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Clinical neuroanatomy
Dissociable spatial and non-spatial attentional deficits after circumscribed thalamic stroke Antje Kraft a,b,*, Kerstin Irlbacher a, Kathrin Finke c, Christian Kaufmann d, Stefanie Kehrer a, Daniela Liebermann a, Claus Bundesen e and Stephan A. Brandt a € tsmedizin Berlin, Berlin, Germany Department of Neurology, Charite Universita €tsmedizin Berlin, Berlin, Germany Berlin Institute of Health, Charite Universita c Department of Psychology, General and Experimental Psychology, Ludwig-Maximilians-University, Munich, Germany d € t zu Berlin, Berlin, Germany Clinical Psychology, Department of Psychology, Humboldt-Universita e Center of Visual Cognition, Department of Psychology, University of Copenhagen, Copenhagen, Denmark a
b
article info
abstract
Article history:
Thalamic nuclei act as sensory, motor and cognitive relays between multiple subcortical
Received 27 March 2014
areas and the cerebral cortex. They play a crucial role in cognitive functions such as ex-
Reviewed 26 May 2014
ecutive functioning, memory and attention. In the acute period after thalamic stroke
Revised 25 June 2014
attentional deficits are common. The precise functional relevance of specific nuclei or
Accepted 8 December 2014
vascular sub regions of the thalamus for attentional sub functions is still unclear. The
Action editor Marco Catani
theory of visual attention (TVA) allows the measurement of four independent attentional
Published online 30 December 2014
parameters (visual short term memory storage capacity (VSTM), visual perceptual processing speed, selective control and spatial weighting). We combined parameter-based
Keywords:
assessment based on TVA with lesion symptom mapping in standard stereotactic space
Thalamic infarction
in sixteen patients (mean age 41.2 ± 11.0 SD, 6 females), with focal thalamic lesions in the
TVA
medial (N ¼ 9), lateral (N ¼ 5), anterior (N ¼ 1) or posterior (N ¼ 1) vascular territories of the
Vascular syndromes
thalamus. Compared with an age-matched control group of 52 subjects (mean age
Visual attention deficits
40.1 ± 6.4, 35 females), the patients with thalamic lesions were, on the group level, mildly
Visual processing speed
impaired in visual processing speed and VSTM. Patients with lateral thalamic lesions showed a deficit in processing speed while all other TVA parameters were within the normal range. Medial thalamic lesions can be associated with a spatial bias and extinction of targets either in the ipsilesional or the contralesional field. A posterior case with a thalamic lesion of the pulvinar replicated a finding of Habekost and Rostrup (2006), demonstrating a spatial bias to the ipsilesional field, as suggested by the neural theory of visual attention (NTVA) (Bundesen, Habekost, & Kyllingsbæk, 2011). A case with
Abbreviations: ACC, anterior cingulate cortex; DLPFC, dorsolateral prefrontal cortex; FEF, frontal eye field; MR, magnetic resonance; LGN, lateral geniculate nucleus; MWT-B, Mehrfachwahl-Wortschatz-Intelligenz-Test; NTVA, neural theory of visual attention; PPC, posterior parietal cortex; ROCF, Rey-Ostherrieth Complex Figure Test; RWT, Regensburger-Wortflu¨ssigkeits-Test; SD, standard deviation; TPJ, temporal parietal junction; TVA, theory of visual attention; VBM, voxel-based morphormetry; VOI, volume of interest; VSTM, visual short term memory; WCST, Wisconsin Card Sorting Test. Universita € tsmedizin Berlin, Charite platz 1, 10117 Berlin, Germany. * Corresponding author. Department of Neurology, Charite E-mail address: [email protected] (A. Kraft). http://dx.doi.org/10.1016/j.cortex.2014.12.005 0010-9452/© 2015 Elsevier Ltd. All rights reserved.
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an anterior-medial thalamic lesion showed reduced selective attentional control. We conclude that lesions in distinct vascular sub regions of the thalamus are associated with distinct attentional syndromes (medial ¼ spatial bias, lateral ¼ processing speed). © 2015 Elsevier Ltd. All rights reserved.
1.
Introduction
The thalamus is thought to be the gate to consciousness and is involved in nearly all behavioral functions. It is a critical component of cortical-basal ganglia-thalamic circuits that mediate planning and cognition, motivation, and emotional drive and the expression of goal-directed behaviors (Haber & McFarland, 2001). The thalamus consists of a large number of nuclei, which can be well displayed with the digital line drawings of Anne Morel's stereotactic atlas (Morel, 2007). The nuclei are mainly supplied by four distinct arteries: tuberothalamic artery, paramedian artery, inferolateral artery and posterior choroidal artery. However, it is difficult to define which nuclei in the human thalamus mediate specific cognitive functions, as lesions of the thalamus are typically large and encompass multiple nuclei (Van der Werf et al., 1999). So far, few researchers have investigated a sufficient number of patients with small thalamic lesions to make it possible to ascribe specific behavioral changes to lesions in circumscribed vascular territories or nuclei within the human thalamus (e.g., Liebermann, Ploner, Kraft, Kopp, & Ostendorf, 2013). Recent studies (e.g., Carrera & Bogousslavsky, 2006; Nolte, Endres, & Jungehu¨lsing, 2011; Schmahmann, 2003) which made comparisons of cases with different lesion localisations, suggest that characteristic behavioral changes after thalamic lesions can be delineated on the basis of the four vascular territories (i.e., vascular syndromes of the thalamus). In the acute period the rare cases with isolated anterior (tubero) thalamic infarction showed an “anterior behavioral syndrome” with apathy, amnesia and perseveration or executive dysfunction. Paramedian infarction is associated with a decreased level of consciousness, gaze paresis and cognitive impairment, such as disinhibited behavior or amnesia, while inferolateral infarction results in ataxia and hemihypesthesia. Isolated posterior choroidal infarction is also extremely rare. For the few cases with posterior choroidal infarction, visual field defects and neglect were observed (Habekost & Rostrup, 2006; Karnath, Himmelbach, & Rorden, 2002; Nolte et al., 2011). These distinct vascular syndromes of the thalamus occur because specific regions of the thalamus are connected with specific areas of each basal ganglia structure and specific cortical regions. For example, the frontal eye field (FEF) and the dorsolateral prefrontal cortex (DLPFC) are connected with the corpus of the caudate nucleus and the ventral lateral and mesial part of the mediodorsal nucleus of the thalamus, thus resulting in gaze paresis and cognitive impairment after paramedian infarction. However, recent data indicate that the thalamus not only relays information back to the cortex, but may also serve as an important center of integration of networks that underlie the ability to modulate behavior (Haber & McFarland, 2001). For example, the “attention network”,
involves multiple cortical areas [DLPFC, FEF, anterior cingulate cortex (ACC), posterior parietal cortex (PPC), temporo-parietal junction (TPJ)] and structures of the basal ganglia (caudate nucleus, putamen) that are connected with specific nuclei of the thalamus (ventral anterior nucleus, mediodorsal nucleus, ventral lateral nucleus, pulvinar). It has not yet been clarified whether distinct attentional deficits (e.g., bias in spatial weighting, reduced/enhanced selective control, reduced processing speed) can be observed if specific nuclei/vascular territories of the thalamus are lesioned. Bundesen and colleagues have proposed a thalamic model for the theory of attention (TVA, Bundesen, 1990) called “neural theory of attention” (NTVA) which is mainly built upon neurophysiological findings in macaque monkeys (Bundesen, Habekost, & Kyllingsbæk, 2005; Bundesen et al., 2011). According to NTVA, visual information is first processed in an unselective wave from the retina to the lateral geniculate nucleus (LGN) of the thalamus and then to the striate and extrastriate visual cortex. In the cortex, individual perceptual values for each object are computed and multiplied by pertinence values. The information then enters the pulvinar nucleus of the thalamus where a saliency map is located and products are summed up as attentional weights. Weighted information is then processed in a second selective wave from the pulvinar to higher level visual processing areas in the cortex. The resulting perceptual values are multiplied by bias values, and the products are