehand) were asked to use their left hand; all other patients were free to choose their right or left hands for imitation. Thus, 85 patients used their left and 60 patients used their right hand for imitation; for patients without videotaping (n = 11, see below), information about the hand used was not available. The testing was performed by specifically trained occupational therapists with extensive experience in working with acute stroke patients.

Error Classification and Scoring

In accordance with the original scoring instructions (Bartolo et al. 2008), each imitation item was marked either correct or incorrect; therefore, a maximum score of 10 in each set of items was possible (Trans and Intrans), leading to a total score of 20 (Complete). Cut-off scores were determined based on the performance of the 29 healthy control subjects (Table 2). Consistent with previous studies, scores below the fifth percentile of the performance of the healthy individuals were considered pathological. In addition, the cut-off scores were confirmed using modified t-tests for the comparison of an individual patient's performance with a control group (2-tailed P = 0.009 for Complete and Trans; P< 0.001 for Intrans) (Crawford and Garthwaite 2002).

Table 2

Number of patients in imitation tasks and error categories

 Complete (n = 155)
Cut-off score 18/20 
Trans (n = 156)
Cut-off score 8/10 
Intrans (n = 155)
Cut-off score 9/10 
n with errors n below cut-off n with errors n below cut-off n with errors n below cut-off 
Overall performance 111 67 108 52 51 29 
Error category       
Movement 64  50  23  
Distance 29  25   
Configuration 60  53  18  
BPO 47  47  — — 
Orientation 57  51  15  
Unrecognizable 30  23  18  
Semantic 13    
 Complete (n = 155)
Cut-off score 18/20 
Trans (n = 156)
Cut-off score 8/10 
Intrans (n = 155)
Cut-off score 9/10 
n with errors n below cut-off n with errors n below cut-off n with errors n below cut-off 
Overall performance 111 67 108 52 51 29 
Error category       
Movement 64  50  23  
Distance 29  25   
Configuration 60  53  18  
BPO 47  47  — — 
Orientation 57  51  15  
Unrecognizable 30  23  18  
Semantic 13    

Description of error categories. Movement: incorrect amplitude, timing, or trajectory. Distance: incorrect distance of the hand used in reference to the body or the table. Configuration: incorrect grasp-configuration of the hand. Body part as object (BPO): use of a body part like a tool (only scored in transitive gestures). Orientation: incorrect hand/wrist orientation. Unrecognizable response: not recognizable movement. Semantic: performance of semantically incorrect gesture

In addition, errors were further characterized using the following classification (Bartolo et al. 2008): internal hand-configuration errors (C; e.g., writing with whole-hand grip) (Power et al. 2010), body part as object (BPO) errors (e.g., brushing teeth with the index finger; only scored for transitive gesture imitation), distance errors (D; e.g., ironing without distance to the table) (Goldenberg 2013), hand/wrist-orientation errors (O; e.g., cutting in a way that the blade of the knife would be oriented perpendicularly to the direction of the back-and forth movement; “hush” sign with the back of the hand facing away from the patient instead of sideways), movement errors (M; incorrect amplitude/timing/trajectory, e.g., only slight turning movement when gesturing “using a key”; omitting to tip “the glass” after putting it to the lips; shaking the fist with an abnormally large amplitude for “threatening”), semantic errors (S; e.g., brushing teeth instead of combing hair, shielding eyes from the sun instead of military salute), and unrecognizable response (UR; e.g., indiscriminate back-and-forth movements).

For scoring, performances of the 145/156 patients with a video available were assessed separately by 2 independent raters, respectively (M.M. and either V.M.L. or A.D.), with one rater being blind to location and extent of the lesion. In case of differently scored items, both raters reviewed the videos jointly to establish consensus rating. Patients without videotaped testing (n = 11) due to technical problems or objections to videotaping were scored directly by the examining occupational therapist. Of the 156 patients included, all underwent testing of transitive gestures; 1 patient did not complete testing of intransitive gestures due to time constraints (n = 155 for intransitive gestures).

Interrater agreement was assessed by Cohen's κ for comparison with other studies using similar behavioral tests (Goldenberg et al. 2007; Martin et al. 2016c). Correlations were substantial for Trans (κ = 0.454, P < 0.001) and Intrans (κ = 0.618, P < 0.001). Interrater reliability for different error categories was lowest for D errors (for Trans: κ = 0.395, P < 0.001; for Intrans: κ = 0.130, P < 0.05) and highest for BPO errors during Trans (κ = 0.896, P< 0.001), and C errors during Intrans (κ = 0.692, P < 0.001). The low interrater reliability for D errors, particularly during Intrans, may, has been caused by the low overall numbers of D errors (Table 2). See

for a comprehensive overview of the values for all error types.

Pantomimed and Actual Tool Use

The imitation data were compared with in part previously published results from studies on pantomimed tool use (Hoeren et al. 2014) and actual tool use (Martin et al. 2016a). These data were obtained in the same patients who also completed the imitation tests presently reported for the first time. Briefly, for pantomime, patients were asked to demonstrate (gesture) the use of 14 common tools depicted as line drawings (e.g., hammer, key). The actual tool-use test originally designed by Goldenberg and Spatt (2009) involves, first, a subtest for matching 5 tools to recipients (ToolSelect; e.g., selecting a nail from a set of 5 objects when given a hammer), and second, a subtest for the performance of 5 tool-associated actions (ToolUse; e.g., hammering in the nail). Errors during pantomimed and actual tool use are classified along the same criteria as outlined for imitation (e.g., configuration, orientation, etc. (see Hoeren et al. 2014; Martin et al. 2016a for details). Data on pantomimed and actual tool use were available for 145 and 154 patients, respectively.

Additional Tests and Scores

Out of 156 patients, 144 completed the Token test of the Aachen Aphasia Test (Huber et al. 1984), test scores are presented as correct items (max. 50). Token test scores of the remaining patients could not be obtained due to either very severe aphasia (n = 5), organizational reasons (e.g., rapid discharge, n = 4), or because they were non-native German speakers (n = 3). For these 12 patients, the reports of the routine non-standardized assessments by speech therapists were reviewed to determine if patients had language impairments. In addition, the Corsi block-tapping test for short-term and working memory (Kessels et al. 2000, 2008) was administered to all patients. General clinical measures of disability included the modified ranking scale, Barthel index, and the National Institute of Health Stroke Scale (NIHSS).

Statistical Analysis

All statistical analyses on the behavioral data were performed using the Statistical Package for the Social Sciences (SPSS) versions 21and 23 (IBM). The common variance of transitive and intransitive gesture imitation, pantomime, recipient selection, and performance of actual tool use was extracted by a principal component analysis (PCA) with Varimax rotation. One factor was extracted based on the Scree plot and an Eigenvalue > 1. Adequacy of the data for the PCA was demonstrated by Bartlett's test of sphericity (P < 0.001) and the Kaiser–Meyer–Olkin measure (0.827). Factor loadings were 0.891 for pantomime, 0.898 for Trans, 0.780 for Intrans, 0.884 for tool-recipient selection, and 0.773 for tool use. Furthermore, an “omnibus-PCA” (Halai et al. 2016) with multiple test scores (i.e., additionally including the Corsi block-tapping test and the token test to the 5 apraxia scores) was calculated, resulting in one factor for apraxia and aphasia test scores and an separate factor for the Cosi test (data not shown). By means of the PCA, we aimed to separate the variance reflecting processes underlying meaningful action production more generally from the variance related to the different testing modalities (e.g., pantomime vs. imitation) (Butler et al. 2014; Halai et al. 2016; Martin et al. 2016c).

Magnetic Resonance Imaging

MRI scans were obtained on a 1.5-T Avanto scanner or a 3-T Trio scanner (Siemens, Germany) with an 8 channel head coil, including diffusion-weighted images (DWI) (standard sequence: 23 slices, matrix = 128 × 128 pixel, voxel size = 1.8 × 1.8 × 5 mm3, repetition time = 3.1 s, echo time = 79 ms, flip angle = 90, 6 diffusion-encoding gradient directions with a b-factor of 1000 s/mm2), FLAIR (fluid attenuated inversion recovery) images (repetition time = 9000 ms, echo time = 93.0 ms, flip angle = 140°, matrix 200 × 256 pixel, voxel size = 0.94 × 0.94 × 5.00 mm3, 23 slices), and high-resolution T1 anatomical scans (repetition time = 2200 ms, echo time = 2.15 ms, flip angle = 12°, matrix = 256 × 256 pixel, voxel size = 1 × 1 × 1 mm3, 176 slices).

Lesion Mapping

As previously reported (Hoeren et al. 2014; Martin et al. 2016a), the ischemic lesions were first delineated on the DWIs based on intensity thresholds using a customized region-of-interest toolbox implemented in SPM8 (http://www.fil.ion.ucl.ac.uk/spm/software/spm8). Subsequently, specially trained assistants who were blind to the patient's behavioral results further refined the lesion delineations manually. In one case with no available DWI, the lesion was directly drawn on the FLAIR image. Prior to normalization, the exact correspondence between lesion map and lesion was checked by M.M., L.B. or A.D. Lesion mapping and inspection were performed in MRICron (http://www.cabiatl.com/mrico/mricon/stats.html). For normalization, the DWIs (or the FLAIR image) and corresponding lesion maps were co-registered to the anatomical T1 scans (n = 149), or when no T1 scan was available (n = 7), to the FLAIR images. The T1 (or FLAIR) scans were segmented using the VBM8 toolbox (r435; http://dbm.neuro.uni-jena.de/vbm/download/), and deformation field parameters for nonlinear normalization into the stereotactic Montreal Neurological Institute (MNI) standard space were obtained using the DARTEL approach (diffeomorphic anatomical registration through exponentiated lie algebra) (Ashburner 2007) implemented in VBM8. Following normalization, the individual lesion maps were again inspected and compared with the lesions in native subject space to ensure that the extent of the ischemic damage was delineated accurately in MNI space.

Lesion Analysis

Voxel-Based Lesion-Symptom Mapping

The first set of voxel-wise statistical analyses was performed using the nonparametric mapping (NPM) software (http://www.cabiatl.com/mrico/mricon/stats.html) distributed with MRICron. The Brunner–Munzel test, a rank test for continuous behavioral variables and binary images, was used to determine significant associations between behavioral deficits and lesions in each voxel (Rorden et al. 2007). Only voxels lesioned in at least 8 subjects (i.e., 5% of our patient cohort) were included in the analyses.

Separate analyses were carried out for the overall imitation score (Complete), as well as for transitive and intransitive gesture imitation subscores (Trans, Intrans). In addition, distinct error subtypes (M, C, O, D, BPO, S, and UR) were analyzed for Trans and Intrans separately, and across both scores (Complete). Further analyses were performed for pantomimed tool use, tool-recipient selection (ToolSelect), and performance of actual tool use (ToolUse). To identify regions of general importance to meaningful action tasks, a VLSM analysis was done using the individual scores on the factor extracted by PCA (see above). VLSM was further performed on the available Token Test data. Finally, to delineate areas systematically included in widespread lesions, the individual lesion volumes (in cc) were entered into a VLSM analysis. In addition to the voxel-wise Brunner–Munzel tests, logistic regression analyses with lesion volume as covariate of no interest were performed for each score to control for the effect of lesion size. Differences in lesion distribution between patients performing the imitation tasks with their left or right hands and differences between aphasic and non-aphasic patients were assessed with a voxel-wise Liebermeister test.

