Abstract

There is increasing attention about the role of the thalamus in high cognitive functions, including memory. Although the bulk of the evidence refers to episodic memory, it was recently proposed that the mediodorsal (MD) and the centromedian–parafascicular (CM–Pf) nuclei of the thalamus may process general operations supporting memory performance, not only episodic memory. This perspective agrees with other recent fMRI findings on semantic retrieval in healthy participants. It can therefore be hypothesized that lesions to the MD and the CM–Pf impair semantic retrieval. In this study, 10 patients with focal ischemic lesions in the medial thalamus and 10 healthy controls matched for age, education, and verbal IQ performed a verbal semantic retrieval task. Patients were assigned to a target clinical group and a control clinical group based on lesion localization. Patients did not suffer from aphasia and performed in the range of controls in a categorization and a semantic association task. However, target patients performed poorer than healthy controls on semantic retrieval. The deficit was not because of higher distractibility but of an increased rate of false recall and, in some patients, of a considerably increased rate of misses. The latter deficit yielded a striking difference between the target and the control clinical groups and is consistent with anomia. Follow-up high-resolution structural scanning session in a subsample of patients revealed that lesions in the CM–Pf and MD were primarily associated with semantic retrieval deficits. We conclude that integrity of the MD and the CM–Pf is required for semantic retrieval, possibly because of their role in the activation of phonological representations.

INTRODUCTION

Declarative memory is thought to consist of two components: episodic and semantic memory. Episodic memory entails the information one collects regarding oneself, one's experiences and thoughts (Tulving, 2002). Semantic memory is concerned with learning and retrieving facts about the world, including the meaning of verbal and nonverbal stimuli and the relationships between items (Goldenberg, 1997; Tulving, 1972). Knowledge of highly frequent associations between items, for example, between honey and bees, hammer and nails, and so forth, is thought to be processed by this memory system, as opposed to single-trial associations in which the contribution of episodic memory is greater.

Experimental evidence shows that these two systems rely on partly different neural substrates. Episodic memory recruits the medial-temporal lobe, the anterior thalamus, the mammillary bodies, the retrosplenial and posterior cingulate cortices as well as the prefrontal cortices (for reviews, see Aggleton, Dumont, & Warburton, 2011; Shimamura, 2010; Mitchell & Johnson, 2009; Eichenbaum, Yonelinas, & Ranganath, 2007; Squire, Wixted, & Clark, 2007). Semantic memory is supported by a neural network including the lateral temporal lobe, the left inferior frontal gyrus, the occipito-temporo-parietal cortex, the prefrontal cortices, and the medial thalamus (reviewed by Binder & Desai, 2011; Greenberg & Verfaellie, 2010; Patterson, Nestor, & Rogers, 2007).

The thalamus has been involved in the semantic memory network by a pioneer clinical study conducted by Wallesch, Kornhuber, Kunz, and Brunner (1983). The authors compared the performances of 13 patients with unilateral thalamic lesions with those of healthy controls and of patient controls with cortical lesions in several cognitive tasks. Patients with more anterior thalamic lesions suffered from working memory deficits, whereas patients with more posterior lesions were impaired on tasks related to semantic memory, such as the similarities subtest of the Wechsler Adult Intelligence Scale. Unfortunately, the pattern of impairments shown by patients appeared rather unselective, including deficits on IQ, immediate recall, and executive function.