then transmitted from the cortex to the thalamic reticular nucleus (TRN) where a visual short term memory storage capacity (VSTM) map of locations is localized. TVA is a mathematical model which allows disentangling four independent attention parameters: Using whole and partial report paradigm allows measuring of the perceptual processing speed, VSTM, selective control and the spatial distribution of attentional weights reliably in normal participants, as well as in neurological patients, such as patients suffering from stroke (Duncan, et al., 1999) or Huntington's disease (Finke, Bublak, Dose, Mu¨ller, & Schneider, 2006). In recent years the TVA-based methodology has been used to investigate selective attention deficits after persistent and transient lesions of cortical sub regions, revealing that lesions in the entire cortical attention network consisting of the FEF, the middle frontal gyrus, the DLPFC, the TPJ, posterior PPC and inferior parietal regions lead to selective attention deficits in TVA parameters (Bublak et al., 2005; Duncan et al., 1999; Finke et al., 2006; Habekost & Bundesen, 2003; Habekost & Rostrup, 2006, 2007; Peers et al., 2005, see Habekost & Starrfelt, 2009 for a review). So far, distinct thalamic lesions have not been investigated with the TVA-based methodology. However, a number of studies report attentional deficits after thalamic or basal
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ganglia lesions. For example neglect or spatial bias has been repeatedly reported after lesions of the caudate nucleus and putamen and the ventral nuclei of the thalamus (Fimm et al., 2001; Finke et al., 2006; Habekost & Rostrup, 2006; Karnath et al., 2002), as well as after lesion of the pulvinar (Habekost & Rostrup, 2006; Karnath et al., 2002). Executive deficits (and complex attentional deficits) have been associated with lesions of the intralaminar nuclei and the mediodorsal nucleus by Van der Werf and colleagues (Van der Werf et al., 2003) and Liebermann et al. (2013). Patients with lesions of the putamen showed reductions of processing speed (Finke et al., 2006; Habekost & Rostrup, 2006). Congruent with the NTVA model Habekost and Rostrup (2006) found a spatial bias to the ipsilesional field in one patient with a focal damage in the right pulvinar nucleus of the thalamus. The aim of the study was to test if very circumscribed damage to distinct nuclei of the thalamus leads to specific attention deficits. For this purpose, we combined parameterbased assessment of TVA (Finke et al., 2005) with lesion symptom mapping in standard stereotactic space in patients with focal thalamic lesions in the medial, lateral, anterior or posterior vascular territories of the thalamus. A previous study (Van der Werf et al., 2003) has shown that it is highly relevant to check whether patients with thalamic lesions have additional structural damage, as additional lesions (e.g., white matter lesions) can explain variance in neuropsychological deficits between patients (Habekost & Rostrup, 2006). To exclude this possibility, we only considered patients with pure thalamic damage.
2.
Method
2.1.
Participants
An overall number of sixteen patients (mean age 41.2 ± 11.0 SD, 6 females) with the diagnosis thalamus infarction as evidenced by high resolution MRI scans participated in this study. Patients were recruited at the Department of Neurology, Universita € tsmedizin (Berlin, Germany) and at the Charite Stroke Unit of the Medical Hospital Gesundheit Nord Klinikum Bremen-Mitte (Bremen, Germany). Patients were included with an age 14.48] in TVA. The images are thresholded at 15%, i.e., only regions affected in at least 15% of patients are displayed. Overlay plots of the superimposed lesions of processing speed deficient (N ¼ 6) minus normal group (N ¼ 9) is illustrated in blue colors (dark blue difference 15% to green difference 100%); overlay plots of the superimposed lesions of processing speed normal (N ¼ 9) minus deficient group (N ¼ 6) is illustrated in red colors (dark red difference 15% to light yellow difference 100%). The upper panel illustrates one coronal and axial section, the lower panel illustrates seven coronal sections from anterior to posterior. Note that left-sided lesions are flipped to the right side.
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Fig. 5 e Spatial attentional weighting. A) Example of one patient with deficient spatial weighting. Bars indicate partial report performance for ipsilesional targets (left diagram) or contralesional targets (right diagram), respectively. The deficit is indicated with black arrows. B) Overlay lesion plots of patients with deficient [wl < .45 or wl > .59] or normal spatial weighting [.45 < wl < .59] in TVA. The images are thresholded at 15%, i.e., only regions affected in at least 15% of patients are displayed. Overlay plots of the superimposed lesions of spatial weighting deficient (N ¼ 5) minus normal group (N ¼ 10) is illustrated in blue colors (dark blue difference 15% to green difference 100%); overlay plots of the superimposed lesions of spatial weighting normal (N ¼ 10) minus deficient group (N ¼ 5) is illustrated in red colors (dark red difference 15% to light yellow difference 100%). The upper panel illustrates one coronal and axial section, the lower panel illustrates seven coronal sections from anterior to posterior. Note that left-sided lesions are flipped to the right side.
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visual field and furthermore, extinction for contralesional targets if targets were presented across hemifields. However, the patient showed normal performance if two targets were presented in the contralesional visual field, which indicates that the patient had no basic perceptual deficit within the contralesional visual field. Overall five patients had a deficit in spatial weighting (four had left-sided lesions, one had a rightsided lesion). Four patients showed a bias to the ipsilesional side while one patient had a bias to the contralesional side. Ten patients showed no spatial bias (one patient did not participate in the partial report task). TSL and age did not differ between patients with no spatial bias or patients with a deficit in spatial weighting [TSL: t(13) ¼ .52; p > .05; age: t(13) ¼ .32; p > .05]. Subtraction analysis revealed that lesions of patients with a lateral bias in spatial weighting are more medial or posterior compared to patients with normal spatial weighting (see Fig. 5B). In line with this finding VBM analysis showed a greater amount of grey matter in the left medial dorsal nucleus (MNI peak coordinate 3 16 13 at an uncorrected p-value of .001, k ¼ 214, t-value 3.54) for patients without spatial bias as compared to patients with spatial bias (see Fig. 6B). VBM on the whole brain level revealed no significant results at an uncorrected p-value of .001 (with extent threshold k > 200), presumably due to the small sample size within the subgroups.
3.5.
Neuropsychological results
Table 5 depicts the results of neuropsychological testing. As also reported previously in the study of Liebermann et al. (2013), some patients showed a deficit in memory tests (three in ROCF immediate recall, three in ROCF delayed recall, three in digit span, five in block span). Moreover, six patients showed a deficit in at least one measure of the WCST. Voxelbased lesion to symptom mapping for WCST deficient vs. normal is reported in Liebermann et al. (2013).
4.
Discussion
TVA-based assessment revealed selective, dissociated attention deficits after focal thalamic stroke in distinct vascular territories. We found a specificity of deficits if distinct thalamic nuclei were affected: In patients with lateral lesions, visual processing speed was reduced. In contrast, patients with medial lesions did not show a reduction of visual processing speed. However, some patients with medial lesions showed a spatial bias to the ipsilesional or contralesional field. Two single cases with anterior or posterior thalamic lesions respectively, indicate a variation of attentional selective control. These findings will be discussed in the following sections with respect to prior data on consequences of thalamic lesions on attentional functions. Furthermore, it will be discussed how they relate to the theoretical framework provided by NTVA, its explicit suggestions on the neuronal implementation of the various attentional parameters proposed within the human brain and, especially, whether they fit into the NTVA assumption of the role of thalamic structures on attentional processing.