In addition to these well-established analysis procedures (Karnath et al. 2011; Kuemmerer et al. 2013; Hoeren et al. 2014), we used a newly developed toolbox that enables voxel-wise nonparametric testing for interaction effects between a voxel's lesion status (lesioned/not-lesioned) and 2 (or more) behavioral measures (here: transitive and intransitive imitation scores) (Nitschke et al. forthcoming). The NIX toolbox implements nonparametric rank tests for longitudinal data (Brunner et al. 2002) allowing to assess main effects and interactions in multi-factorial designs with within- and between-subject factors. Post hoc testing for simple effects is implemented to further characterize differences in behavioral tasks between patients with lesions and without lesions in voxels for each level of the repeated measures task factor(s) where significant interaction effects were found. The open-source NIX toolbox is written in Matlab (Mathworks, Natick, MA). To ensure comparability to the analyses calculated in NPM, only voxels with at least 8 patients in either lesioned or not-lesioned group were included in the analyses. In addition, since the Brunner–Munzel test may result in inflated z-scores in regions with less than 10 subjects in either the lesioned or not-lesioned groups (Medina et al. 2010), we ensured that all significant voxels detected by the NIX toolbox were situated in regions where at least 10 patients had a lesion. This step was not necessary for analyses with NPM because a permutation-based correction is implemented to avoid this caveat (Medina et al. 2010).

Two analyses were performed with the NIX toolbox to identify regions commonly and differentially related to transitive and intransitive imitation. The first analysis was carried out across the 155 patients for whom both Trans and Intrans scores had been obtained, and involved the 2 factors lesion status (group factor levels lesioned/not-lesioned) and gesture type (transitive/intransitive). This analysis aimed to delineate areas where lesions led to greater impairments in transitive versus intransitive gestures or vice versa compared with the subgroup of no lesion in that area. In the second analysis, the laterality of the hand used was introduced as a third factor (group factor hand; factor levels left or right). Thus, we intended to delineate regions where lesions differentially affected gesture type performance depending on whether the right or left hand was used (2-way interaction between the factors lesion status and hand, and 3-way interaction between the factors lesion status, hand and gesture type). Only the data from the 145 patients for whom the hand used were known (see above) were entered into this latter analysis.

Since the main effect of lesion in the NIX analyses may be significant in regions where only one condition (i.e., either Trans or Intrans) has a strong loading, formal conjunctions of the VLSM results for transitive and intransitive gestures were calculated as the overlap between the binarized results maps obtained by the voxel-wise Brunner–Munzel tests (thresholded at P < 0.05, false-discovery rate, FDR adjusted). In addition, to confirm the regions found to be differentially related to transitive versus intransitive gestures in the NIX analyses, the differences between the binarized maps were also calculated.

To identify modality-specific regions (e.g., imitation of tool-use gestures vs. actual tool use), further NIX analyses were performed using the following pairs of scores: (i) transitive imitation and pantomimed tool use (n = 145); (ii) transitive imitation and actual tool use (ToolUse) (n = 154); and (iii), pantomimed and actual tool use (n = 144).

Relation Between VLSM Results and Association Fibers

To determine associations between lesions to dorsal and ventral tracts and behavioral deficits, the VLSM maps were overlaid onto the anatomical maps of the association fibers involved in ventro-dorsal (superior longitudinal fascicle III) and ventral streams (extreme capsule) (Vry et al. 2015); see

.

Presentation of the Results

All results are displayed on an in-house average template of 50 nonlinearly normalized T1 scans from a sample of healthy subjects who had participated in other studies in our laboratory (mean ± SD, 47 ± 20.75 years, 25 male) (Beume et al. 2015).

In accordance with previous studies (Goldenberg and Spatt 2009; Martin et al. 2016a), we report results below a FDR-adjusted threshold of P< 0.05. One exception was made for the voxels significant for the interaction lesion status × gesture type (Fig. 4): As no voxels were found where lesions significantly affected intransitive more than transitive imitation at an FDR-adjusted threshold of P < 0.05, we additionally explored the results of the NIX analyses at uncorrected thresholds (P< 0.01 and P < 0.001) to assess potential subthreshold effects. Finally, to quantify the involvement of different regions in the behavioral tasks, for each statistical results map, we calculated the volume of significant voxels (applying the FDR-adjusted threshold of P < 0.05) within each of the different regions of the Automatic Anatomical Labeling (AAL)-atlas (Tzourio-Mazoyer et al. 2002). The resulting volumes were expressed as a percentage of the AAL region (

).

Results

Demographic and Behavioral Results

Demographic Data and General Clinical Scores

See Table 1 for a summary of demographic data, test scores for Complete, Trans and Intrans, other apraxia test scores, general clinical information, and test scores for working memory and language (Table 1). Our cohort of patients was predominantly male; however, as sex differences could not be found in any of the imitation scores (Mann–Whitney-U-Tests: 0.16 < P< 1.00), a significant bias is unlikely. As in previous studies, correlations between low performance in imitation tests and higher age, large lesion size and more severe clinical impairment, as well as low performance in other apraxia tests and in the Corsi block-tapping test could be detected (Hoeren et al. 2014; Martin et al. 2016a) (

). However, since the correlations were overall of a similar order of magnitude for all imitation scores, a confounding influence again appears unlikely. Performance in Trans and Intrans as well as error scores did not depend on the hand used for the imitation task (ipsi- or contralesional) (Mann–Whitney-U-Tests: 0.16 < P < 0.97), except for movement errors in transitive gestures (patients performed worse with the right hand, P = 0.04). Reflecting the requirement that patients with contralesional motor impairments use their ipsilesional hand, left hand use was associated with higher overall neurological disability (mean ± SD, NIHSS on admission 8.4 ± 6.3 for left hand vs. 6.0 ± 5.5 for right hand; P = 0.02), with higher motor impairment (NIHSS subscore for right arm paresis 0.9 ± 1.3 for left hand vs. 0.5 ± 0.2 for right hand; P < 0.001), and with a tendency toward higher lesion volumes (lesion volume 33.0 ± 41.2 cc for left hand vs. 21.0 ± 24.7 cc for right hand; P = 0.08).

Imitation of Meaningful Gestures

Of the 156 patients in the study, 52 patients (33.33%) showed a deficit in the imitation of transitive gestures and 29 patients (18.59%) showed a deficit in the imitation of intransitive gestures. In 23 patients, a combined Trans and Intrans deficit was observed, whereas 29 and 6 patients presented with isolated Trans and Intrans deficits, respectively. Of note, 98 patients showed no deficit at all (Table 2). Deficits differed significantly between groups (Chi-square-test P < 0.001). In accordance with these results, we found a significant correlation between Trans and Intrans performance (τ = 0.466, P < 0.01); moreover, given the larger variation of errors during transitive compared with intransitive imitation, overall scores (Complete) were more strongly correlated with Trans (τ = 0.895, P < 0.01) compared with Intrans (τ = 0.653, P < 0.01) (see

for a comprehensive list of the rank correlations between all scores and error types). As in our control group, patients generally obtained lower scores in Trans compared with Intrans (Wilcoxon rank-sum test P < 0.001; see Table 1).

Error Categorization

Table 2 depicts the numbers of patients with different types of errors. On the whole, movement, configuration, orientation, and to a somewhat lesser extent, BPO errors constituted the majority of errors; conversely, non-recognizable, distance and, in particular, semantic errors were observed more rarely. Compared with intransitive imitation, numbers of patients with errors during transitive imitation were similar for semantic errors, slightly higher for non-recognizable errors, and markedly higher for all other categories (Table 2).

Association Between Gesture Imitation and Aphasia

Aphasia occurred in 85 of 156 patients; 43 of 52 patients (82.7%) with transitive imitation deficits and 25 of 29 patients (86.2%) with intransitive imitation deficits were clinically classified as aphasic; thus, the frequency of aphasia was similar for both gesture types (Fisher's exact test, P = 0.76). Conversely, 22 and 4 patients with aphasia had an isolated deficit in transitive and intransitive imitation, respectively; 21 presented with a combined deficit. Therefore, with respect to dissociations between language and gesture production, 34 patients had aphasia with normal gesture production, and 11 patients had imitation deficits without aphasia (of these, 2 had combined transitive/intransitive deficits, 7 had transitive deficits only, and 2 had intransitive deficits only). In addition, transitive and intransitive imitation performance were significantly correlated with token test percentile ranks; these correlations were of a similar magnitude for the 2 gesture types (τ = 0.420, 0.356, respectively;

). Overall, while these results confirm previous reports (Papeo and Rumiati 2013; Mengotti et al. 2013a), future studies should use more elaborate language testing to further elucidate potential differences between language functions and transitive versus intransitive gesture production (see e.g., Goldenberg and Randerath 2015; Mengotti et al. 2013a).

Lesion Distribution

Figure 2 shows an overlap of the binarized lesions of all included patients. Lesions were distributed over the complete territory of the middle cerebral artery. As in previous studies (Kuemmerer et al. 2013; Hoeren et al. 2014), maximum lesion overlap (n = 40) was located in the subcortical areas of the middle cerebral artery territory. Consistent with the course of the middle cerebral artery, the VLSM analysis for lesion volume revealed that larger infarcts systematically included insula and periinsular cortex. In total, 120 patients presented with cortical infarcts, 36 patients had purely subcortical (mostly striatocapsular) infarcts. An additional analysis using the Liebermeister statistics revealed no significant difference in lesion distribution between patients who used their left versus their right hands for imitation.

Figure 2.

Lesion overlap and VLSM map for lesion volume. Overlap of the binarized lesions of the 156 patients included in the analysis (A). The color bar indicates the degree of overlap of lesions from 1 (black) to 40 (white) patients. The VLSM map for lesion volume (B) indicates voxels significantly associated with infarct size. Results are reported at a threshold of P < 0.05 FDR adjusted. The color bar shows Z-scores, the threshold for significant voxels is indicated.

Figure 2.

Lesion overlap and VLSM map for lesion volume. Overlap of the binarized lesions of the 156 patients included in the analysis (A). The color bar indicates the degree of overlap of lesions from 1 (black) to 40 (white) patients. The VLSM map for lesion volume (B) indicates voxels significantly associated with infarct size. Results are reported at a threshold of P < 0.05 FDR adjusted. The color bar shows Z-scores, the threshold for significant voxels is indicated.

Imitation of Transitive and Intransitive Gestures

Voxel-Wise Brunner–Munzel Analyses for Imitation of Transitive and Intransitive Gestures

Both transitive and intransitive deficits were associated with lesions within the anterior IPL and the posterior lateral temporal cortex (Figs. 3B,C and 4C). However, a higher number of voxels at the lateral occipito-parietal junction, around the caudal aspect of the intraparietal sulcus and within the PMC was significantly associated with lower transitive gesture imitation scores, whereas intransitive gesture imitation was more affected by anterior temporal lesions (Fig. 3B,C,

). Given that the variance of the overall imitation score (Complete) was largely determined by the transitive gesture imitation performance (see above), the VLSM results for Complete (Fig. 3A) largely corresponded to those found for Trans (Fig. 3B).
Figure 3.