Since the study by Wallesch et al. (1983), evidence has accumulated in favor of the involvement of the human thalamus in episodic memory (reviewed by Aggleton et al., 2011; Carlesimo, Lombardi, & Caltagirone, 2011). Investigations on the role of the thalamus in semantic memory have been less numerous and less clear cut. Wiggs, Weisberg, and Martin (1999), for instance, in a PET study tapping both semantic and episodic memory, found that the thalamus (especially in the right hemisphere) was more activated during an episodic retrieval task than during semantic retrieval. However, fMRI investigations showed that the thalamus, especially in the left hemisphere, was activated during performance of a semantic retrieval task (Assaf et al., 2006; Kraut et al., 2002). The term “semantic retrieval” was employed and defined by Kraut et al. (2006, 2007) and refers to the activation of an internal representation of an item resulting from combination of two names semantically related to it, for example, from the cues “honey” and “sting,” participants should activate the item “bee.” For the sake of simplicity, we will refer to this task with the expression “semantic retrieval” throughout the article; this terminology is not meant to imply that the task used solely taps conceptual skills, because it also requires naming. Kraut et al. (2002) could show that several brain areas, including the thalamus, were activated during semantic retrieval but not during a categorization and a semantic association task. A single-case study with a patient displaying a left-sided antero-medial ischemic lesion in the thalamus supported the hypothesis that damage to the thalamic node of the network disrupts semantic retrieval (Segal, Williams, Kraut, & Hart, 2003). Other clinical studies demonstrated that posterior thalamic lesions can cause lexical–semantic deficits (Johnson & Ojemann, 2000; Metter et al., 1988), which accords with the findings by Wallesch et al. (1983). Neuroimaging studies confirmed that semantic retrieval elicits increased blood perfusion in the thalamus of healthy participants (Assaf et al., 2006). Clinical and neuroimaging investigations converge on attributing a greater role to the left thalamus in semantic memory (Nadeau & Crosson, 1997).

In general, there is consistent evidence on the role of posterior thalamic nuclei such as the pulvinar and the lateral posterior nucleus in semantic memory (reviewed by Carrera & Bogousslavsky, 2006; Schmahmann, 2003; Nadeau & Crosson, 1997; see also Hart et al., 2012). The function of the posterior thalamic nuclei has been primarily associated with aphasic symptoms, possibly because of their influence on parietal, temporal, and frontal cortices (Nadeau & Crosson, 1997). There is little consensus, instead, on the role of the medial thalamus (especially the mediodorsal and intralaminar nuclei) on semantic memory. Nadeau and Crosson (1997) proposed that damage to the mediodorsal thalamic nucleus (MD) could be responsible for prelinguistic semantic deficits, that is, failures in activating object representations to make them available for declarative memory; additionally, they proposed that the centromedian–parafascicular complex (CM–Pf) may be involved in modulating selective engagement of specific cortical areas, including those subserving attention.

In our view, it is necessary to take into account one noteworthy innovation of the tasks introduced by Kraut and coworkers: the activation of mental representations. This feature appears crucial to elicit thalamic activation (Assaf et al., 2006; Kraut et al., 2002). Supporting this view, Burianova and Grady (2007) found thalamic activation during performance of a semantic retrieval task in which participants were required to answer a semantic question relating to a previously shown item. Hence, it can be hypothesized that the thalamus is recruited in particular when the task requires activation of an object representation. Kraut and coworkers (Assaf et al., 2006; Kraut et al., 2002) suggested that the MD may be particularly critical for semantic retrieval performance; yet, because of the lack of accurate mapping procedures of the functional activations, this suggestion remains a working hypothesis. Moreover, the semantic retrieval task allows detection of false alarms and incorrect responses, which may be a consequence of impaired selective engagement coordinated by the CM–Pf complex (Nadeau & Crosson, 1997).

Although the fMRI evidence consistently suggests involvement of the thalamus in semantic retrieval, clinical evidence with respect to the involvement of the medial thalamus in semantic memory remains wanting. Although the patient reported by Segal et al. (2003) did show impaired semantic retrieval, a verbal fluency deficit was also apparent, hence it is not clear whether the deficits in this patient were specific for semantic retrieval or rather a by-product of mild aphasia. The lack of clinical group studies entangles the attempts to explain the cognitive operations performed by medial thalamic regions and thalamo-cortical networks. The anteromedial thalamus is also involved in episodic recall (Aggleton et al., 2011; Carlesimo et al., 2011), executive function (Van der Werf, Jolles, Witter, & Uylings, 2003), and performance monitoring (Peterburs et al., 2011; Seifert, von Cramon, Imperati, Tittgemeyer, & Ullsperger, 2011), hence precise mapping of the lesions is crucial to understand how basic operations common to this diverse spectrum of cognitive abilities are supported by the thalamic nuclei.