Fig. 6 e VBM analysis results. (A) Visual processing speed. One coronal section is illustrated, showing a greater amount of grey matter in the left anterior medial thalamus [MNI peak coordinate ¡2, ¡2, 2 at an uncorrected p-value of .001; t-values are depicted from 2 (red) to 4 (white)] for patients with reduced processing speed as compared to patients with intact processing speed. (B) Spatial attentional weighting. One coronal section is illustrated, showing a greater amount of grey matter in the left medial dorsal nucleus [MNI peak coordinate ¡3 ¡16 13 at an uncorrected p-value of .001; t-values are depicted from 2 (red) to 3.8 (white)] for patients without spatial bias as compared to patients with spatial bias.
Earlier patient studies described attentional deficits following thalamic lesions. A complex attention deficit has been associated with lesions of the intralaminar nuclei (Van der Werf et al., 2003), which also lead to executive deficits (Liebermann et al., 2013; Van der Werf et al., 2003). Some studies reported a spatial bias after lesion of the pulvinar (Habekost & Rostrup, 2006; Karnath et al., 2002). So far, different selective attention deficits that are resulting from circumscribed lesions to distinct regions of the thalamus have not been described and compared.
Table 5 e Neuropsychological Testing. Line bisection (1 ¼ normal, 2 ¼ deficient), line cancellation (1 ¼ normal, 2 ¼ deficient), ROCF copy (percentile rank, PR), ROCF immediate recall (PR), ROCF delayed recall, digit span forward (PR), digit span backward (PR), block span forward (PR), block span (PR), Demtect (18e13 ¼ normal, 12e9 ¼ mild cognitive impairment, ≤ 8 ¼ dementia suspicion), Stroop (1 ¼ normal, 2 ¼ deficient in at least one Stroop measure), RWT lexical 1 min (PR), RWT lexical 2 min (PR), RWT semantic 1 min (PR), RWT semantic 2 min (PR), WCST (1 ¼ normal in all WCST measures, 2 ¼ deficient in at least one WCST measure).
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4.1.
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Spatial attentional weighting
The spatial bias to the ipsilesional field in our patient with a posterior (pulvinar) lesion is congruent to the finding of Habekost and Rostrup (2006) and the NTVA model (Bundesen et al., 2005). Note that the patient of Habekost and Rostrup (2006) has a right-sided pulvinar lesion while our patient has a left-sided pulvinar lesion. While the patient of Habekost and Rostrup (2006) showed a bias to the right, our patient showed a bias to the left side. The spatial bias after medial thalamic lesions can be consistent with a previous study reporting attention deficits after paramedian lesions in one third of all patients (Hermann et al., 2008). Attention deficits occurred especially after leftsided or bilateral lesions, but the type of attentional deficit was not further specified in this study. Spatial deficits in eye movements after lesion of the medial thalamic nuclei are described both in patients (e.g., Ostendorf, Liebermann, & Ploner, 2010), as well as in primates (e.g., Sommer & Wurtz, 2008; Tanaka, 2007). The finding that some patients had an ipsilesional bias while others had a contralesional bias is consistent with electrophysiological work in primates by Tanaka (2007) that activity at the central thalamic level can represent both ipsi- and contralateral space. As described in the introduction, the medial thalamus is connected with the FEF, DLPFC, ACC and orbitofrontal cortex via connections of the caudate nucleus and the putamen (Haber & McFarland, 2001). Thalamo-cortical disconnection between these areas could also lead to deficits in spatial weighting, as these cortical structures are known to be involved in mechanism of spatial attention (Corbetta, Patel, & Shulman, 2008 for an overview).
4.2.
Selective attentional control
Our single case finding indicates that a pulvinar lesion can also result in changes of selective attentional control. This is congruent with the NTVA (Bundesen et al., 2005), as well as current studies investigating the functional role of the pulvinar in healthy subjects using functional brain imaging (Rotshtein, Soto, Grecucci, Geng, & Humphreys, 2011; Strumpf et al., 2013) or diffusion tensor imaging (Saalman, Pinsk, Wang, Li, & Kastner, 2012), suggesting that the pulvinar is involved in selective visual attention processes (e.g., distractor filtering). However, in our case selective control was actually enhanced, resulting in particularly focused visual processing. Other studies reported deficits in feature binding (Ward, Danziger, Owen, & Rafal, 2002) and spatial selection (Snow, Allen, Rafal, & Humphreys, 2009) reflecting that pulvinar lesions can also have the opposite effect, i.e., reduce the degree of top-down control in processing. Moreover, our single case with an anterior medial lesion showed such a reduction of selective attentional control. Future studies with a larger number of patients with anterior and posterior thalamic lesions are needed to replicate our findings. Moreover, it should be tested to determine in which attentional paradigms patients with pulvinar lesion show deficits (e.g., TVA partial report vs. distinct visual search tasks). Further, it is known that the pulvinar is connected via the caudate nucleus and the putamen with the PPC and occipito-
temporal areas (Bundesen et al., 2005; Haber & McFarland, 2001) and that the anterior medial nuclei are connected via the caudate nucleus and the putamen with the DLPFC (Haber & McFarland, 2001). Thalamo-cortical disconnection of these structures could result in enhanced/reduced selective attentional control, as these cortical areas are involved in distractor filtering, feature binding and selective spatial attention (Corbetta et al., 2008 for an overview).
4.3.
Visual perceptual processing speed
Our results clearly show that patients with thalamic lesions are not generally slowed in visual attentional processing. Instead, visual attentional processing speed reductions occurred especially after lateral lesions of the thalamus. This finding is not reported previously in the literature. Congruent with previous TVA-based studies investigating TVA capacity parameters after cortical lesions, processing speed reductions occur in both the ipsi- and contralesional field (Duncan et al., 1999; Habekost & Rostrup, 2006, 2007). Moreover, it is known that processing speed in TVA is reduced in patients with basal ganglia lesions (Huntington's disease; Finke et al., 2006) and in patients with white matter lesions (Habekost & Rostrup, 2006). The etiology of lateral thalamic lesions is oftentimes microangiopathic accompanied by white matter lesions in the whole brain, but these patients were excluded from the present study. Lateral lesions can lead to hemiataxia and a “thalamic hand”ea choreodystonic type of involuntary movement due to impaired proprioception (Foix & Hillemand, 1925; Carrera & Bogousslavsky, 2006), which might impair motor responses and, thus, reaction times. In TVA however, the estimation of visual processing speed is not confounded by motor speed and, therefore the reduction in visual processing speed cannot be explained by a motor deficit. Furthermore it cannot be explained by medication sideeffects, as we also excluded patients under neurological or psychiatric medication that might lead to attentional slowing.
4.4.