VLSM: Transitive and intransitive gesture imitation. VLSM maps for imitation of meaningful gestures (Complete, A), imitation of transitive (B) and intransitive (C) gestures. Results are reported at a threshold of P < 0.05 FDR adjusted. Color bars show Z-scores, the threshold for significant voxels is indicated.

Figure 3.

VLSM: Transitive and intransitive gesture imitation. VLSM maps for imitation of meaningful gestures (Complete, A), imitation of transitive (B) and intransitive (C) gestures. Results are reported at a threshold of P < 0.05 FDR adjusted. Color bars show Z-scores, the threshold for significant voxels is indicated.

Figure 4.

NIX in transitive and intransitive gesture imitation. Results calculated with the newly developed NIX toolbox for the voxel-wise analysis of the factors lesion status (lesioned/non-lesioned) and gesture type (transitive and intransitive imitation). (A) The effect of lesion across both imitation subscores, that is, lesion locations that lead to deficits in both scores. Results are thresholded at P < 0.05, FDR adjusted for multiple comparisons. (B) Voxels where significant interaction effects between lesion status and gesture type were found; as indicated by post hoc tests, dorsal lesions (blue) differentially affected transitive imitation, whereas anterior temporal damage (red) had a greater effect on communicative emblems. Boxplots illustrate the behavioral data from patients with and without lesions at the premotor and anterior temporal peak voxels. To explore potential subthreshold effects, results in B are presented not only at the threshold of P < 0.05 FDR adjusted, but also at uncorrected P < 0.01 and P < 0.001. (C) An overlap of the binarized result maps obtained by the voxel-wise Brunner–Munzel tests (thresholded at P < 0.05, FDR adjusted); overlapping regions are depicted in green. In addition, to confirm the regions found to be differentially related to transitive versus intransitive gestures in the NIX analyses, the differences between the binarized maps were calculated (blue for transitive gestures only, red for intransitive gestures only).

Figure 4.

NIX in transitive and intransitive gesture imitation. Results calculated with the newly developed NIX toolbox for the voxel-wise analysis of the factors lesion status (lesioned/non-lesioned) and gesture type (transitive and intransitive imitation). (A) The effect of lesion across both imitation subscores, that is, lesion locations that lead to deficits in both scores. Results are thresholded at P < 0.05, FDR adjusted for multiple comparisons. (B) Voxels where significant interaction effects between lesion status and gesture type were found; as indicated by post hoc tests, dorsal lesions (blue) differentially affected transitive imitation, whereas anterior temporal damage (red) had a greater effect on communicative emblems. Boxplots illustrate the behavioral data from patients with and without lesions at the premotor and anterior temporal peak voxels. To explore potential subthreshold effects, results in B are presented not only at the threshold of P < 0.05 FDR adjusted, but also at uncorrected P < 0.01 and P < 0.001. (C) An overlap of the binarized result maps obtained by the voxel-wise Brunner–Munzel tests (thresholded at P < 0.05, FDR adjusted); overlapping regions are depicted in green. In addition, to confirm the regions found to be differentially related to transitive versus intransitive gestures in the NIX analyses, the differences between the binarized maps were calculated (blue for transitive gestures only, red for intransitive gestures only).

No regions were significantly associated with different imitation scores corrected for lesion volume at a threshold of P < 0.05 FDR adjusted. At a lower threshold of P < 0.05 uncorrected, the association between inferior-parietal (and, to a lesser extent, temporal) lesions and both transitive and intransitive imitation deficits could be confirmed (

).

Interaction Effects Between Lesion Status and Gesture Type

Applying the FDR-adjusted threshold of P < 0.05, the main effect of lesion status on imitation performance across transitive and intransitive gestures corroborated the common relevance of IPL and posterior superior temporal sulcus/superior temporal gyrus for both imitation subtasks (Fig. 4A). Significant interactions between the factors lesion status (lesioned/not-lesioned) and gesture type (transitive/intransitive) were found within PMC (P < 0.05 FDR adjusted) and in the lateral occipito-parietal junction (P < 0.001 uncorrected). Post hoc testing revealed that the significant interaction effect was due to a significant impact of premotor lesions on transitive compared with no impact on intransitive gestures (Fig. 4B). However, in line with the greater extent of anterior temporal voxels associated with intransitive compared with transitive gestures (Fig. 3), further explorations using uncorrected thresholds of P < 0.01 and P < 0.001 confirmed the significant impact of anterior temporal lesions on intransitive imitation compared with the impact on transitive items (Fig. 4B). In summary, the voxel-wise analyses for the main effect of factor lesion status and for interaction effects between lesion status and gesture type substantiated the results from the “conventional” VLSM analyses described above (Fig. 3,

) and their “visual” comparison by inspection of Figure 3B versus C. The conjunction analysis for transitive and intransitive deficits overall confirmed the results obtained by the NIX analyses (Fig. 4C).

Given that the analyses for single error types (see next section) revealed a specific association between hand/wrist-orientation errors during transitive imitation and premotor damage, we further explored the error profiles of the patients with lesions at the premotor peak voxel found for the interaction effect between lesion status and gesture type (−43.5/6/−37.5; see Fig. 4B). Among the 11 patients with lesions at the premotor peak voxel, we observed movement errors in 5 patients, hand-configuration errors in 7, distance errors in 2, incorrect hand/wrist orientation in 7, and body part as object errors in 2 patients. We concluded that the differential impact of premotor lesions on transitive compared with intransitive gesture imitation was not mediated by the presence of orientation errors alone.

In the analysis with the hand used as an additional group factor, no significant voxels emerged for the 2-way or 3-way interactions lesion status × hand, and lesion status × hand × gesture type; thus, no lesion locations had a significant differential impact on one or both imitation scores depending on whether the patients used their left or right hand (P < 0.05 FDR adjusted). Explorations using uncorrected thresholds (P < 0.01) revealed only few scattered voxels in the insula, basal ganglia, and adjacent subcortical white matter.

Error Categories

Voxel-Wise Brunner–Munzel Analyses for Error Categories

Single error type analyses for transitive gestures (Fig. 5,

) revealed that hand/wrist-orientation errors occurred mainly in consequence to premotor lesions, while movement errors resulted from lateral occipito-temporal and inferior-parietal damage; in addition, incorrect hand configurations were related to voxels clustered around the lateral border of the anterior intraparietal sulcus. The analysis for non-recognizable movements yielded a widespread parieto-temporal pattern. No regions were significantly associated with distance errors (which were observed only rarely, see Table 2), BPO errors (see Discussion), and semantic errors.
Figure 5.

VLSM: error analysis in transitive gestures. Lesion locations significantly associated with single error types in transitive gesture imitation. IPL and lateral temporo-occipital lesions were related to movement errors (A), whereas hand/wrist-orientation errors (C) were associated with premotor lesions. Anterior intraparietal lesions were linked to hand/wrist-configuration errors (B). A widespread parieto-temporal pattern of voxels was related to non-recognizable movements (D). Results are reported at a threshold of P < 0.05 FDR adjusted. Color bars indicate Z-scores.

Figure 5.

VLSM: error analysis in transitive gestures. Lesion locations significantly associated with single error types in transitive gesture imitation. IPL and lateral temporo-occipital lesions were related to movement errors (A), whereas hand/wrist-orientation errors (C) were associated with premotor lesions. Anterior intraparietal lesions were linked to hand/wrist-configuration errors (B). A widespread parieto-temporal pattern of voxels was related to non-recognizable movements (D). Results are reported at a threshold of P < 0.05 FDR adjusted. Color bars indicate Z-scores.

For Intrans, errors of movement, configuration, orientation and non-recognizable errors were associated with fronto-parietal patterns that were similar to the results from the analyses with overall Intrans scores (data not shown). Likely reflecting their rare occurrence during intransitive gesture imitation (Table 2), no regions were significantly related to distance and semantic errors. In contrast to the results for tool-associated gesture imitation (see above), we could, therefore, not identify regions differentially tuned to distinct spatio-temporal features of communicative emblems.

Finally, the numbers of movement and non-recognizable errors noted across both transitive and intransitive imitation was associated with similar widespread parieto-temporal patterns (comparable to the results for non-recognizable movements during transitive imitation, Fig. 5); conversely, the total number of orientation errors was related to premotor damage. No significant results were found for the remaining error categories.

Overlap Between VLSM Analyses and Fiber Tracts

For both types of imitation deficits, the majority of significant voxels was situated within or in close proximity to the cerebral cortex, while the subcortical white matter tracts that were found to connect frontal and posterior parietal regions in fMRI studies on healthy individuals (Vry et al. 2012; Hoeren et al. 2013) were relatively spared. Moreover, voxels associated with Trans and Intrans were situated in the proximity of either tract so that differential reliance of transitive or intransitive gesture imitation on either the superior longitudinal fascicle or the extreme capsule did not become obvious (

).

Comparison Between Gesture Imitation and Associated Behavioral Tasks

Pantomime and Actual Tool Use

The VLSM analyses for pantomime, ToolUse and ToolSelect, and error categories confirmed the results of previous studies (see Hoeren et al. 2014; Martin et al. 2016a; data on VLSM maps for single tests and error categories are, thus, not reported). Lower values in the factor extracted by PCA from all apraxia scores (transitive and intransitive imitation, pantomimed and actual tool use, tool-recipient selection) were associated mainly with inferior-parietal lesions (Fig. 6A); after correction for lesion volume, the inferior aspect of the IPL adjacent to the sylvian fissure remained significant (Fig. 6B). The analysis with the factor extracted in the “omnibus-PCA” gave highly similar results (data not shown).

Figure 6.

Imitation compared with pantomime and tool use. In a PCA with Varimax rotation the common variance of transitive and intransitive gesture imitation, pantomime, recipient selection, and performance of actual tool use was extracted. A Brunner–Munzel analysis for individual scores on the extracted factor (A) and with lesion volume as covariate (B) reveals an association of lesion in the IPL with the common variance of the different tests. Results are reported at a threshold of P < 0.05 FDR adjusted. Color bars indicate Z-scores. Modality-specific effects were detected by NIX analyses. Differential significant effects could be detected for lesioned voxels (i) in the insula cortex and subjacent extreme capsule for pantomime (C) and to a lesser extent for ToolUse (D) compared with transitive imitation, (ii) in the IPL for pantomime compared with transitive imitation (C) and (iii) in the PMC for transitive imitation compared with ToolUse; (D) to explore potential subthreshold effects, results in C and D are presented not only at the threshold of P < 0.05 FDR adjusted, but also at uncorrected P < 0.01 and P < 0.001.

Figure 6.

Imitation compared with pantomime and tool use. In a PCA with Varimax rotation the common variance of transitive and intransitive gesture imitation, pantomime, recipient selection, and performance of actual tool use was extracted. A Brunner–Munzel analysis for individual scores on the extracted factor (A) and with lesion volume as covariate (B) reveals an association of lesion in the IPL with the common variance of the different tests. Results are reported at a threshold of P < 0.05 FDR adjusted. Color bars indicate Z-scores. Modality-specific effects were detected by NIX analyses. Differential significant effects could be detected for lesioned voxels (i) in the insula cortex and subjacent extreme capsule for pantomime (C) and to a lesser extent for ToolUse (D) compared with transitive imitation, (ii) in the IPL for pantomime compared with transitive imitation (C) and (iii) in the PMC for transitive imitation compared with ToolUse; (D) to explore potential subthreshold effects, results in C and D are presented not only at the threshold of P < 0.05 FDR adjusted, but also at uncorrected P < 0.01 and P < 0.001.