This study aimed to directly investigate the role of the thalamus in semantic retrieval by testing a group of 10 patients with ischemic lesions in the thalamus and 10 matched healthy control participants with an adaptation of the task developed by Kraut et al. (2002). With respect to the previous literature, this article focuses more on the role of medial thalamic structures in semantic memory, a topic insufficiently explored in previous investigations. We employed standard neuropsychological tests to rule out the influence of nonspecific cognitive deficits in the performance of the patients, including aphasia. Moreover, participants performed two control semantic tasks to test the specificity of the deficits. Patients were attributed to a target clinical group and a control clinical group based on lesion localization.

We predicted that the target clinical group would perform more poorly than healthy controls selectively in the semantic retrieval task, because of the role played by the medial thalamus in activation of mental representations (von Zerssen, Mecklinger, Opitz, & von Cramon, 2001; Nadeau & Crosson, 1997).

The lesions were assessed in the chronic phase of the disease and also, years later, in a follow-up high-resolution structural magnetic resonance (MR) investigation conducted in a subsample of patients, which allowed for localization and quantitative assessment of the lesioned areas in the thalamus. We expected that, in impaired patients, the lesions would particularly affect the MD and the CM–Pf complex.

METHODS

Participants

Ten patients with focal ischemic lesions of the thalamus and 10 healthy control participants took part in the study. Patients and controls were matched according to age, sex, years of education, and IQ. All participants had normal or corrected-to-normal vision. The study was approved by the ethics committee of the medical faculty of the Ruhr University of Bochum. All patients and control participants gave written informed consent before participating, in accordance with the Declaration of Helsinki.

The patients were outpatients of the Klinikum Dortmund, Germany. In all cases, the diagnosis of probable thalamic stroke was the motivation for the MR investigation. Only patients for whom two experienced raters (M. S. and B. K.) expressed the consensual diagnosis of thalamic infarction without significant encephalic damage outside the thalamus were included in the study. Only patient P2 presented an additional ischemic lesion located in the cerebellum. For this study, it is of special importance to note that no abnormalities were detected in regions that might impact lexical semantic function, except for expanded Virchow–Robin spaces in the BG of patient P8. For none of the patients, there was known substance abuse either at the time of the MR or at the time of testing. Thalamic lesions were documented with MR using a standard three-dimensional T2-weighted sequence for transverse sections and a standard three-dimensional T1-weighted sequence for coronal sections (1 mm × 5 mm × 5 mm voxel size; see Figure 1).

Figure 1. 

Brain sections of all patients in T2-weighted (axial sections) and T1-weighted (coronal sections) contrasts. The arrows indicate the site of thalamic ischemia.

Figure 1. 

Brain sections of all patients in T2-weighted (axial sections) and T1-weighted (coronal sections) contrasts. The arrows indicate the site of thalamic ischemia.

Thalamic lesions were classified with respect to affected nuclei on the basis of the MR images and an established atlas (Morel, 2007). To further characterize the lesions, patients were contacted for a follow-up scan, and 6 of the 10 patients of this study underwent new high-resolution scans (3-T General Electrics scanner: www.ge.com/). The new images were acquired using a FSGPR BRAVO axial sequence for the T1-weighted scans (0.9 mm × 0.9 mm × 1.2 mm voxel size; flip angle = 13°, field of view = 24.0, slice thickness = 1.2 mm, slice spacing = 0 mm, slice number = 110). T2-weighted images were also acquired (FLAIR axial sequence, 0.5 mm × 0.5 mm × 5.5 mm voxel size; echo time = 120.0, repetition time = 8000.0, field of view = 24.0, slice thickness = 5.0 mm, slice spacing = 0.5 mm, slice number = 25). The T1-weighted high-resolution images were manually normalized to a template derived by the atlas used for the assessment (Morel, 2007). The normalization procedure has been described elsewhere (Pergola, Suchan, et al., 2012). The images were then overlaid on the atlas (this analysis was performed by a third independent rater, G. P.). Figure 2 reports two overlays, located in planes 3 mm above (left) and 5 mm above (left) the intercommissural plane. This procedure also allowed us to compute the normalized volume of the lacunae and to extract the percentage of volume loss in the MD and in the CM–Pf as a consequence of the ischemic episode (Pergola, Suchan, et al., 2012). We reported these measures to improve patients' description.