VSTM storage capacity
None of our patients showed a significant reduction in VSTM, as tested by TVA. However, as in the study of Van der Werf et al. (2003) some patients showed memory deficits in further neuropsychological testing, but these deficits were not associated with a specific area in the thalamus. In TVA, the parameters VSTM storage capacity and processing speed are defined as independent, though it has been shown that the parameters correlate about .40 empirically (Finke et al., 2005). This finding was replicated in our control group. However, alertness manipulation studies in healthy subjects showed visual processing speed can be enhanced via cueing without necessarily affecting VSTM capacity (Matthias et al., 2010; Vangkilde, Coull, & Bundesen, 2012), suggesting a certain degree of independence between these parameters. In stroke patients with cortical lesions both parameters were often affected, suggesting overlapping cortical networks (Habekost & Rostrup, 2006; Peers et al., 2005). The fact that this is different in thalamic lesions, i.e., our finding of a dissociation between impaired visual processing speed and preserved VSTM storage capacity suggests that these parameters rely on
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the integrity of distinct thalamic structures. Accordingly, we found no significant correlation between the parameters in the patient group.
4.5.
Limitations of the study
Due to the resolution of MR imaging, the delineation of the boundaries of a lesion and classification of lesion is rather approximate than exact. The period of time from when the lesion occurred varied in the present study. Recovery of symptoms occurs after stroke especially in the first six month after infarction. While severe attention deficits in the acute period of thalamic stroke are well known, the present study shows that subtle attentional deficits can persist into the chronic stage after stroke. In future studies it would be interesting to differentiate between acute, sub-acute and chronic attentional deficits using a follow-up design. We only included patients without white matter lesions or other lesions in the brain. Given these selection criteria the mean age of our patient group was 42.1 years. This is below the common age for thalamic stroke. Our study shows that TVA allows the detection of selective deficits after focal thalamic lesions. A larger sample of patients, especially those with anterior and posterior lesions, is necessary in order to ascribe specific visual attentional deficits to specific thalamic nuclei on a robust statistical level. A larger sample of patients would also allow a differentiation of attentional deficits between left-sided and right-sided lesion in specific thalamic sub regions.
4.6.
Conclusion
We conclude from our data that not only the “visual thalamus” (LGN, pulvinar and TRN, see Bundesen et al., 2005; Saalmann & Kastner, 2011) is relevant for distinct parameters of visual attention such as visual processing speed, VSTM, selective attentional control and spatial attentional weighting. Instead also anterior, medial and lateral nuclei of thalamus are relevant and lead to distinct visual attentional deficits if damaged. This is plausible, as anterior, lateral, medial and posterior nuclei of the thalamus are connected via cortical-basal ganglia circuits with cortical areas such as the FEF, DLPFC, ACC, PPC and occipital-temporal cortex that are involved in visual attentional subprocesses. In our opinion, lesion-symptom mapping and VBM analysis in a larger sample of patients with circumscribed lesions in distinct vascular territories of the thalamus will further expand our knowledge on attentional deficits and their anatomical relationships to distinct thalamic nuclei. A larger sample would allow statistical voxelbased lesion-symptom mapping on the basis of continuous behavioral data as described by Bates et al. (2003) or Rorden et al. (2007). Moreover, lesion of the four vascular thalamic territories may lead to a very different hypo-metabolism of cortical areas of the brain (i.e., diaschisis) due to distinct thalamo-cortical networks (Schmahmann, 2003). In the present study, a VBM analysis computed on the whole brain level revealed no significant changes. However, a larger sample of subjects or the use of positron emission tomography (PET) might be necessary to illustrate depressed levels of metabolic
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activity in cortical areas after discrete thalamic lesion in different vascular territories. Further insight might be gained by investigating changes in thalamo-cortical networks after circumscribed thalamic lesions using diffusion tensor imaging. Moreover, it would be interesting to evaluate if a specific involvement of distinct thalamic nuclei for subprocesses of attention can be generalized to other sensory modalities such as acoustic attention or somatosensory attention.
Funding This work was supported by the Deutsche Forschungsgemeinschaft (BR 1691/3-3 and IR 48/2-2 in FOR 778/1-1).
Acknowledgments We thank C. Grimsen for recruitment of one patient at the University of Bremen. We thank J. England for corrections to the English text.
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circumscribed subcortical vascular lesions. Journal of Neurology, Neurosurgery & Psychiatry, 71(5), 652e657. Finke, K., Bublak, P., Dose, M., Mu¨ller, H. J., & Schneider, W. X. (2006). Parameter-based assessment of spatial and non-spatial attentional deficits in Huntington's disease. Brain, 129(Pt 5), 1137e1151. Finke, K., Bublak, P., Krummenacher, J., Kyllingsbaek, S., Muller, H. J., & Schneider, W. X. (2005). Usability of a theory of visual attention (TVA) for parameter-based measurement of attention I: evidence from normal subjects. Journal of the International Neuropsychological Society, 11(7), 832e842. res de la xe ence phalique Foix, C., & Hillemand, P. (1925). Les arte phale incluisment. Revue neurologique (Paris), 2, jusqu’au dience 705e739. Habekost, T., & Bundesen, C. (2003). Patient assessment based on a theory of visual attention (TVA): subtle deficits after a right frontal-subcortical lesion. Neuropsychologia, 41(9), 1171e1188. Habekost, T., & Rostrup, E. (2006). Persisting asymmetries of vision after right side lesions. Neuropsychologia, 44(6), 876e895. Habekost, T., & Rostrup, E. (2007). Visual attention capacity after right hemisphere lesions. Neuropsychologia, 45(7), 1474e1488. Habekost, T., & Starrfelt, R. (2009). Visual attention capacity: a review of TVA-based patient studies. Scandinavian Journal of Psychology, 50(1), 23e32. Haber, S., & McFarland, N. R. (2001). The place of the thalamus in frontal cortical-basal ganglia circuits. Neuroscientist, 7(4), 315e324. Heaton, R. K., Chelune, G. J., Talley, J. L., Kay, G. G., & Curtiss, G. (1993). Wisconsin card sorting test manual. Odessa, FL: Psychological Assessment Resources. Hermann, D. M., Siccoli, M., Brugger, P., Wachter, K., Mathis, J., Achermann, P., et al. (2008). Evolution of neurological, neuropsychological and sleep-wake disturbances after paramedian thalamic stroke. Stroke, 39(1), 62e68. Ishihara, S. (1917). Tests for colour-blindness. Handaya, Tokyo: Hongo Harukicho. Kalbe, E., Kessler, J., Calabrese, P., Smith, R., Passmore, A. P., Brand, M., et al. (2004). DemTect: a new, sensitive cognitive screening test to support the diagnosis of mild cognitive impairment and early dementia. International Journal of Geriatric Psychiatry, 19(2), 136e143. Karnath, H. O., Himmelbach, M., & Rorden, C. (2002). The subcortical anatomy of human spatial neglect: putamen, caudate nucleus and pulvinar. Brain, 125(Pt 2), 350e360. Lehrl, S. (1977). Mehrfachwahl-Wortschatz-intelligenztest MWT-B. Balingen: Spitta Verlag. Liebermann, D., Ploner, C. J., Kraft, A., Kopp, U. A., & Ostendorf, F. (2013). A dysexecutive syndrome of the medial thalamus. Cortex, 49(1), 40e49. Matthias, E., Bublak, P., Mu¨ller, H. J., Schneider, W. X., Krummenacher, J., & Finke, K. (2010). The influence of alertness on spatial and nonspatial components of visual attention. Journal of Experimental Psychology: Human Perception and Performance, 36(1), 38e56. Morel, A. (2007). Stereotactic atlas of the human thalamus and basal ganglia. New York: Informa Healthcare. Nichols, T. E., & Holmes, A. P. (2002). Nonparametric permutation tests for functional neuroimaging: a primer with examples. Human Brain Mapping, 15(1), 1e25. Nolte, C. H., Endres, M., & Jungehu¨lsing, G. J. (2011). Vascular syndromes of the thalamus. Nervenarzt, 82(2), 231e241 (German).