Modality-specific effects (Fig. 6C,D,

) were detected by the NIX analyses (i) in the PMC for transitive imitation versus ToolUse (Fig. 6D); (ii) in the insula cortex and subjacent extreme capsule for Pantomime (and, to a lesser extent, ToolUse) versus transitive imitation (Fig. 6C,D), and (iii) in the IPL for pantomime versus transitive imitation (Fig. 6C). For pantomime versus tool use, a widespread temporo-parieto-frontal pattern emerged (); this result may be better explained by a greater sensitivity of pantomime to disturbances within the larger network related to tool-associated actions than by particular modality-specific differences.

Aphasia

Regions associated with aphasia comprised IPL, posterior superior temporal gyrus/sulcus, middle temporal gyrus (MTG), and inferior frontal gyrus (

); since these regions included both areas specific for transitive and intransitive imitation, no clear conclusions on a greater overlap between language and intransitive versus transitive gestures could be drawn (see also behavioral data above and Papeo and Rumiati 2013).

Discussion

We investigated a large cohort of 156 acute left-hemispheric stroke patients to elucidate the neuroanatomical bases underlying imitation of gestures expressing tool-associated actions and communicative emblems using VLSM.

Similar to previous studies from our laboratory as well as from other authors, this study aimed to clarify the role of ventral and dorsal streams for cognitive motor functions (Vry et al. 2012; Binkofski and Buxbaum 2013; Buxbaum et al. 2014; Hoeren et al. 2014; Vry et al. 2015; Hamzei et al. 2016; Martin et al. 2016a, 2016c). However, this is the first VLSM study to directly compare lesion patterns associated with transitive and intransitive gesture imitation deficits, and the first study to report VLSM data on meaningful gesture imitation deficits in acute stroke patients. In addition, while previous investigations found dissociable regions when dichotomizing different types of errors during gesture performance into 2 categories (e.g., conceptual versus movement; Hoeren et al. 2014), this is the first VLSM study to report areas related to single spatio-temporal errors (e.g., hand configuration, kinematics, and hand–wrist orientation). Moreover, our results are underlined by a new statistical analysis tool for the nonparametric assessment of interaction effects between lesion status and performance in different types of gesture imitation (NIX toolbox). As of yet, a direct statistical analysis for interaction effects between lesion status and task effects was not feasible. Besides visual comparison of lesion patterns, one common indirect way to assess regions of differential relevance for a behavioral task in lesion studies is the logistic regression approach (Kalenine et al. 2010; Kuemmerer et al. 2013) which tests for the association between the presence of a lesion (the dependent variable) and the variation in one behavioral score (the predictor variable) while controlling for variability in a second score (the covariate). This approach, however, does not explicitly test for a dissociation between the 2 variables (i.e., differential effects of the lesion on the performance in the predictor and the covariate), but for incremental shares of variance in the association with the lesion. A second indirect way is the subtraction of 2 raw scores to be compared per participant and testing for a difference between the group with or without a lesion for that difference score (Hoeren et al. 2014; Martin et al. 2016a; Salazar-Lopez et al. 2016). This approach, however, requires data for which parametric model assumptions are tenable—an assumption that is typically violated in lesion studies. A last approach is to dichotomize continuous or ordinal behavioral measures, leading to a loss of information and lower statistical power. By testing for interaction effects between a voxel's lesion status and the performances in different behavioral tasks (here, transitive vs. intransitive imitation), the NIX toolbox overcomes the limitations of these previous strategies and provides a direct nonparametric statistical testing approach for regions that are differentially relevant for distinct behavioral tasks. Our study delineates regions with common and differential relevance for the imitation of tool-action gestures and communicative emblems. While both gesture types depended on the integrity of inferior-parietal and posterior lateral temporal cortex in the ventro-dorsal stream, more specific associations emerged between transitive deficits and premotor and occipito-parietal lesions (ventro-dorsal stream), as well as between anterior temporal damage (ventral stream) and intransitive gesture imitation impairments (Figs 3 and 4). However, the differences were relative rather than absolute as low numbers of significant voxels in ATL and PMC were also found for transitive and intransitive gestures, respectively. Tool-action gestures and emblems thus seem to be supported by a common underlying network in which the importance of different regions varies, but is not strictly split according to the gesture type. Moreover, separate analyses for different error types revealed specific effects of anterior intraparietal, premotor, as well as inferior-parietal and occipito-temporal lesions on hand configuration, hand/wrist orientation and movement dynamics during transitive gesture imitation, respectively (Fig. 5). Finally, our results may indicate only a limited effect of damage to association fibers for meaningful gesture imitation deficits (

).

Differential Relevance of Ventro-Dorsal and Ventral Streams for Transitive and Intransitive Gestures

The effect of lesions to the IPL as well as to the lateral temporal lobe (Figs 3 and 4) on both transitive and intransitive gestures indicated a role of the ventro-dorsal stream for meaningful gesture imitation regardless of gesture type. Posterior MTG and IPL may be important for maintaining representations of skilled motor acts (Heilman et al. 1982; Rijntjes et al. 1999; Peeters et al. 2009; Hermsdörfer et al. 2013; Orban and Caruana 2014). Confirming results from fMRI studies with healthy participants (e.g., Rumiati et al. 2004) patients with IPL or posterior MTG damage display spatio-temporal errors during pantomimed and actual tool use, and during meaningful gesture imitation (Goldenberg et al. 2007; Goldenberg and Spatt 2009; Hoeren et al. 2014; Goldenberg and Randerath 2015; Martin et al. 2016a, 2016c). By dynamically monitoring the spatial relations between body parts (Goldenberg 2009), the IPL may also be relevant for motor control during gesture execution (Hermsdörfer and Goldenberg 2002; Schaefer et al. 2009). Finally, temporo-parietal regions are involved in semantic control processes that, among other functions, enable the task-dependent selection of relevant knowledge (Heilman et al. 1982; Rijntjes et al. 1999; Peeters et al. 2009; Hermsdörfer et al. 2013; Orban and Caruana 2014). Since deficient semantic control processes were previously associated with impaired object use (Corbett et al. 2009), these deficits may also have contributed to poor performance of meaningful gestures (see Goldenberg et al. 2007 for a related view).

The significantly greater impact of damage within PMC as well as within lateral occipito-parietal and posterior intraparietal sulcus regions on transitive compared with intransitive gesture imitation (Figs 35) likely relates to the higher spatio-temporal complexity of tool-use gestures which, in turn, leads to increased demands on the decoding of kinematic and postural features of observed gestures, as well as on motor control (Fig. 1) (Mozaz et al. 2002; Bohlhalter et al. 2009; Carmo and Rumiati 2009). Lateral occipito-parietal cortex and caudal intraparietal sulcus code spatial features of visually perceived objects, such as position or surface orientation that are relevant for goal-directed hand actions (Taira et al. 1990; Sakata et al. 1997; Faillenot et al. 1999; Culham and Kanwisher 2001). During imitation, these regions may be important for apprehending the spatial alignment of the body parts that are part of observed gestures, and for monitoring limb position and configuration during gesture execution (Goldenberg 2009; Naito et al. 2016). The PMC is thought to represent actions that are part of an individual's repertoire in a motor format (Graziano and Aflalo 2007; Gazzola and Keysers 2009), and to translate input from posterior parietal regions putatively involved in storing spatio-temporal action characteristics (e.g., supramarginal gyrus) into actual motor output (Heilman et al. 1982; Buxbaum et al. 2014). Alternatively, the specific effect of fronto-parietal lesions may reflect that the greater spatio-temporal complexity of transitive gestures entails greater demands on performance monitoring, working memory, top-down control of attention. These domain-general cognitive control functions are now thought to be mediated by a multiple-demand system for which intraparietal sulcus and PMC are key regions (Fedorenko et al. 2013; for related accounts, see e.g., Corbetta and Shulman 2002; Dosenbach et al. 2007; Power and Petersen 2013).

The specific impact of anterior temporal lesions on intransitive gestures is in line with their mandatory access on semantic knowledge (Andric and Small 2012; Andric et al. 2013; Proverbio et al. 2015). Tool-use gestures reference actions by depicting their salient and defining spatio-temporal features (Goldenberg et al. 2007; Goldenberg 2013), while intransitive gestures transport messages that are often arbitrarily associated with the gestural movements, even to the extent that identical gestures have opposite meanings in different cultures. Understanding intransitive gestures is, therefore, more challenging to the retrieval of semantic information in response to sensory stimuli (Andric et al. 2013). Moreover, the meanings conveyed by emblems frequently involve abstract concepts that are largely unrelated to sensorimotor experience (Mahon and Caramazza 2008; Jefferies 2013), such as states of mind or emotions. Examples include craziness (tapping the index finger on the temple), confusion (scratching one's head), surrender (holding up hands), or anger (shaking a fist). In accordance with these considerations, previous functional imaging studies consistently demonstrated anterior temporal activity in tasks requiring retrieval and manipulation of semantic knowledge in response to a wide variety of stimulus categories (Vandenberghe et al. 1996; Bright et al. 2004; Zahn et al. 2007; Visser et al. 2010a; Skipper et al. 2011; for reviews, see Binder et al. 2009; Wang et al. 2010; Jefferies 2013). In summary, the specific association between intransitive imitation deficits and anterior temporal lesions corroborates the concept of a domain-general ventral stream (Weiller et al. 2009, 2011, 2015a) involved in deriving meaning from sensory stimuli (Saur et al. 2008; Rijntjes et al. 2012; Kuemmerer et al. 2013), and in maintaining semantic knowledge (Patterson et al. 2007; Lambon Ralph 2014).

Differences Between Error Types During Transitive Gesture Imitation

While the widespread parieto-temporal pattern of voxels related to non-recognizable movements indicated that gestures may become non-intelligible due to various underlying deficits (e.g., severe spatio-temporal errors, defective retrieval of action representations) (Hoeren et al. 2014), configuration, orientation, and movement errors during transitive gesture performance were associated with more circumscribed regions (Fig. 5). Conversely, no areas were significantly related to the rarely observed distance or semantic errors (Table 2), or with BPO “errors” which occur frequently in healthy subjects, too (Raymer et al. 1997).