Figure 2. 

Overlap of the lesions of six patients, drawn based on the high-resolution T1-weighed images. The white lines border the regions lesioned in at least four patients. Modified from Morel (2007). ac = coordinates of the anterior commissure; AM = anteromedial nucleus; Cd = caudate nucleus; D 2.7 = plane 2.7 mm dorsal to the intercommissural plane; D 5.4 = plane 5.4 mm dorsal to the intercommissural plane; CeM = center medial; CL = centrolateral nucleus; CM = centromedian nucleus; GPe = globus pallidus, pars externa; Hb = habenular nucleus; ic = internal capsula; Li = limitans nucleus; mtt = mammillothalamic tract; LP = lateral posterior nucleus; MDmc = MD, magnocellular portion; MDpc = MD, parvocellular portion; MDpl = MD, paralamellar portion; MV = medioventral nucleus; P1 through 10 = Patients 1 through 10; pc = coordinates of the posterior commissure; PuA = anterior pulvinar; PuL = lateral pulvinar; PuM = medial pulvinar; PuT = putamen; Pv = paraventricular nucleus; R = reticular nucleus; sm = stria medullaris; St = striatum; VAmc = ventral anterior nucleus, magnocellular portion; VApc = ventral anterior nucleus, parvocellular portion; VLa = VL, anterior portion; VLpv = VL, posterior ventral portion; VM = ventromedial nucleus; VPLa = ventral posterior lateral nucleus, anterior portion; VPLp = ventral posterior lateral nucleus, posterior portion.

Figure 2. 

Overlap of the lesions of six patients, drawn based on the high-resolution T1-weighed images. The white lines border the regions lesioned in at least four patients. Modified from Morel (2007). ac = coordinates of the anterior commissure; AM = anteromedial nucleus; Cd = caudate nucleus; D 2.7 = plane 2.7 mm dorsal to the intercommissural plane; D 5.4 = plane 5.4 mm dorsal to the intercommissural plane; CeM = center medial; CL = centrolateral nucleus; CM = centromedian nucleus; GPe = globus pallidus, pars externa; Hb = habenular nucleus; ic = internal capsula; Li = limitans nucleus; mtt = mammillothalamic tract; LP = lateral posterior nucleus; MDmc = MD, magnocellular portion; MDpc = MD, parvocellular portion; MDpl = MD, paralamellar portion; MV = medioventral nucleus; P1 through 10 = Patients 1 through 10; pc = coordinates of the posterior commissure; PuA = anterior pulvinar; PuL = lateral pulvinar; PuM = medial pulvinar; PuT = putamen; Pv = paraventricular nucleus; R = reticular nucleus; sm = stria medullaris; St = striatum; VAmc = ventral anterior nucleus, magnocellular portion; VApc = ventral anterior nucleus, parvocellular portion; VLa = VL, anterior portion; VLpv = VL, posterior ventral portion; VM = ventromedial nucleus; VPLa = ventral posterior lateral nucleus, anterior portion; VPLp = ventral posterior lateral nucleus, posterior portion.

In all but one patient (P10), the lesion test interval was at least 1 year, which allowed inflammatory phenomena and edema related to ischemia to subside. Table 1 lists time since lesion, affected thalamic nuclei, additional lesions, and neurological status for each patient. None of the patients suffered from a psychiatric disorder at the time of the test.

Table 1. 