Oldfield, R. C. (1971). The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia, 9, 97e113. Ostendorf, F., Liebermann, D., & Ploner, C. J. (2010). Human thalamus contributes to perceptual stability across eye movements. Proceedings of the National Academy of Sciences of the United States of America, 107(3), 1229e1234. Peers, P. V., Ludwig, C. J., Rorden, C., Cusack, R., Bonfiglioli, C., Bundesen, C., et al. (2005). Attentional functions of parietal and frontal cortex. Cerebral Cortex, 15(10), 1469e1484. Rey, A. (1941). L'examen psychologique dans les cas d’encephalopathie traumatique. Archives de Psychologie, 28, 286e340. Rorden, C., Karnath, H. O., & Bonilha, L. (2007). Improving lesionsymptom mapping. Journal of Cognitive Neuroscience, 19(7), 1081e1088. Rotshtein, P., Soto, D., Grecucci, A., Geng, J. J., & Humphreys, G. W. (2011). The role of the pulvinar in resolving competition between memory and visual selection: a functional connectivity study. Neuropsychologia, 49(6), 1544e1552. Saalmann, Y. B., & Kastner, S. (2011). Cognitive and perceptual functions of the visual thalamus. Neuron, 71(2), 209e223. Saalmann, Y. B., Pinsk, M. A., Wang, L., Li, X., & Kastner, S. (2012). The pulvinar regulates information transmission between cortical areas based on attention demands. Science, 337(6095), 753e756. Schmahmann, J. D. (2003). Vascular syndromes of the thalamus. Stroke, 34(9), 2264e2278. Snow, J. C., Allen, H. A., Rafal, R. D., & Humphreys, G. W. (2009). Impaired attentional selection following lesions to human pulvinar: evidence for homology between human and monkey. Proceedings of the National Academy of Sciences of the United States of America, 106(10), 4054e4059. Sommer, M. A., & Wurtz, R. H. (2008). Brain circuits for the internal monitoring of movements. Annual Review of Neuroscience, 31, 317e338. Sperling, G. (1960). The information available in brief visual presenations. Psychological monographs, 74, 11. Strumpf, H., Mangun, G. R., Boehler, C. N., Stoppel, C., Schoenfeld, M. A., Heinze, H. J., et al. (2013). The role of the pulvinar in distractor processing and visual search. Human Brain Mapping, 34(5), 1115e1132. Tanaka, M. (2007). Spatiotemporal properties of eye position signals in the primate central thalamus. Cerebral Cortex, 17(7), 1504e1515. Vangkilde, S., Coull, J. T., & Bundesen, C. (2012). Great expectations: temporal expectation modulates perceptual processing speed. Journal of Experimental Psychology: Human Perception and Performance, 38(5), 1183e1191. Van der Werf, Y. D., Scheltens, P., Lindeboom, J., Witter, M. P., Uylings, H. B., & Jolles, J. (2003). Deficits of memory, executive functioning and attention following infarction in the thalamus; a study of 22 cases with localised lesions. Neuropsychologia, 41(10), 1330e1344. Van der Werf, Y. D., Weerts, J. G., Jolles, J., Witter, M. P., Lindeboom, J., & Scheltens, P. (1999). Neuropsychological correlates of a right unilateral lacunar thalamic infarction. Journal of Neurology, Neurosurgery & Psychiatry, 66(1), 36e42. Ward, R., Danziger, S., Owen, V., & Rafal, R. (2002). Deficits in spatial coding and feature binding following damage to spatiotopic maps in the human pulvinar. Nature Neuroscience, 5(2), 99e100. Wechsler, D. (1987). Wechsler memory scale e revised edition. Manual. New York: The Psychological Corporation.
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Clinical neuroanatomy
Dissociable spatial and non-spatial attentional deficits after circumscribed thalamic stroke Antje Kraft a,b,*, Kerstin Irlbacher a, Kathrin Finke c, Christian Kaufmann d, Stefanie Kehrer a, Daniela Liebermann a, Claus Bundesen e and Stephan A. Brandt a € tsmedizin Berlin, Berlin, Germany Department of Neurology, Charite Universita €tsmedizin Berlin, Berlin, Germany Berlin Institute of Health, Charite Universita c Department of Psychology, General and Experimental Psychology, Ludwig-Maximilians-University, Munich, Germany d € t zu Berlin, Berlin, Germany Clinical Psychology, Department of Psychology, Humboldt-Universita e Center of Visual Cognition, Department of Psychology, University of Copenhagen, Copenhagen, Denmark a
b
article info
abstract
Article history:
Thalamic nuclei act as sensory, motor and cognitive relays between multiple subcortical
Received 27 March 2014
areas and the cerebral cortex. They play a crucial role in cognitive functions such as ex-
Reviewed 26 May 2014
ecutive functioning, memory and attention. In the acute period after thalamic stroke
Revised 25 June 2014
attentional deficits are common. The precise functional relevance of specific nuclei or
Accepted 8 December 2014
vascular sub regions of the thalamus for attentional sub functions is still unclear. The
Action editor Marco Catani
theory of visual attention (TVA) allows the measurement of four independent attentional
Published online 30 December 2014
parameters (visual short term memory storage capacity (VSTM), visual perceptual processing speed, selective control and spatial weighting). We combined parameter-based
Keywords:
assessment based on TVA with lesion symptom mapping in standard stereotactic space
Thalamic infarction
in sixteen patients (mean age 41.2 ± 11.0 SD, 6 females), with focal thalamic lesions in the
TVA
medial (N ¼ 9), lateral (N ¼ 5), anterior (N ¼ 1) or posterior (N ¼ 1) vascular territories of the
Vascular syndromes
thalamus. Compared with an age-matched control group of 52 subjects (mean age
Visual attention deficits
40.1 ± 6.4, 35 females), the patients with thalamic lesions were, on the group level, mildly
Visual processing speed
impaired in visual processing speed and VSTM. Patients with lateral thalamic lesions showed a deficit in processing speed while all other TVA parameters were within the normal range. Medial thalamic lesions can be associated with a spatial bias and extinction of targets either in the ipsilesional or the contralesional field. A posterior case with a thalamic lesion of the pulvinar replicated a finding of Habekost and Rostrup (2006), demonstrating a spatial bias to the ipsilesional field, as suggested by the neural theory of visual attention (NTVA) (Bundesen, Habekost, & Kyllingsbæk, 2011). A case with
Abbreviations: ACC, anterior cingulate cortex; DLPFC, dorsolateral prefrontal cortex; FEF, frontal eye field; MR, magnetic resonance; LGN, lateral geniculate nucleus; MWT-B, Mehrfachwahl-Wortschatz-Intelligenz-Test; NTVA, neural theory of visual attention; PPC, posterior parietal cortex; ROCF, Rey-Ostherrieth Complex Figure Test; RWT, Regensburger-Wortflu¨ssigkeits-Test; SD, standard deviation; TPJ, temporal parietal junction; TVA, theory of visual attention; VBM, voxel-based morphormetry; VOI, volume of interest; VSTM, visual short term memory; WCST, Wisconsin Card Sorting Test. Universita € tsmedizin Berlin, Charite platz 1, 10117 Berlin, Germany. * Corresponding author. Department of Neurology, Charite E-mail address: [email protected] (A. Kraft). http://dx.doi.org/10.1016/j.cortex.2014.12.005 0010-9452/© 2015 Elsevier Ltd. All rights reserved.