The lateral anterior intraparietal sulcus region and the PMC, where lesions were associated with configuration and orientation errors, respectively, mediate fine motor control of the distal upper extremity for grasping (Binkofski et al. 1998; Oztop and Kawato 2009; Cavina-Pratesi et al. 2010; Grafton 2010; Jacobs et al. 2010; Davare et al. 2011; Hamzei et al. 2016). The PMC may, in particular, be crucial for coordinating hand shape and other movement components, such as lifting (Davare et al. 2006). The association between movement errors and lesions to IPL and lateral occipito-temporal cortex may be explained by impaired online motor control (Hermsdörfer and Goldenberg 2002; Goldenberg 2009), defective spatio-temporal action representations (Heilman et al. 1982; Rijntjes et al. 1999; Hoeren et al. 2014), or by disrupted visual feedback during gestural performance (Ogawa et al. 2006). Together with the specific association between configuration errors and anterior intraparietal sulcus region damage (which appeared relatively spared in results for movement errors, Fig. 5B,C), the impact of inferior-parietal damage on movement dynamics corroborates a functional parcellation of the IPL (Garcea and Mahon 2014; Orban and Caruana 2014; Vingerhoets 2014). However, more research is needed to explore potential further dissociations between different spatio-temporal aspects, which were presently subsumed under the label of movement errors, e.g., amplitude, velocity, or trajectory (Hermsdörfer et al. 2013).

By contrast, all error types occurring with sufficient frequency during intransitive gesture imitation to yield significant results in the VLSM analyses (as for transitive gestures: C, O, M, UR, Table 2, Fig. 5) were associated with temporo-parietal patterns that resembled the distribution of voxels significantly related to overall deficits in intransitive gesture imitation. Given that the postural and kinematic features of communicative emblems are easier to perform (see Table 2 and Discussion), the distinct components may less specifically rely on specialized areas, and isolated deficits may be compensated for more easily. Thus, the frequency of all relevant error types may increase uniformly as damage to the network involved in intransitive gesture imitation limits available resources.

Commonalities and Differences Between Gesture Imitation, Pantomime, and Actual Tool Use

The VLSM analysis based on the common variance extracted by PCA from transitive and intransitive gesture imitation, pantomimed, and actual tool use, as well as tool-recipient matching highlighted the importance of the IPL for tool-associated tasks irrespective of the testing modality (Fig. 6). As described above, the common relevance may be explained by shared demands on stored action representations (Heilman et al. 1982), on the processing of spatial relationships between body parts (Goldenberg 2009), or even domain-general executive functions (Jefferies and Lambon Ralph 2006; Corbett et al. 2009; Jefferies 2013).

With respect to modality-specific effects, the stronger effect of premotor lesions on transitive imitation than actual tool use may be explained by higher demands on motor control. Gesturing involves actively assuming spatio-temporal features (e.g., grip aperture) that during actual tool use are facilitated by the physical dimensions of the tools (e.g., size of the handle). Conversely, the higher relevance of the insular/subinsular region for pantomime compared with transitive imitation may be aligned with an impaired top-down retrieval of actions, as lesions to the extreme capsule may disrupt association fibers that connect the inferior frontal gyrus to posterior temporal and parietal lobes (Hoeren et al. 2014; Vry et al. 2015). Pantomime may be more susceptible to retrieval deficits, as actions need to be recalled actively by the patient, whereas during imitation, the action is specified by the examiner. Finally, the greater impact of inferior-parietal lesions on pantomime compared with transitive imitation may result from a greater dependence of pantomime on stored action representations, as during imitation, defective action representations (Heilman et al. 1982) may be compensated by visuo-motor matching.

Other than hypothesized, no regions previously involved in visuo-perceptive processes appeared to be more relevant to imitation compared with pantomime or actual tool use (cf. Martin et al. 2016c). Putatively, regions involved in decoding bodily motion such as the posterior superior temporal gyrus/sulcus may not only be required for gesture recognition but also for online feedback during action execution (Gazzola and Keysers 2009).

Limitations and Methodological Considerations

Obtaining behavioral and MRI data in the acute post-stroke phase offers several advantages over investigating chronic patients (Umarova et al. 2011; Kuemmerer et al. 2013; Hoeren et al. 2014; Martin et al. 2016a), but faces disadvantages as well. In acute patients, associations between lesion locations and symptoms may be less influenced by compensatory brain reorganization, so that lesion analyses may yield a more accurate approximation of the networks that are functionally relevant in healthy individuals (Saur et al. 2006). Moreover, although the chronic lesion may not be fully formed in the acute neuroimaging examination, in our experience, lesions observed in acute/subacute MRI scans generally show good correspondence to the chronic stage and, in our opinion, allow for a more precise lesion delineation than chronic MRI scans because the anatomical changes ensuing tissue loss are not as pronounced (e.g., enlargement of the ventricles, translation of typical anatomical landmarks; see Martin et al. 2016a for more examples). By contrast, performances in acute patients may be affected more strongly by unspecific sequelae of acute brain injury, such as an inability to sustain attention (Hoeren et al. 2014), that may make a precise neuropsychological exam more challenging. In addition, given that no or little recovery has taken place, a significant number of patients who might be able to undergo testing after recovery in the chronic stage cannot be included in the acute phase. Finally, diaschisis, the dysfunction of regions remote to the actual lesion might impair patients in the acute phase (Saur et al. 2006; Carrera and Tononi 2014; Weiller et al. 2015b). However, diaschisis is thought to occur mainly in networks of functionally related regions (Price et al. 2001), which makes the false-positive detection of task-irrelevant areas unlikely. Moreover, diaschisis is also relevant in chronic patients for cognitive motor and language abilities (Price et al. 2001; Martin et al. 2016c) and, therefore, should be considered regardless of the time of examination. Longitudinal assessments in both acute and chronic phases may aid to better assess these potentially time-dependent factors in future studies.

As in several previous lesion studies (e.g., Kuemmerer et al. 2013; Hoeren et al. 2014; Halai et al. 2016), no regions were significantly associated with different test scores after controlling for lesion volume. Nonetheless, several considerations indicate that the key finding of the study, that is, the differential relevance of ATL and PMC/posterior IPL for intransitive and transitive gestures, respectively, is not due to a confounding effect of lesion volume. First, ATL and PMC/posterior IPL were only weakly associated with lesion volume; conversely, the regions most significantly associated with higher lesion volume, that is, the anterior insula and adjacent tissue, were not among the regions strongly related to imitation performance. Second, transitive and intransitive gesture performance were both similarly correlated with lesion volume (Kendall's Tau: −0.361 and −0.307, respectively), so that it in direct comparisons (Fig. 4), the effect of lesion volume should have largely been cancelled out. Third, at a lowered threshold, the overall pattern of regions associated with gesture performance after correcting for lesion volume was overall similar to the results without lesion volume as covariate (

). Potential strategies to achieve a clearer independence of lesion volume in future studies include embedding the tests of interest in a larger battery of action-related as well as additional tests for more basic cognitive functions (e.g., semantic, executive) with subsequent use of PCA for the extraction of more robust, orthogonal components (see Butler et al. 2014; Halai et al. 2016 for details; this method also allows for further insights into underlying cognitive mechanisms). Alternatively, inclusion criteria could be adapted to restrict testing to patients with similar lesion sizes (e.g., Kalenine et al. 2010).

Moreover, given that only one hand was tested per patient, we cannot rule out that cases with dissociations between left and right hand performances were overlooked. This may be relevant as the subcortical damage noted in a considerable number of patients (Fig. 2) might have affected fibers connecting the 2 hemispheres through the corpus callosum. However, to the best of our knowledge and in line with our clinical experience, callosal apraxia is relatively rare and has only been described in single cases with direct, extensive lesions to the corpus callosum, which were not observed in our cohort (Watson and Heilman 1983; Petreska et al. 2010). A significant influence of undetected callosal apraxia on our present results, therefore, seems unlikely.

Finally, our study did not investigate if the relationship between lesion location and imitation performance is further modulated by factors such as familiarity with different gestures (i.e., more frequently vs. rarely used gestures), or the individual reliance on different imitation-related processes (e.g., the extent to which patients use “direct” visuo-to-motor matching rather than retrieval of stored motor engrams; see e.g., Tessari et al. 2007 for a related study). Results from object use in semantic dementia patients (Bozeat et al. 2002), as well as studies in the field of reading, past-tense generation, and semantic processing (e.g., Patterson et al. 2006; Woollams et al. 2007; Hoffman et al. 2015) may point to a particular impact of ventral stream lesions on the imitation of relatively unfamiliar gestures in patients with poor visuo-to-motor matching capabilities; this hypothesis should be explored in future studies.

Supplementary Material

.

Funding

BrainLinks-BrainTools Cluster of Excellence;  German Research Foundation (DFG, grant #EXC1086).

Notes

We thank Hansjörg Mast for assistance in data acquisition. We thank Ursula Kücking, Susanne Karn, Güldane Akca-Freund, Sarah Höfer, and Gabriele Lind for conducting the neuropsychological testing; without their careful examinations, this study would not have been possible. Conflict of Interest: None declared.