Descriptive Data on the Clinical Sample

Patient
Sex
Hand Preference
Age (years)
Lesion Test Interval
Test Scan Interval (High Resolution)
Lesioned Nuclei
Lesion Side
Clinical Symptoms on Hospitalization
P1 left 40 7 years 4.3 years MD right Impairment in ocular movements and psychiatric symptoms 
P2 right 71 6 years  MD, VL left Imbalance possibly because of concurrent thalamic and cerebellar strokes 
P3 right 68 7 years  MD, VL right Facial paresis and impaired ocular movements 
P4 right 53 4 years 5.1 years MD (right, left), VL (right, left) bilateral Acutely reduced consciousness 
P5 right 72 7 years  VL left Sudden onset of paresthesia 
P6 right 48 5 years 5.3 years VL lefta Sudden onset of paresthesia 
P7 right 60 1 year 4.3 years MD left Midbrain symptoms and impaired ocular movements 
P8 right 26 8 years 5.3 years MD left Acute behavioral changes and memory deficits 
P9 right 60 6 years  VL left Sudden onset of paresthesia 
P10 right 55 3 weeks 4.3 years MD left Imbalanceb 
Patient
Sex
Hand Preference
Age (years)
Lesion Test Interval
Test Scan Interval (High Resolution)
Lesioned Nuclei
Lesion Side
Clinical Symptoms on Hospitalization
P1 left 40 7 years 4.3 years MD right Impairment in ocular movements and psychiatric symptoms 
P2 right 71 6 years  MD, VL left Imbalance possibly because of concurrent thalamic and cerebellar strokes 
P3 right 68 7 years  MD, VL right Facial paresis and impaired ocular movements 
P4 right 53 4 years 5.1 years MD (right, left), VL (right, left) bilateral Acutely reduced consciousness 
P5 right 72 7 years  VL left Sudden onset of paresthesia 
P6 right 48 5 years 5.3 years VL lefta Sudden onset of paresthesia 
P7 right 60 1 year 4.3 years MD left Midbrain symptoms and impaired ocular movements 
P8 right 26 8 years 5.3 years MD left Acute behavioral changes and memory deficits 
P9 right 60 6 years  VL left Sudden onset of paresthesia 
P10 right 55 3 weeks 4.3 years MD left Imbalanceb 

m = male; f = female.

aThe follow-up scan revealed a smaller ischemic lesion in the same location on the right side, that is, this patient had a symmetric bilateral lesion affecting the VL and the ventral posterior nucleus.

bThe MR investigation was requested because of imbalance symptoms, but the radiological results suggested that the onset of ischemia was by far earlier. Although it was impossible to establish the exact date of lesion onset, it was hypothesized that several years had passed since then.

Control participants were chosen from a large pool of healthy volunteers at the Department of Neuropsychology of the Ruhr University Bochum. Exclusion criteria were history of neurological or psychiatric disorders and alcohol or substance abuse. Both the patient and control groups comprised six women and four men. The target clinical group had a median age of 57 years, the control patients had a median of 54 years, and healthy control participants had a median of 58.5 years. There was no significant age difference between the groups (Kruskal–Wallis test, p = .86).

Lesion Localization in Individual Patients

The lesions of Patients 1, 7, 8, and 10 mainly affected the medial part of the thalamus including the MD, mostly sparing the lateral part involving the ventrolateral nucleus (VL). Of these patients, only Patient 1 had a right-sided lesion; in the other patients, the lesion affected the left thalamus.

In Patients 5, 6, and 9, MR images suggest the VL as the nucleus mainly damaged, with all lesions affecting the left side, although the lesion in patient P5 was more posterior and likely affecting the pulvinar. Follow-up scans revealed an additional smaller ischemic lesion in the right thalamus of patient P6. The lesion affected the same region affected on the left side (the left-sided lesion is shown in Figure 2), including the VL and also the ventral posterior nucleus.

In patients P2 (left-sided lesion) and P3 (right-sided lesion), lesions appeared to affect both the MD and the VL. Patient P4 exhibited a bilateral lesion. On the left side, the lesion affected the MD; on the right side, the lesion affected the MD and the VL (the left lesion was used for the overlaps in Figure 2). The intralaminar nuclei of the thalamus were affected to a variable extent (Figure 2, left; note that the CM–Pf complex was affected in several patients). The centrolateral nucleus and the paralamellar MD (thought by anatomists to belong to the centrolateral nucleus; see Jones, 2007, for a review), which are also components of the intralaminar nuclei, were also variably affected.

On the basis of the lesion localization and on the literature, patients were divided in two groups: a target clinical group, in which we expected deficits in semantic retrieval, and a control clinical group, in which no impairment was expected. All patients with a lesion affecting the left paramedian thalamus (P2, P4, P7, P8, P10) and patient P5, who showed a more posterior lesion affecting not only the VL but also the pulvinar, formed the target clinical group. Patients with unilateral right-sided paramedian lesions (P1, P3) and patients with tuberothalamic lesions mainly affecting the VL of the thalamus (P6, P9) formed the control clinical group.