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an anterior-medial thalamic lesion showed reduced selective attentional control. We conclude that lesions in distinct vascular sub regions of the thalamus are associated with distinct attentional syndromes (medial ¼ spatial bias, lateral ¼ processing speed). © 2015 Elsevier Ltd. All rights reserved.
1.
Introduction
The thalamus is thought to be the gate to consciousness and is involved in nearly all behavioral functions. It is a critical component of cortical-basal ganglia-thalamic circuits that mediate planning and cognition, motivation, and emotional drive and the expression of goal-directed behaviors (Haber & McFarland, 2001). The thalamus consists of a large number of nuclei, which can be well displayed with the digital line drawings of Anne Morel's stereotactic atlas (Morel, 2007). The nuclei are mainly supplied by four distinct arteries: tuberothalamic artery, paramedian artery, inferolateral artery and posterior choroidal artery. However, it is difficult to define which nuclei in the human thalamus mediate specific cognitive functions, as lesions of the thalamus are typically large and encompass multiple nuclei (Van der Werf et al., 1999). So far, few researchers have investigated a sufficient number of patients with small thalamic lesions to make it possible to ascribe specific behavioral changes to lesions in circumscribed vascular territories or nuclei within the human thalamus (e.g., Liebermann, Ploner, Kraft, Kopp, & Ostendorf, 2013). Recent studies (e.g., Carrera & Bogousslavsky, 2006; Nolte, Endres, & Jungehu¨lsing, 2011; Schmahmann, 2003) which made comparisons of cases with different lesion localisations, suggest that characteristic behavioral changes after thalamic lesions can be delineated on the basis of the four vascular territories (i.e., vascular syndromes of the thalamus). In the acute period the rare cases with isolated anterior (tubero) thalamic infarction showed an “anterior behavioral syndrome” with apathy, amnesia and perseveration or executive dysfunction. Paramedian infarction is associated with a decreased level of consciousness, gaze paresis and cognitive impairment, such as disinhibited behavior or amnesia, while inferolateral infarction results in ataxia and hemihypesthesia. Isolated posterior choroidal infarction is also extremely rare. For the few cases with posterior choroidal infarction, visual field defects and neglect were observed (Habekost & Rostrup, 2006; Karnath, Himmelbach, & Rorden, 2002; Nolte et al., 2011). These distinct vascular syndromes of the thalamus occur because specific regions of the thalamus are connected with specific areas of each basal ganglia structure and specific cortical regions. For example, the frontal eye field (FEF) and the dorsolateral prefrontal cortex (DLPFC) are connected with the corpus of the caudate nucleus and the ventral lateral and mesial part of the mediodorsal nucleus of the thalamus, thus resulting in gaze paresis and cognitive impairment after paramedian infarction. However, recent data indicate that the thalamus not only relays information back to the cortex, but may also serve as an important center of integration of networks that underlie the ability to modulate behavior (Haber & McFarland, 2001). For example, the “attention network”,
involves multiple cortical areas [DLPFC, FEF, anterior cingulate cortex (ACC), posterior parietal cortex (PPC), temporo-parietal junction (TPJ)] and structures of the basal ganglia (caudate nucleus, putamen) that are connected with specific nuclei of the thalamus (ventral anterior nucleus, mediodorsal nucleus, ventral lateral nucleus, pulvinar). It has not yet been clarified whether distinct attentional deficits (e.g., bias in spatial weighting, reduced/enhanced selective control, reduced processing speed) can be observed if specific nuclei/vascular territories of the thalamus are lesioned. Bundesen and colleagues have proposed a thalamic model for the theory of attention (TVA, Bundesen, 1990) called “neural theory of attention” (NTVA) which is mainly built upon neurophysiological findings in macaque monkeys (Bundesen, Habekost, & Kyllingsbæk, 2005; Bundesen et al., 2011). According to NTVA, visual information is first processed in an unselective wave from the retina to the lateral geniculate nucleus (LGN) of the thalamus and then to the striate and extrastriate visual cortex. In the cortex, individual perceptual values for each object are computed and multiplied by pertinence values. The information then enters the pulvinar nucleus of the thalamus where a saliency map is located and products are summed up as attentional weights. Weighted information is then processed in a second selective wave from the pulvinar to higher level visual processing areas in the cortex. The resulting perceptual values are multiplied by bias values, and the products are then transmitted from the cortex to the thalamic reticular nucleus (TRN) where a visual short term memory storage capacity (VSTM) map of locations is localized. TVA is a mathematical model which allows disentangling four independent attention parameters: Using whole and partial report paradigm allows measuring of the perceptual processing speed, VSTM, selective control and the spatial distribution of attentional weights reliably in normal participants, as well as in neurological patients, such as patients suffering from stroke (Duncan, et al., 1999) or Huntington's disease (Finke, Bublak, Dose, Mu¨ller, & Schneider, 2006). In recent years the TVA-based methodology has been used to investigate selective attention deficits after persistent and transient lesions of cortical sub regions, revealing that lesions in the entire cortical attention network consisting of the FEF, the middle frontal gyrus, the DLPFC, the TPJ, posterior PPC and inferior parietal regions lead to selective attention deficits in TVA parameters (Bublak et al., 2005; Duncan et al., 1999; Finke et al., 2006; Habekost & Bundesen, 2003; Habekost & Rostrup, 2006, 2007; Peers et al., 2005, see Habekost & Starrfelt, 2009 for a review). So far, distinct thalamic lesions have not been investigated with the TVA-based methodology. However, a number of studies report attentional deficits after thalamic or basal
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ganglia lesions. For example neglect or spatial bias has been repeatedly reported after lesions of the caudate nucleus and putamen and the ventral nuclei of the thalamus (Fimm et al., 2001; Finke et al., 2006; Habekost & Rostrup, 2006; Karnath et al., 2002), as well as after lesion of the pulvinar (Habekost & Rostrup, 2006; Karnath et al., 2002). Executive deficits (and complex attentional deficits) have been associated with lesions of the intralaminar nuclei and the mediodorsal nucleus by Van der Werf and colleagues (Van der Werf et al., 2003) and Liebermann et al. (2013). Patients with lesions of the putamen showed reductions of processing speed (Finke et al., 2006; Habekost & Rostrup, 2006). Congruent with the NTVA model Habekost and Rostrup (2006) found a spatial bias to the ipsilesional field in one patient with a focal damage in the right pulvinar nucleus of the thalamus. The aim of the study was to test if very circumscribed damage to distinct nuclei of the thalamus leads to specific attention deficits. For this purpose, we combined parameterbased assessment of TVA (Finke et al., 2005) with lesion symptom mapping in standard stereotactic space in patients with focal thalamic lesions in the medial, lateral, anterior or posterior vascular territories of the thalamus. A previous study (Van der Werf et al., 2003) has shown that it is highly relevant to check whether patients with thalamic lesions have additional structural damage, as additional lesions (e.g., white matter lesions) can explain variance in neuropsychological deficits between patients (Habekost & Rostrup, 2006). To exclude this possibility, we only considered patients with pure thalamic damage.
2.
Method
2.1.