References

Andric
M
,
Small
SL
.
2012
.
Gesture's neural language
.
Front Psychol
 .
3
:
99
.
Andric
M
,
Solodkin
A
,
Buccino
G
,
Goldin-Meadow
S
,
Rizzolatti
G
,
Small
SL
.
2013
.
Brain function overlaps when people observe emblems, speech, and grasping
.
Neuropsychologia
 .
51
:
1619
1629
.
Ashburner
J
.
2007
.
A fast diffeomorphic image registration algorithm
.
Neuroimage
 .
38
:
95
113
.
Bartolo
A
,
Cubelli
R
,
Della Sala
S
.
2008
.
Cognitive approach to the assessment of limb apraxia
.
Clin Neuropsychol
 .
22
:
27
45
.
Beume
LA
,
Kaller
CP
,
Hoeren
M
,
Kloeppel
S
,
Kuemmerer
D
,
Glauche
V
,
Koestering
L
,
Mader
I
,
Rijntjes
M
,
Weiller
C
, et al
.
2015
.
Processing of bilateral versus unilateral conditions: evidence for the functional contribution of the ventral attention network
.
Cortex
 .
66
:
91
102
.
Binder
JR
,
Desai
RH
,
Graves
WW
,
Conant
LL
.
2009
.
Where is the semantic system? A critical review and meta-analysis of 120 functional neuroimaging studies
.
Cereb Cortex
 .
19
:
2767
2796
.
Binkofski
F
,
Buxbaum
LJ
.
2013
.
Two action systems in the human brain
.
Brain Lang
 .
127
:
222
229
.
Binkofski
F
,
Dohle
C
,
Posse
S
,
Stephan
KM
,
Hefter
H
,
Seitz
RJ
,
Freund
HJ
.
1998
.
Human anterior intraparietal area subserves prehension: a combined lesion and functional MRI activation study
.
Neurology
 .
50
:
1253
1259
.
Bohlhalter
S
,
Hattori
N
,
Wheaton
L
,
Fridman
E
,
Shamim
EA
,
Garraux
G
,
Hallett
M
.
2009
.
Gesture subtype-dependent left lateralization of praxis planning: an event-related fMRI study
.
Cereb Cortex
 .
19
:
1256
1262
.
Bonivento
C
,
Rothstein
P
,
Humphreys
G
,
Chechlacz
M
.
2014
.
Neural correlates of transitive and intransitive action imitation: an investigation using voxel-based morphometry
.
Neuroimage Clin
 .
6
:
488
497
.
Bozeat
S
,
Lambon Ralph
MA
,
Patterson
K
,
Hodges
JR
.
2002
.
When objects lose their meaning: what happens to their use
.
Cogn Affect Behav Neurosci
 .
2
:
236
251
.
Bright
P
,
Moss
H
,
Tyler
LK
.
2004
.
Unitary vs multiple semantics: PET studies of word and picture processing
.
Brain Lang
 .
89
:
417
432
.
Brunner
E
,
Domhof
S
,
Langer
F
.
2002
.
Nonparametric analysis of longitudinal data in factorial experiments
 .
New York
:
Wiley
.
Butler
RA
,
Lambon Ralph
MA
,
Woollams
AM
.
2014
.
Capturing multidimensionality in stroke aphasia: mapping principal behavioural components to neural structures
.
Brain
 .
137
:
3248
3266
.
Buxbaum
LJ
,
Johnson-Frey
SH
,
Bartlett-Williams
M
.
2005
a.
Deficient internal models for planning hand-object interactions in apraxia
.
Neuropsychologia
 .
43
:
917
929
.
Buxbaum
LJ
,
Kalenine
S
.
2010
.
Action knowledge, visuomotor activation, and embodiment in the two action systems
.
Ann NY Acad Sci
 .
1191
:
201
218
.
Buxbaum
LJ
,
Kyle
K
,
Grossman
M
,
Coslett
HB
.
2007
.
Left inferior parietal representations for skilled hand-object interactions: evidence from stroke and corticobasal degeneration
.
Cortex
 .
43
:
411
423
.
Buxbaum
LJ
,
Kyle
KM
,
Menon
R
.
2005
b.
On beyond mirror neurons: internal representations subserving imitation and recognition of skilled object-related actions in humans
.
Brain Res Cogn Brain Res
 .
25
:
226
239
.
Buxbaum
LJ
,
Shapiro
AD
,
Coslett
HB
.
2014
.
Critical brain regions for tool-related and imitative actions: a componential analysis
.
Brain
 .
137
:
1971
1985
.
Buxbaum
LJ
,
Sirigu
A
,
Schwartz
MF
,
Klatzky
R
.
2003
.
Cognitive representations of hand posture in ideomotor apraxia
.
Neuropsychologia
 .
41
:
1091
1113
.
Carmo
JC
,
Rumiati
RI
.
2009
.
Imitation of transitive and intransitive actions in healthy individuals
.
Brain Cogn
 .
69
:
460
464
.
Carrera
E
,
Tononi
G
.
2014
.
Diaschisis: past, present, future
.
Brain
 .
137
:
2408
2422
.
Cavina-Pratesi
C
,
Monaco
S
,
Fattori
P
,
Galletti
C
,
McAdam
TD
,
Quinlan
DJ
,
Goodale
MA
,
Culham
JC
.
2010
.
Functional magnetic resonance imaging reveals the neural substrates of arm transport and grip formation in reach-to-grasp actions in humans
.
J Neurosci
 .
30
:
10306
10323
.
Corbett
F
,
Jefferies
E
,
Ehsan
S
,
Lambon Ralph
MA
.
2009
.
Different impairments of semantic cognition in semantic dementia and semantic aphasia: evidence from the non-verbal domain
.
Brain
 .
132
:
2593
2608
.
Corbetta
M
,
Shulman
GL
.
2002
.
Control of goal-directed and stimulus-driven attention in the brain
.
Nat Rev Neurosci
 .
3
:
201
215
.
Crawford
JR
,
Garthwaite
PH
.
2002
.
Investigation of the single case in neuropsychology: confidence limits on the abnormality of test scores and test score differences
.
Neuropsychologia
 .
40
:
1196
1208
.
Culham
JC
,
Kanwisher
NG
.
2001
.
Neuroimaging of cognitive functions in human parietal cortex
.
Curr Opin Neurobiol
 .
11
:
157
163
.
Davare
M
,
Andres
M
,
Cosnard
G
,
Thonnard
JL
,
Olivier
E
.
2006
.
Dissociating the role of ventral and dorsal premotor cortex in precision grasping
.
J Neurosci
 .
26
:
2260
2268
.
Davare
M
,
Kraskov
A
,
Rothwell
JC
,
Lemon
RN
.
2011
.
Interactions between areas of the cortical grasping network
.
Curr Opin Neurobiol
 .
21
:
565
570
.
De Renzi
E
.
1985
. Methods of limb apraxia examination and their bearing on the interpretation of the disorder. In:
Roy
EA
, editor
.
Neuropsychological studies of apraxia and related disorders
 .
1st ed
.
Amsterdam (NL)
:
North-Holland
. p.
45
64
.
Donkervoort
M
,
Dekker
J
,
Deelman
B
.
2006
.
The course of apraxia and ADL functioning in left hemisphere stroke patients treated in rehabilitation centres and nursing homes
.
Clin Rehabil
 .
20
:
1085
1093
.
Dosenbach
NU
,
Fair
DA
,
Miezin
FM
,
Cohen
AL
,
Wenger
KK
,
Dosenbach
RA
,
Fox
MD
,
Snyder
AZ
,
Vincent
JL
,
Raichle
ME
, et al
.
2007
.
Distinct brain networks for adaptive and stable task control in humans
.
Proc Natl Acad Sci USA
 .
104
:
11073
11078
.
Du
YP
,
Dalwani
M
,
Wylie
K
,
Claus
E
,
Tregellas
JR
.
2007
.
Reducing susceptibility artifacts in fMRI using volume-selective z-shim compensation
.
Magn Reson Med
 .
57
:
396
404
.
Ekman
P
,
Friesen
WV
.
1969
.
The repertoire of nonverbal behavior: categories, origins, usage and coding
.
Semiotica
 .
1
:
49
98
.
Faillenot
I
,
Decety
J
,
Jeannerod
M
.
1999
.
Human brain activity related to the perception of spatial features of objects
.
Neuroimage
 .
10
:
114
124
.
Fedorenko
E
,
Duncan
J
,
Kanwisher
N
.
2013
.
Broad domain generality in focal regions of frontal and parietal cortex
.
Proc Natl Acad Sci USA
 .
110
:
16616
16621
.
Foundas
AL
,
Macauley
BL
,
Raymer
AM
,
Maher
LM
,
Rothi
LJ
,
Heilman
KM
.
1999
.
Ideomotor apraxia in Alzheimer disease and left hemisphere stroke: limb transitive and intransitive movements
.
Neuropsychiatry Neuropsychol Behav Neurol
 .
12
:
161
166
.
Garcea
FE
,
Mahon
BZ
.
2014
.
Parcellation of left parietal tool representations by functional connectivity
.
Neuropsychologia
 .
60
:
131
143
.
Gazzola
V
,
Keysers
C
.
2009
.
The observation and execution of actions share motor and somatosensory voxels in all tested subjects: single-subject analyses of unsmoothed fMRI data
.
Cereb Cortex
 .
19
:
1239
1255
.
Goldenberg
G
.
2001
.
Imitation and matching of hand and finger postures
.
Neuroimage
 .
14
:
132
136
.
Goldenberg
G
.
2008
. Apraxia. In:
Goldenberg
G
,
Miller
B
, editors
.
Handbook of clinical neurology
 .
Edinburgh
:
Elsevier
. p.
323
338
.
Goldenberg
G
.
2009
.
Apraxia and the parietal lobes
.
Neuropsychologia
 .
47
:
1449
1459
.
Goldenberg
G
.
2013
.
Apraxia: the cognitive side of motor control
 .
Oxford (NY)
:
Oxford University Press
.
Goldenberg
G
,
Hermsdörfer
J
,
Glindemann
R
,
Rorden
C
,
Karnath
HO
.
2007
.
Pantomime of tool use depends on integrity of left inferior frontal cortex
.
Cereb Cortex
 .
17
:
2769
2776
.
Goldenberg
G
,
Randerath
J
.
2015
.
Shared neural substrates of apraxia and aphasia
.
Neuropsychologia
 .
75
:
40
49
.
Goldenberg
G
,
Spatt
J
.
2009
.
The neural basis of tool use
.
Brain
 .
132
:
1645
1655
.
Goodale
MA
,
Milner
AD
.
1992
.
Separate visual pathways for perception and action
.
Trends Neurosci
 .
15
:
20
25
.
Grafton
ST
.
2010
.
The cognitive neuroscience of prehension: recent developments
.
Exp Brain Res
 .
204
:
475
491
.
Graziano
MS
,
Aflalo
TN
.
2007
.
Mapping behavioral repertoire onto the cortex
.
Neuron
 .
56
:
239
251
.
Haaland
KY
,
Flaherty
D
.
1984
.
The different types of limb apraxia errors made by patients with left vs. right hemisphere damage
.
Brain Cogn
 .
3
:
370
384
.
Haaland
KY
,
Harrington
DL
,
Knight
RT
.
2000
.
Neural representations of skilled movement
.
Brain
 .
123
:
2306
2313
.
Halai
AD
,
Woollams
AM
,
Lambon Ralph
MA
.
2016
.
Using principal component analysis to capture individual differences within a unified neuropsychological model of chronic post-stroke aphasia: revealing the unique neural correlates of speech fluency, phonology and semantics
.
Cortex
 . Epub ahead of print.
Hamzei
F
,
Vry
MS
,
Saur
D
,
Glauche
V
,
Hoeren
M
,
Mader
I
,
Weiller
C
,
Rijntjes
M
.