Because the standard deviation is a biased estimator of the dispersion of the distribution for very small samples (Johnson, Kotz, & Balakrishnan, 1994), we employed nonparametric statistics to compare the groups (Kruskal–Wallis ANOVA and Mann–Whitney U).

IQ

Current IQ was estimated by means of two subtests of a German short version of the Wechsler Adult Intelligence Scale, with the similarities test as a measure of the verbal IQ and the picture completion test as a measure of performance IQ (Dahl, 1972, 1986). The mean of the two subtests provides a measure of current IQ, which was applied to rule out general between-groups differences in cognitive functioning (Lamar, Swenson, Kaplan, & Libon, 2004; Kazui, Hashimoto, Hirono, & Mori, 2003). In addition, the separate subtests provide meaningful measures of different aspects of the IQ by themselves and were therefore separately compared between groups.

Naming

To exclude aphasic symptoms in the patients, naming performance was assessed using a subtest of the Aachener Aphasie Test (AAT, subtest naming; Huber, Poeck, Weniger, & Wilmes, 1983). Participants are required to name objects (single or compound words) or colors and to name or describe situations or actions. Objects, situations, and actions are presented to the participant via line drawings; colors are presented on color panels. For the naming of each item, maximally three points are given, indicating correct naming. The maximum number of points for the whole test is 120. Scores below 114 are considered to reflect an aphasic symptom.

Word Lists: Pilot Study

Using different German word lists, categorization, semantic association, and semantic retrieval were assessed in patients and controls. All word lists were specifically designed for this study, following the procedure described by Kraut et al. (2002) for English versions of the tasks. Figure 3 illustrates the tasks.

Figure 3. 

Illustration of the main cognitive tasks used in this investigation. (A) The categorization task requires acknowledgement of the features of the items to match a set of criteria identifying a category. No relationship is required between the items. (B) Semantic association establishes a bilateral relationship between the items because they belong to a common context but not necessarily to the same category. (C) In the semantic retrieval task, the items in the pair are not semantically related, but both are semantically related to a third item, whose representation should be activated during task performance (the example in the figure was given by Kraut et al., 2002).

Figure 3. 

Illustration of the main cognitive tasks used in this investigation. (A) The categorization task requires acknowledgement of the features of the items to match a set of criteria identifying a category. No relationship is required between the items. (B) Semantic association establishes a bilateral relationship between the items because they belong to a common context but not necessarily to the same category. (C) In the semantic retrieval task, the items in the pair are not semantically related, but both are semantically related to a third item, whose representation should be activated during task performance (the example in the figure was given by Kraut et al., 2002).

In a first step, lists of items were created for each type of task.

For the categorization task, which required participants to decide whether two items belonged to the same category, the original list consisted of 144 German concrete substantives, with an average length of 6.9 letters (SD = 2.9 letters), arranged in 72 pairs. Half of the pairs were targets, that is, both words belonged to the same category, which could be tools (e.g., hammer–nail), animals (e.g., cat–dog), or fruits/vegetables (e.g., carrot–tomato). All other pairs were distracters, in which the members of the pair did not belong to the same category. The distracters were rearrangements of the substantives constituting the target pairs, so that each substantive appeared twice in the list.

In the semantic association task, participants were asked whether two words were semantically related. The original word list for this task entailed 64 word pairs. The substantives (average length = 5.7 letters, SD = 2.0) of the 32 target pairs were semantically related (e.g., money–purse, cook–stove), and the 32 distracter pairs again consisted of the same single substantives as the target pairs, but in new combinations, resulting in pairs without semantic relationships (e.g., sun–thief).

Finally, the original list for the semantic retrieval task entailed 88 pairs of substantives (average length = 5.8 letters, SD = 0.8). In half of these pairs, the two substantives together were intended to activate a particular object (e.g., desert–bump → camel, wheels–street → car); participants were asked to name this object. The other pairs were distracters again, which were composed of the same single substantives and were not supposed to activate an object (e.g., color–horse).