Participants
An overall number of sixteen patients (mean age 41.2 ± 11.0 SD, 6 females) with the diagnosis thalamus infarction as evidenced by high resolution MRI scans participated in this study. Patients were recruited at the Department of Neurology, Universita € tsmedizin (Berlin, Germany) and at the Charite Stroke Unit of the Medical Hospital Gesundheit Nord Klinikum Bremen-Mitte (Bremen, Germany). Patients were included with an age 14.48] in TVA. The images are thresholded at 15%, i.e., only regions affected in at least 15% of patients are displayed. Overlay plots of the superimposed lesions of processing speed deficient (N ¼ 6) minus normal group (N ¼ 9) is illustrated in blue colors (dark blue difference 15% to green difference 100%); overlay plots of the superimposed lesions of processing speed normal (N ¼ 9) minus deficient group (N ¼ 6) is illustrated in red colors (dark red difference 15% to light yellow difference 100%). The upper panel illustrates one coronal and axial section, the lower panel illustrates seven coronal sections from anterior to posterior. Note that left-sided lesions are flipped to the right side.
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Fig. 5 e Spatial attentional weighting. A) Example of one patient with deficient spatial weighting. Bars indicate partial report performance for ipsilesional targets (left diagram) or contralesional targets (right diagram), respectively. The deficit is indicated with black arrows. B) Overlay lesion plots of patients with deficient [wl < .45 or wl > .59] or normal spatial weighting [.45 < wl < .59] in TVA. The images are thresholded at 15%, i.e., only regions affected in at least 15% of patients are displayed. Overlay plots of the superimposed lesions of spatial weighting deficient (N ¼ 5) minus normal group (N ¼ 10) is illustrated in blue colors (dark blue difference 15% to green difference 100%); overlay plots of the superimposed lesions of spatial weighting normal (N ¼ 10) minus deficient group (N ¼ 5) is illustrated in red colors (dark red difference 15% to light yellow difference 100%). The upper panel illustrates one coronal and axial section, the lower panel illustrates seven coronal sections from anterior to posterior. Note that left-sided lesions are flipped to the right side.
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visual field and furthermore, extinction for contralesional targets if targets were presented across hemifields. However, the patient showed normal performance if two targets were presented in the contralesional visual field, which indicates that the patient had no basic perceptual deficit within the contralesional visual field. Overall five patients had a deficit in spatial weighting (four had left-sided lesions, one had a rightsided lesion). Four patients showed a bias to the ipsilesional side while one patient had a bias to the contralesional side. Ten patients showed no spatial bias (one patient did not participate in the partial report task). TSL and age did not differ between patients with no spatial bias or patients with a deficit in spatial weighting [TSL: t(13) ¼ .52; p > .05; age: t(13) ¼ .32; p > .05]. Subtraction analysis revealed that lesions of patients with a lateral bias in spatial weighting are more medial or posterior compared to patients with normal spatial weighting (see Fig. 5B). In line with this finding VBM analysis showed a greater amount of grey matter in the left medial dorsal nucleus (MNI peak coordinate 3 16 13 at an uncorrected p-value of .001, k ¼ 214, t-value 3.54) for patients without spatial bias as compared to patients with spatial bias (see Fig. 6B). VBM on the whole brain level revealed no significant results at an uncorrected p-value of .001 (with extent threshold k > 200), presumably due to the small sample size within the subgroups.
3.5.
Neuropsychological results
Table 5 depicts the results of neuropsychological testing. As also reported previously in the study of Liebermann et al. (2013), some patients showed a deficit in memory tests (three in ROCF immediate recall, three in ROCF delayed recall, three in digit span, five in block span). Moreover, six patients showed a deficit in at least one measure of the WCST. Voxelbased lesion to symptom mapping for WCST deficient vs. normal is reported in Liebermann et al. (2013).
4.
Discussion
TVA-based assessment revealed selective, dissociated attention deficits after focal thalamic stroke in distinct vascular territories. We found a specificity of deficits if distinct thalamic nuclei were affected: In patients with lateral lesions, visual processing speed was reduced. In contrast, patients with medial lesions did not show a reduction of visual processing speed. However, some patients with medial lesions showed a spatial bias to the ipsilesional or contralesional field. Two single cases with anterior or posterior thalamic lesions respectively, indicate a variation of attentional selective control. These findings will be discussed in the following sections with respect to prior data on consequences of thalamic lesions on attentional functions. Furthermore, it will be discussed how they relate to the theoretical framework provided by NTVA, its explicit suggestions on the neuronal implementation of the various attentional parameters proposed within the human brain and, especially, whether they fit into the NTVA assumption of the role of thalamic structures on attentional processing.
Fig. 6 e VBM analysis results. (A) Visual processing speed. One coronal section is illustrated, showing a greater amount of grey matter in the left anterior medial thalamus [MNI peak coordinate ¡2, ¡2, 2 at an uncorrected p-value of .001; t-values are depicted from 2 (red) to 4 (white)] for patients with reduced processing speed as compared to patients with intact processing speed. (B) Spatial attentional weighting. One coronal section is illustrated, showing a greater amount of grey matter in the left medial dorsal nucleus [MNI peak coordinate ¡3 ¡16 13 at an uncorrected p-value of .001; t-values are depicted from 2 (red) to 3.8 (white)] for patients without spatial bias as compared to patients with spatial bias.
Earlier patient studies described attentional deficits following thalamic lesions. A complex attention deficit has been associated with lesions of the intralaminar nuclei (Van der Werf et al., 2003), which also lead to executive deficits (Liebermann et al., 2013; Van der Werf et al., 2003). Some studies reported a spatial bias after lesion of the pulvinar (Habekost & Rostrup, 2006; Karnath et al., 2002). So far, different selective attention deficits that are resulting from circumscribed lesions to distinct regions of the thalamus have not been described and compared.
Table 5 e Neuropsychological Testing. Line bisection (1 ¼ normal, 2 ¼ deficient), line cancellation (1 ¼ normal, 2 ¼ deficient), ROCF copy (percentile rank, PR), ROCF immediate recall (PR), ROCF delayed recall, digit span forward (PR), digit span backward (PR), block span forward (PR), block span (PR), Demtect (18e13 ¼ normal, 12e9 ¼ mild cognitive impairment, ≤ 8 ¼ dementia suspicion), Stroop (1 ¼ normal, 2 ¼ deficient in at least one Stroop measure), RWT lexical 1 min (PR), RWT lexical 2 min (PR), RWT semantic 1 min (PR), RWT semantic 2 min (PR), WCST (1 ¼ normal in all WCST measures, 2 ¼ deficient in at least one WCST measure).
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4.1.
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Spatial attentional weighting
The spatial bias to the ipsilesional field in our patient with a posterior (pulvinar) lesion is congruent to the finding of Habekost and Rostrup (2006) and the NTVA model (Bundesen et al., 2005). Note that the patient of Habekost and Rostrup (2006) has a right-sided pulvinar lesion while our patient has a left-sided pulvinar lesion. While the patient of Habekost and Rostrup (2006) showed a bias to the right, our patient showed a bias to the left side. The spatial bias after medial thalamic lesions can be consistent with a previous study reporting attention deficits after paramedian lesions in one third of all patients (Hermann et al., 2008). Attention deficits occurred especially after leftsided or bilateral lesions, but the type of attentional deficit was not further specified in this study. Spatial deficits in eye movements after lesion of the medial thalamic nuclei are described both in patients (e.g., Ostendorf, Liebermann, & Ploner, 2010), as well as in primates (e.g., Sommer & Wurtz, 2008; Tanaka, 2007). The finding that some patients had an ipsilesional bias while others had a contralesional bias is consistent with electrophysiological work in primates by Tanaka (2007) that activity at the central thalamic level can represent both ipsi- and contralateral space. As described in the introduction, the medial thalamus is connected with the FEF, DLPFC, ACC and orbitofrontal cortex via connections of the caudate nucleus and the putamen (Haber & McFarland, 2001). Thalamo-cortical disconnection between these areas could also lead to deficits in spatial weighting, as these cortical structures are known to be involved in mechanism of spatial attention (Corbetta, Patel, & Shulman, 2008 for an overview).