2016
.
The dual-loop model and the human mirror neuron system: an exploratory combined fMRI and DTI study of the inferior frontal gyrus
.
Cereb Cortex
 .
26
:
2215
2224
.
Heilman
KM
,
Rothi
LG
.
1993
. Apraxia. In:
Heilman
KM
,
Valenstein
E
, editors
.
Clinical neuropsychology
 .
3rd ed
.
New York
:
Oxford University Press
. p.
141
163
.
Heilman
KM
,
Rothi
LJ
,
Valenstein
E
.
1982
.
2 forms of ideomotor apraxia
.
Neurology
 .
32
:
342
346
.
Hermsdörfer
J
,
Goldenberg
G
.
2002
.
Ipsilesional deficits during fast diadochokinetic hand movements following unilateral brain damage
.
Neuropsychologia
 .
40
:
2100
2115
.
Hermsdörfer
J
,
Li
Y
,
Randerath
J
,
Roby-Brami
A
,
Goldenberg
G
.
2013
.
Tool use kinematics across different modes of execution. Implications for action representation and apraxia
.
Cortex
 .
49
:
184
199
.
Hewes
GW
.
1973
.
Primate communication and the gestural origin of language
.
Curr Anthropol
 .
14
:
4
25
.
Hodges
JR
,
Spatt
J
,
Patterson
K
.
1999
.
“What” and “how”: evidence for the dissociation of object knowledge and mechanical problem-solving skills in the human brain
.
Proc Natl Acad Sci USA
 .
96
:
9444
9448
.
Hoeren
M
,
Kaller
CP
,
Glauche
V
,
Vry
MS
,
Rijntjes
M
,
Hamzei
F
,
Weiller
C
.
2013
.
Action semantics and movement characteristics engage distinct processing streams during the observation of tool use
.
Exp Brain Res
 .
229
:
243
260
.
Hoeren
M
,
Kuemmerer
D
,
Bormann
T
,
Beume
L
,
Ludwig
VM
,
Vry
MS
,
Mader
I
,
Rijntjes
M
,
Kaller
CP
,
Weiller
C
.
2014
.
Neural bases of imitation and pantomime in acute stroke patients: distinct streams for praxis
.
Brain
 .
137
:
2796
2810
.
Hoffman
P
,
Binney
RJ
,
Lambon Ralph
MA
.
2015
.
Differing contributions of inferior prefrontal and anterior temporal cortex to concrete and abstract conceptual knowledge
.
Cortex
 .
63
:
250
266
.
Hogrefe
K
,
Ziegler
W
,
Weidinger
N
,
Goldenberg
G
.
2012
.
Non-verbal communication in severe aphasia: influence of aphasia, apraxia, or semantic processing
.
Cortex
 .
48
:
952
962
.
Huber
W
,
Poeck
K
,
Willmes
K
.
1984
.
The Aachen aphasia test
.
Adv Neurol
 .
42
:
291
303
.
Humphreys
GF
,
Hoffman
P
,
Visser
M
,
Binney
RJ
,
Lambon Ralph
MA
.
2015
.
Establishing task- and modality-dependent dissociations between the semantic and default mode networks
.
Proc Natl Acad Sci USA
 .
112
:
7857
7862
.
Jacobs
S
,
Danielmeier
C
,
Frey
SH
.
2010
.
Human anterior intraparietal and ventral premotor cortices support representations of grasping with the hand or a novel tool
.
J Cogn Neurosci
 .
22
:
2594
2608
.
Jefferies
E
.
2013
.
The neural basis of semantic cognition: converging evidence from neuropsychology, neuroimaging and TMS
.
Cortex
 .
49
:
611
625
.
Jefferies
E
,
Lambon Ralph
MA
.
2006
.
Semantic impairment in stroke aphasia versus semantic dementia: a case-series comparison
.
Brain
 .
129
:
2132
2147
.
Johnson-Frey
SH
,
Newman-Norlund
R
,
Grafton
ST
.
2005
.
A distributed left hemisphere network active during planning of everyday tool use skills
.
Cereb Cortex
 .
15
:
681
695
.
Kalenine
S
,
Buxbaum
LJ
,
Coslett
HB
.
2010
.
Critical brain regions for action recognition: lesion symptom mapping in left hemisphere stroke
.
Brain
 .
133
:
3269
3280
.
Karnath
HO
,
Rennig
J
,
Johannsen
L
,
Rorden
C
.
2011
.
The anatomy underlying acute versus chronic spatial neglect: a longitudinal study
.
Brain
 .
134
:
903
912
.
Kessels
RP
,
van den Berg
E
,
Ruis
C
,
Brands
AM
.
2008
.
The backward span of the Corsi block-tapping task and its association with the WAIS-III Digit Span
.
Assessment
 .
15
:
426
434
.
Kessels
RP
,
van Zandvoort
MJ
,
Postma
A
,
Kappelle
LJ
,
de Haan
EH
.
2000
.
The Corsi block-tapping task: standardization and normative data
.
Appl Neuropsychol
 .
7
:
252
258
.
Kimberg
DY
,
Coslett
HB
,
Schwartz
MF
.
2007
.
Power in voxel-based lesion-symptom mapping
.
J Cogn Neurosci
 .
19
:
1067
1080
.
Klein
E
,
Moeller
K
,
Glauche
V
,
Weiller
C
,
Willmes
K
.
2013
.
Processing pathways in mental arithmetic-evidence from probabilistic fiber tracking
.
PLoS One
 .
8
:
e55455
.
Kroliczak
G
,
Frey
SH
.
2009
.
A common network in the left cerebral hemisphere represents planning of tool use pantomimes and familiar intransitive gestures at the hand-independent level
.
Cereb Cortex
 .
19
:
2396
2410
.
Kuemmerer
D
,
Hartwigsen
G
,
Kellmeyer
P
,
Glauche
V
,
Mader
I
,
Kloeppel
S
,
Suchan
J
,
Karnath
HO
,
Weiller
C
,
Saur
D
.
2013
.
Damage to ventral and dorsal language pathways in acute aphasia
.
Brain
 .
136
:
619
629
.
Lambon Ralph
MA
.
2014
.
Neurocognitive insights on conceptual knowledge and its breakdown
.
Philos Trans R Soc Lond B Biol Sci
 .
369
:
20120392
.
Leiguarda
RC
,
Marsden
CD
.
2000
.
Limb apraxias: higher-order disorders of sensorimotor integration
.
Brain
 .
123
:
860
879
.
Lotze
M
,
Heymans
U
,
Birbaumer
N
,
Veit
R
,
Erb
M
,
Flor
H
,
Halsband
U
.
2006
.
Differential cerebral activation during observation of expressive gestures and motor acts
.
Neuropsychologia
 .
44
:
1787
1795
.
Mahon
BZ
,
Caramazza
A
.
2008
.
A critical look at the embodied cognition hypothesis and a new proposal for grounding conceptual content
.
J Physiol Paris
 .
102
:
59
70
.
Makris
N
,
Pandya
DN
.
2009
.
The extreme capsule in humans and rethinking of the language circuitry
.
Brain Struct Funct
 .
213
:
343
358
.
Martin
M
,
Beume
L
,
Kuemmerer
D
,
Schmidt
CS
,
Bormann
T
,
Dressing
A
,
Ludwig
VM
,
Umarova
RM
,
Mader
I
,
Rijntjes
M
, et al
.
2016
a.
Differential roles of ventral and dorsal streams for conceptual and production-related components of tool use in acute stroke patients
.
Cereb Cortex
 .
26
:
3754
3771
.
Martin
M
,
Dressing
A
,
Bormann
T
,
Schmidt
CS
,
Kummerer
D
,
Beume
L
,
Saur
D
,
Mader
I
,
Rijntjes
M
,
Kaller
CP
, et al
.
2016
b.
Componential network for the recognition of tool-associated actions: evidence from voxel-based lesion-symptom mapping in acute stroke patients
.
Cereb Cortex
 . Epub ahead of print.
Martin
M
,
Nitschke
K
,
Beume
L
,
Dressing
A
,
Buehler
LE
,
Ludwig
VM
,
Mader
I
,
Rijntjes
M
,
Kaller
CP
,
Weiller
C
.
2016
c.
Brain activity underlying tool-related and imitative skills after major left hemisphere stroke
.
Brain
 .
139
:
1497
1516
.
Medina
J
,
Kimberg
DY
,
Chatterjee
A
,
Coslett
HB
.
2010
.
Inappropriate usage of the Brunner-Munzel test in recent voxel-based lesion-symptom mapping studies
.
Neuropsychologia
 .
48
:
341
343
.
Mengotti
P
,
Corradi-Dell'Acqua
C
,
Negri
GA
,
Ukmar
M
,
Pesavento
V
,
Rumiati
RI
.
2013
a.
Selective imitation impairments differentially interact with language processing
.
Brain
 .
136
:
2602
2618
.
Mengotti
P
,
Ticini
LF
,
Waszak
F
,
Schutz-Bosbach
S
,
Rumiati
RI
.
2013
b.
Imitating others’ actions: transcranial magnetic stimulation of the parietal opercula reveals the processes underlying automatic imitation
.
Eur J Neurosci
 .
37
:
316
322
.
Montgomery
KJ
,
Isenberg
N
,
Haxby
JV
.
2007
.
Communicative hand gestures and object-directed hand movements activated the mirror neuron system
.
Soc Cogn Affect Neurosci
 .
2
:
114
122
.
Mozaz
M
,
Rothi
LJ
,
Anderson
JM
,
Crucian
GP
,
Heilman
KM
.
2002
.
Postural knowledge of transitive pantomimes and intransitive gestures
.
J Int Neuropsychol Soc
 .
8
:
958
962
.
Musso
M
,
Weiller
C
,
Horn
A
,
Glauche
V
,
Umarova
R
,
Hennig
J
,
Schneider
A
,
Rijntjes
M
.
2015
.
A single dual-stream framework for syntactic computations in music and language
.
Neuroimage
 .
117
:
267
283
.
Naito
E
,
Morita
T
,
Amemiya
K
.
2016
.
Body representations in the human brain revealed by kinesthetic illusions and their essential contributions to motor control and corporeal awareness
.
Neurosci Res
 .
104
:
16
30
.
Nitschke
K
,
Martin
M
,
Willmes
K
,
Weiller
C
,
Kaller
CP
. forthcoming. Testing Dissociations in Lesion-Symptom Mapping: A Tool for Nonparametric Interaction Effects (NIX).
Ogawa
K
,
Inui
T
,
Sugio
T
.
2006
.
Separating brain regions involved in internally guided and visual feedback control of moving effectors: an event-related fMRI study
.
Neuroimage
 .
32
:
1760
1770
.
Orban
GA
,
Caruana
F
.
2014
.
The neural basis of human tool use
.
Front Psychol
 .
5
:
310
.
Oztop
E
,
Kawato
M
.
2009
. Models for the control of grasping. In:
Nowak
DA
,
Hermsdoerfer
J
, editors
.
Sensorimotor control of grasping: physiology and pathophysiology
 .
1st ed
.
Cambridge, UK
:
Cambridge University Press
. p.
110
124
.
Papeo
L
,
Rumiati
RI
.
2013
.
Lexical and gestural symbols in left-damaged patients
.
Cortex
 .
49
:
1668
1678
.
Patterson
K
,
Lambon Ralph
MA
,
Jefferies
E
,
Woollams
A
,
Jones
R
,
Hodges
JR
,
Rogers
TT
.
2006
.
“Presemantic” cognition in semantic dementia: six deficits in search of an explanation
.
J Cogn Neurosci
 .
18
:
169
183
.
Patterson
K
,
Nestor
PJ
,
Rogers
TT
.
2007
.
Where do you know what you know? The representation of semantic knowledge in the human brain
.
Nat Rev Neurosci
 .
8
:
976
987
.
Pazzaglia
M
,
Smania
N
,
Corato
E
,
Aglioti