In a pilot study, 28 healthy participants (19 women and nine men, mean age = 29 years, SD = 9.7 years, range = 20–70 years) were presented the original item lists. After they had been given examples for each type of list, they were asked to mark those items in which both words belonged to the same category (categorization list), were semantically related (semantic association list), or activated an object (semantic retrieval list). Only a subset of the initial items entered the final word lists used in this study, based on the degree of accordance between pilot participants (see below for details).

Final Word Lists

Categorization

All target items of the original categorization list, which were correctly answered by at least 95% of the pilot participants, entered the final categorization list. It consisted of 44 pairs of words, 22 targets, and 22 distracters, with the distracters being composed of the same substantives as the targets. The length of the words was, on average, 7.0 letters (SD = 3.3 letters).

Semantic Association

For the semantic association list, the cutoff value for targets entering the final version was 100% correct performance in the pilot participants. The word list applied in this study consisted of 46 word pairs, 23 targets, and 23 distracters. As described above, both types of items consisted of the same set of substantives. The length of the items was, on average, 5.9 letters (SD = 2.1 letters).

Semantic Retrieval

Table 2 reports the English translation of the list of stimuli used for the semantic retrieval task. The final semantic retrieval list consisted of 16 targets and 16 distracters, with both sets of items again consisting of the same set of substantives. This subset of stimuli was selected from the original list of 88 pairs using as criterion correct responses by at least 80% of pilot participants. The threshold was lower compared with the other two tasks to have a sufficient number of trials. The length of the items was, on average, 5.5 letters (SD = 1.3 letters).

Table 2. 

List of the Stimuli Used in the Semantic Retrieval Task

First Word
Second Word
Activated Word
Activating Pairs 
Hump Desert Camel 
Banana Jungle Monkey/ape 
Bean Filter Coffee 
Worm Hook Fishing rod 
Time (Clock)a Hand Clock 
Tire Road Car 
Breakfast Hen Egg 
Pie Candle Birthday 
Trip Rail Train 
Grape Alcohol Wine 
Wax Light (noun)b Candle 
Paddle Water Boat/canoe 
Prayer House Church 
Nest Feather Bird 
Cow Drink Milk 
Music Key Piano 
 
Nonactivating Pairs 
Drink Paddle  
Trip Grape  
Rail Candle  
Water Pie  
Key Hen  
Feather Light (noun)  
Cow Wax  
Bean House  
Filter Desert  
Tire Nest  
Banana Prayer  
Worm Time  
Music Hook  
Breakfast Road  
Jungle (Clock) Hand  
Hump Alcohol  
First Word
Second Word
Activated Word
Activating Pairs 
Hump Desert Camel 
Banana Jungle Monkey/ape 
Bean Filter Coffee 
Worm Hook Fishing rod 
Time (Clock)a Hand Clock 
Tire Road Car 
Breakfast Hen Egg 
Pie Candle Birthday 
Trip Rail Train 
Grape Alcohol Wine 
Wax Light (noun)b Candle 
Paddle Water Boat/canoe 
Prayer House Church 
Nest Feather Bird 
Cow Drink Milk 
Music Key Piano 
 
Nonactivating Pairs 
Drink Paddle  
Trip Grape  
Rail Candle  
Water Pie  
Key Hen  
Feather Light (noun)  
Cow Wax  
Bean House  
Filter Desert  
Tire Nest  
Banana Prayer  
Worm Time  
Music Hook  
Breakfast Road  
Jungle (Clock) Hand  
Hump Alcohol  

aThe English translation of the German word used in this case, “Zeiger,” requires the additional word “clock,” but in the German version of the task, such an ambiguity was not present.

bThe German word used in this case, “Licht,” is only used for the noun, so in the German version of the task, there was no ambiguity with respect to the word “leicht” (light, adjective).