4.2.
Selective attentional control
Our single case finding indicates that a pulvinar lesion can also result in changes of selective attentional control. This is congruent with the NTVA (Bundesen et al., 2005), as well as current studies investigating the functional role of the pulvinar in healthy subjects using functional brain imaging (Rotshtein, Soto, Grecucci, Geng, & Humphreys, 2011; Strumpf et al., 2013) or diffusion tensor imaging (Saalman, Pinsk, Wang, Li, & Kastner, 2012), suggesting that the pulvinar is involved in selective visual attention processes (e.g., distractor filtering). However, in our case selective control was actually enhanced, resulting in particularly focused visual processing. Other studies reported deficits in feature binding (Ward, Danziger, Owen, & Rafal, 2002) and spatial selection (Snow, Allen, Rafal, & Humphreys, 2009) reflecting that pulvinar lesions can also have the opposite effect, i.e., reduce the degree of top-down control in processing. Moreover, our single case with an anterior medial lesion showed such a reduction of selective attentional control. Future studies with a larger number of patients with anterior and posterior thalamic lesions are needed to replicate our findings. Moreover, it should be tested to determine in which attentional paradigms patients with pulvinar lesion show deficits (e.g., TVA partial report vs. distinct visual search tasks). Further, it is known that the pulvinar is connected via the caudate nucleus and the putamen with the PPC and occipito-
temporal areas (Bundesen et al., 2005; Haber & McFarland, 2001) and that the anterior medial nuclei are connected via the caudate nucleus and the putamen with the DLPFC (Haber & McFarland, 2001). Thalamo-cortical disconnection of these structures could result in enhanced/reduced selective attentional control, as these cortical areas are involved in distractor filtering, feature binding and selective spatial attention (Corbetta et al., 2008 for an overview).
4.3.
Visual perceptual processing speed
Our results clearly show that patients with thalamic lesions are not generally slowed in visual attentional processing. Instead, visual attentional processing speed reductions occurred especially after lateral lesions of the thalamus. This finding is not reported previously in the literature. Congruent with previous TVA-based studies investigating TVA capacity parameters after cortical lesions, processing speed reductions occur in both the ipsi- and contralesional field (Duncan et al., 1999; Habekost & Rostrup, 2006, 2007). Moreover, it is known that processing speed in TVA is reduced in patients with basal ganglia lesions (Huntington's disease; Finke et al., 2006) and in patients with white matter lesions (Habekost & Rostrup, 2006). The etiology of lateral thalamic lesions is oftentimes microangiopathic accompanied by white matter lesions in the whole brain, but these patients were excluded from the present study. Lateral lesions can lead to hemiataxia and a “thalamic hand”ea choreodystonic type of involuntary movement due to impaired proprioception (Foix & Hillemand, 1925; Carrera & Bogousslavsky, 2006), which might impair motor responses and, thus, reaction times. In TVA however, the estimation of visual processing speed is not confounded by motor speed and, therefore the reduction in visual processing speed cannot be explained by a motor deficit. Furthermore it cannot be explained by medication sideeffects, as we also excluded patients under neurological or psychiatric medication that might lead to attentional slowing.
4.4.
VSTM storage capacity
None of our patients showed a significant reduction in VSTM, as tested by TVA. However, as in the study of Van der Werf et al. (2003) some patients showed memory deficits in further neuropsychological testing, but these deficits were not associated with a specific area in the thalamus. In TVA, the parameters VSTM storage capacity and processing speed are defined as independent, though it has been shown that the parameters correlate about .40 empirically (Finke et al., 2005). This finding was replicated in our control group. However, alertness manipulation studies in healthy subjects showed visual processing speed can be enhanced via cueing without necessarily affecting VSTM capacity (Matthias et al., 2010; Vangkilde, Coull, & Bundesen, 2012), suggesting a certain degree of independence between these parameters. In stroke patients with cortical lesions both parameters were often affected, suggesting overlapping cortical networks (Habekost & Rostrup, 2006; Peers et al., 2005). The fact that this is different in thalamic lesions, i.e., our finding of a dissociation between impaired visual processing speed and preserved VSTM storage capacity suggests that these parameters rely on
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the integrity of distinct thalamic structures. Accordingly, we found no significant correlation between the parameters in the patient group.
4.5.
Limitations of the study
Due to the resolution of MR imaging, the delineation of the boundaries of a lesion and classification of lesion is rather approximate than exact. The period of time from when the lesion occurred varied in the present study. Recovery of symptoms occurs after stroke especially in the first six month after infarction. While severe attention deficits in the acute period of thalamic stroke are well known, the present study shows that subtle attentional deficits can persist into the chronic stage after stroke. In future studies it would be interesting to differentiate between acute, sub-acute and chronic attentional deficits using a follow-up design. We only included patients without white matter lesions or other lesions in the brain. Given these selection criteria the mean age of our patient group was 42.1 years. This is below the common age for thalamic stroke. Our study shows that TVA allows the detection of selective deficits after focal thalamic lesions. A larger sample of patients, especially those with anterior and posterior lesions, is necessary in order to ascribe specific visual attentional deficits to specific thalamic nuclei on a robust statistical level. A larger sample of patients would also allow a differentiation of attentional deficits between left-sided and right-sided lesion in specific thalamic sub regions.
4.6.
Conclusion
We conclude from our data that not only the “visual thalamus” (LGN, pulvinar and TRN, see Bundesen et al., 2005; Saalmann & Kastner, 2011) is relevant for distinct parameters of visual attention such as visual processing speed, VSTM, selective attentional control and spatial attentional weighting. Instead also anterior, medial and lateral nuclei of thalamus are relevant and lead to distinct visual attentional deficits if damaged. This is plausible, as anterior, lateral, medial and posterior nuclei of the thalamus are connected via cortical-basal ganglia circuits with cortical areas such as the FEF, DLPFC, ACC, PPC and occipital-temporal cortex that are involved in visual attentional subprocesses. In our opinion, lesion-symptom mapping and VBM analysis in a larger sample of patients with circumscribed lesions in distinct vascular territories of the thalamus will further expand our knowledge on attentional deficits and their anatomical relationships to distinct thalamic nuclei. A larger sample would allow statistical voxelbased lesion-symptom mapping on the basis of continuous behavioral data as described by Bates et al. (2003) or Rorden et al. (2007). Moreover, lesion of the four vascular thalamic territories may lead to a very different hypo-metabolism of cortical areas of the brain (i.e., diaschisis) due to distinct thalamo-cortical networks (Schmahmann, 2003). In the present study, a VBM analysis computed on the whole brain level revealed no significant changes. However, a larger sample of subjects or the use of positron emission tomography (PET) might be necessary to illustrate depressed levels of metabolic
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activity in cortical areas after discrete thalamic lesion in different vascular territories. Further insight might be gained by investigating changes in thalamo-cortical networks after circumscribed thalamic lesions using diffusion tensor imaging. Moreover, it would be interesting to evaluate if a specific involvement of distinct thalamic nuclei for subprocesses of attention can be generalized to other sensory modalities such as acoustic attention or somatosensory attention.
Funding This work was supported by the Deutsche Forschungsgemeinschaft (BR 1691/3-3 and IR 48/2-2 in FOR 778/1-1).
Acknowledgments We thank C. Grimsen for recruitment of one patient at the University of Bremen. We thank J. England for corrections to the English text.
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