SM
.
2008
.
Neural underpinnings of gesture discrimination in patients with limb apraxia
.
J Neurosci
 .
28
:
3030
3041
.
Peeters
R
,
Simone
L
,
Nelissen
K
,
Fabbri-Destro
M
,
Vanduffel
W
,
Rizzolatti
G
,
Orban
GA
.
2009
.
The representation of tool use in humans and monkeys: common and uniquely human features
.
J Neurosci
 .
29
:
11523
11539
.
Petreska
B
,
Billard
A
,
Hermsdorfer
J
,
Goldenberg
G
.
2010
.
Revisiting a study of callosal apraxia: the right hemisphere can imitate the orientation but not the position of the hand
.
Neuropsychologia
 .
48
:
2509
2516
.
Power
E
,
Code
C
,
Croot
K
,
Sheard
C
,
Gonzalez Rothi
LJ
.
2010
.
Florida Apraxia Battery-Extended and revised Sydney (FABERS): design, description, and a healthy control sample
.
J Clin Exp Neuropsychol
 .
32
:
1
18
.
Power
JD
,
Petersen
SE
.
2013
.
Control-related systems in the human brain
.
Curr Opin Neurobiol
 .
23
:
223
228
.
Price
CJ
,
Warburton
EA
,
Moore
CJ
,
Frackowiak
RS
,
Friston
KJ
.
2001
.
Dynamic diaschisis: anatomically remote and context-sensitive human brain lesions
.
J Cogn Neurosci
 .
13
:
419
429
.
Proverbio
AM
,
Gabaro
V
,
Orlandi
A
,
Zani
A
.
2015
.
Semantic brain areas are involved in gesture comprehension: An electrical neuroimaging study
.
Brain Lang
 .
147
:
30
40
.
Raymer
AM
,
Maher
LM
,
Foundas
AL
,
Heilman
KM
,
Rothi
LJ
.
1997
.
The significance of body part as tool errors in limb apraxia
.
Brain Cogn
 .
34
:
287
292
.
Rijntjes
M
,
Dettmers
C
,
Buchel
C
,
Kiebel
S
,
Frackowiak
RS
,
Weiller
C
.
1999
.
A blueprint for movement: functional and anatomical representations in the human motor system
.
J Neurosci
 .
19
:
8043
8048
.
Rijntjes
M
,
Weiller
C
,
Bormann
T
,
Musso
M
.
2012
.
The dual loop model: its relation to language and other modalities
.
Front Evol Neurosci
 .
4
:
9
.
Rizzolatti
G
,
Matelli
M
.
2003
.
Two different streams form the dorsal visual system: anatomy and functions
.
Exp Brain Res
 .
153
:
146
157
.
Rorden
C
,
Karnath
HO
.
2004
.
Using human brain lesions to infer function: a relic from a past era in the fMRI age
.
Nat Rev Neurosci
 .
5
:
813
819
.
Rorden
C
,
Karnath
HO
,
Bonilha
L
.
2007
.
Improving lesion-symptom mapping
.
J Cogn Neurosci
 .
19
:
1081
1088
.
Rothi
LJ
,
Mack
L
,
Verfaellie
M
,
Brown
P
,
Heilman
K
.
1988
.
Ideomotor apraxia: error pattern analysis
.
Aphasiology
 .
2
:
381
387
.
Rothi
LJ
,
Ochipa
C
,
Heilman
KM
.
1991
.
A cognitive neuropsychological model of limb praxis
.
Cogn Neuropsychol
 .
8
:
443
458
.
Rumiati
RI
,
Carmo
JC
,
Corradi-Dell'Acqua
C
.
2009
.
Neuropsychological perspectives on the mechanisms of imitation
.
Philos Trans R Soc Lond B Biol Sci
 .
364
:
2337
2347
.
Rumiati
RI
,
Tessari
A
.
2002
.
Imitation of novel and well-known actions: the role of short-term memory
.
Exp Brain Res
 .
142
:
425
433
.
Rumiati
RI
,
Weiss
PH
,
Shallice
T
,
Ottoboni
G
,
Noth
J
,
Zilles
K
,
Fink
GR
.
2004
.
Neural basis of pantomiming the use of visually presented objects
.
Neuroimage
 .
21
:
1224
1231
.
Rumiati
RI
,
Weiss
PH
,
Tessari
A
,
Assmus
A
,
Zilles
K
,
Herzog
H
,
Fink
GR
.
2005
.
Common and differential neural mechanisms supporting imitation of meaningful and meaningless actions
.
J Cogn Neurosci
 .
17
:
1420
1431
.
Sakata
H
,
Taira
M
,
Kusunoki
M
,
Murata
A
,
Tanaka
Y
.
1997
.
The TINS Lecture. The parietal association cortex in depth perception and visual control of hand action
.
Trends Neurosci
 .
20
:
350
357
.
Salazar-Lopez
E
,
Schwaiger
BJ
,
Hermsdörfer
J
.
2016
.
Lesion correlates of impairments in actual tool use following unilateral brain damage
.
Neuropsychologia
 .
84
:
167
180
.
Saur
D
,
Kreher
BW
,
Schnell
S
,
Kummerer
D
,
Kellmeyer
P
,
Vry
MS
,
Umarova
R
,
Musso
M
,
Glauche
V
,
Abel
S
, et al
.
2008
.
Ventral and dorsal pathways for language
.
Proc Natl Acad Sci USA
 .
105
:
18035
18040
.
Saur
D
,
Lange
R
,
Baumgaertner
A
,
Schraknepper
V
,
Willmes
K
,
Rijntjes
M
,
Weiller
C
.
2006
.
Dynamics of language reorganization after stroke
.
Brain
 .
129
:
1371
1384
.
Schaefer
SY
,
Haaland
KY
,
Sainburg
RL
.
2009
.
Hemispheric specialization and functional impact of ipsilesional deficits in movement coordination and accuracy
.
Neuropsychologia
 .
47
:
2953
2966
.
Sirigu
A
,
Cohen
L
,
Duhamel
JR
,
Pillon
B
,
Dubois
B
,
Agid
Y
.
1995
.
A selective impairment of hand posture for object utilization in apraxia
.
Cortex
 .
31
:
41
55
.
Skipper
LM
,
Ross
LA
,
Olson
IR
.
2011
.
Sensory and semantic category subdivisions within the anterior temporal lobes
.
Neuropsychologia
 .
49
:
3419
3429
.
Stamenova
V
,
Black
SE
,
Roy
EA
.
2012
.
An update on the conceptual-production systems model of apraxia: evidence from stroke
.
Brain Cogn
 .
80
:
53
63
.
Taira
M
,
Mine
S
,
Georgopoulos
AP
,
Murata
A
,
Sakata
H
.
1990
.
Parietal cortex neurons of the monkey related to the visual guidance of hand movement
.
Exp Brain Res
 .
83
:
29
36
.
Tessari
A
,
Canessa
N
,
Ukmar
M
,
Rumiati
RI
.
2007
.
Neuropsychological evidence for a strategic control of multiple routes in imitation
.
Brain
 .
130
:
1111
1126
.
Tessari
A
,
Cubelli
R
.
2014
.
Route selection in action imitation: a matter of strategic choice
.
Cortex
 .
57
:
277
278
.
Tessari
A
,
Rumiati
RI
.
2004
.
The strategic control of multiple routes in imitation of actions
.
J Exp Psychol Hum Percept Perform
 .
30
:
1107
1116
.
Tzourio-Mazoyer
N
,
Landeau
B
,
Papathanassiou
D
,
Crivello
F
,
Etard
O
,
Delcroix
N
,
Mazoyer
B
,
Joliot
M
.
2002
.
Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain
.
Neuroimage
 .
15
:
273
289
.
Umarova
RM
,
Saur
D
,
Kaller
CP
,
Vry
MS
,
Glauche
V
,
Mader
I
,
Hennig
J
,
Weiller
C
.
2011
.
Acute visual neglect and extinction: distinct functional state of the visuospatial attention system
.
Brain
 .
134
:
3310
3325
.
Ungerleider
L
,
Mishkin
M
.
1982
.
Analysis of visual behavior
 .
Cambridge (MA)
:
MIT Press
.
Vandenberghe
R
,
Price
C
,
Wise
R
,
Josephs
O
,
Frackowiak
RS
.
1996
.
Functional anatomy of a common semantic system for words and pictures
.
Nature
 .
383
:
254
256
.
Varney
NR
,
Benton
AL
.
1982
.
Qualitative aspects of pantomime recognition defect in aphasia
.
Brain Cogn
 .
1
:
132
139
.
Villarreal
M
,
Fridman
EA
,
Amengual
A
,
Falasco
G
,
Gerschcovich
ER
,
Ulloa
ER
,
Leiguarda
RC
.
2008
.
The neural substrate of gesture recognition
.
Neuropsychologia
 .
46
:
2371
2382
.
Vingerhoets
G
.
2014
.
Contribution of the posterior parietal cortex in reaching, grasping, and using objects and tools
.
Front Psychol
 .
5
:
151
.
Visser
M
,
Embleton
KV
,
Jefferies
E
,
Parker
GJ
,
Ralph
MA
.
2010
a.
The inferior, anterior temporal lobes and semantic memory clarified: novel evidence from distortion-corrected fMRI
.
Neuropsychologia
 .
48
:
1689
1696
.
Visser
M
,
Jefferies
E
,
Lambon Ralph
MA
.
2010
b.
Semantic processing in the anterior temporal lobes: a meta-analysis of the functional neuroimaging literature
.
J Cogn Neurosci
 .
22
:
1083
1094
.
Vry
MS
,
Saur
D
,
Rijntjes
M
,
Umarova
R
,
Kellmeyer
P
,
Schnell
S
,
Glauche
V
,
Hamzei
F
,
Weiller
C
.
2012
.
Ventral and dorsal fiber systems for imagined and executed movement
.
Exp Brain Res
 .
219
:
203
216
.
Vry
MS
,
Tritschler
LC
,
Hamzei
F
,
Rijntjes
M
,
Kaller
CP
,
Hoeren
M
,
Umarova
R
,
Glauche
V
,
Hermsdoerfer
J
,
Goldenberg
G
, et al
.
2015
.
The ventral fiber pathway for pantomime of object use
.
Neuroimage
 .
106
:
252
263
.
Wang
J
,
Conder
JA
,
Blitzer
DN
,
Shinkareva
SV
.
2010
.
Neural representation of abstract and concrete concepts: a meta-analysis of neuroimaging studies
.
Hum Brain Mapp
 .
31
:
1459
1468
.
Watson
RT
,
Heilman
KM
.
1983
.
Callosal apraxia
.
Brain
 .
106
(
Pt 2
):
391
403
.
Weiller
C
,
Bormann
T
,
Kuemmerer
D
,
Musso
M
,
Rijntjes
M
.
2015
a. The dual loop model in language. In:
Hickock
GS
,
Small
SL
, editors
.
Neurobiology of language
 .
Amsterdam
:
Elsevier
. p.
325
337
.
Weiller
C
,
Bormann
T
,
Saur
D
,
Musso
M
,
Rijntjes
M
.
2011
.
How the ventral pathway got lost: and what its recovery might mean
.
Brain Lang
 .
118
:
29
39
.
Weiller
C
,
Musso
M
,
Rijntjes
M
,
Saur
D
.
2009
.
Please don't underestimate the ventral pathway in language
.
Trends Cogn Sci
 .
13
:
369
371
.
Weiller
C
,
Vry
M
,
Saur
D
,
Umarova
R
,
Rijntjes
M
.
2015
b. Remote dysfunction. In:
Toga
AW
, editor
.
Brain mapping
 .
1st ed
.
Amsterdam
:
Elsevier
. p.
813
821
.
Weiss
PH
,
Ubben
SD
,
Kaesberg
S
,
Kalbe
E
,
Kessler
J
,
Liebig
T
,
Fink
GR
.
2016
.
Where language meets meaningful action: a combined behavior and lesion analysis of aphasia and apraxia
.
Brain Struct Funct
 .
221
:
563
576
.
Woollams
AM
,
Ralph
MA
,
Plaut
DC
,
Patterson
K
.
2007
.
SD-squared: on the association between semantic dementia and surface dyslexia
.
Psychol Rev
 .
114
:
316
339
.
Zahn
R
,
Moll
J
,
Krueger
F
,
Huey
ED
,
Garrido
G
,
Grafman
J
.
2007
.
Social concepts are represented in the superior anterior temporal cortex
.
Proc Natl Acad Sci USA
 .
104
:
6430
6435
.

Supplementary data