Scores Analysis

From the behavioral results, we derived the hit rate (proportion of correctly identified targets over the total of items shown) and the false alarm rate (proportion of erroneous responses to distracters). These two measures alone do not provide a complete description of the behavior. A participant may, for instance, always respond affirmatively and therefore achieve a hit rate of 1.0 and a false alarm rate of 1.0 without being actually able to perform the task. Therefore, we also computed measures widely used in the field of recognition memory to describe performance accuracy (Snodgrass & Corwin, 1988). The performance index (Pr = hit rate − false alarm rate) describes the accuracy of target detection, and the bias index (Br = false alarm rate/[1 − Pr]) describes the tendency to adopt a conservative or overly reliant strategy (e.g., a bias toward increasing misses or false alarms). The assumptions underlying this model are described in detail elsewhere (Snodgrass & Corwin, 1988). Basically, the model assumes that task performance relies on threshold processes, which fits the experimental design used in this study. Performance of the task in fact required a binary decision.

Additionally, in the case of the semantic retrieval task, patients were required to perform a second decision, that is, which object was activated by the cues. Hence, incorrect responses to targets may be misses (the target was not endorsed as a pair activating an object) and incorrect activations (the target was correctly endorsed as activating an object, but the object retrieved was incorrect). To best investigate patients' behavior, we additionally performed separate tests for these errors.

Object Representations

To further control for possible disturbances in object representations, which might affect performance in the semantic retrieval task, two additional measures were obtained. In the first task, 32 line drawings were presented to the participant in eight trials, with one target item and three distracters each. In every trial, an item was named by the experimenter, and the participant was asked to point to the line drawing showing this item. All eight target items (three animals and five objects) were also present (as words to be activated) in the semantic retrieval task. This task served to ensure that participants were able to link the visual representation of the items to the names.

The second task consisted of questions with respect to object features. For each of the eight items (also included in the semantic retrieval list), four questions were asked, two requiring a “yes” answer (e.g., “Is milk drinkable?”) and two requiring a “no” answer (e.g., “Is milk red”?). This task served to assess the integrity of the visual and semantic representation skills in the participants.

Procedure

For both patients and control participants, all data were obtained in one testing session. After participants had signed written informed consent forms, demographic data including the number of years of education were obtained, followed by a systematic assessment of subjective complaints related to the ischemic event in the patients. Then IQ, naming and performance in the three word lists were assessed. Tests were administered with pen and pencil. Participants did not have time constraints during task performance. After completion of the semantic retrieval list, object representation skills were assessed with line drawings and questions about object features (see above, Object Representations section). The complete procedure required 40–60 min. All participants received 20 as expenses refund.

RESULTS

IQ, Years of Education, and Naming

Patients and controls did not differ either on general IQ or on the subtests of the short version of the Wechsler Adult Intelligence Scale (Kruskal–Wallis test, all ps > .05). However, for verbal IQ, a trend for a group difference was found, with the target patients scoring lowest (median target patients = 99, median control patients = 114.5, median healthy controls = 111.5; p = .051). It is conceivable that this particular aspect of the verbal IQ was affected by thalamic damage in some of the patients. This will be further elaborated upon in the Discussion section. Groups did not differ with respect to the number of years of education (median target patients = 10, median control patients = 9, median controls = 10; Kruskal–Wallis test, p = .54).

In the subtest naming of a German test for the assessment of aphasic symptoms (AAT), target patients reached median scores of 117.5, whereas control patients and healthy controls reached scores of 118 and 119, respectively. As the groups did not differ significantly on this measure (Kruskal–Wallis ANOVA, p = .49), there was no evidence of an increased level of aphasic symptoms in the clinical groups. Importantly, none of the individual patients scored lower than 114, indicating that none of the patients suffered from aphasic naming deficits (see Methods section). Note that this test assesses naming from confrontation. This is qualitatively different from naming from conceptual representation (Shuren, Geldmacher, & Heilman, 1993), which has not been assessed in this study.

Categorization, Semantic Association, and Semantic Retrieval

Figure 4 shows the performance of target patients, control patients, and healthy controls in the categorization, semantic association, and semantic retrieval tasks. For both categorization and semantic association, there were no significant differences between the two groups on the performance indices and the hit rates (Kruskal–Wallis test; all ps > .05; Figure 4A and B). In contrast, Kruskal–Wallis test showed a significant difference across groups on the hit rate and the Pr of the semantic retrieval task (p = .014 and p = .028, respectively). Target patients scored significantly lower than healthy control participants in the hit rate and the Pr of the semantic retrieval task (Figure 4C; hit rate: Mann–Whitney U, p = .002; Pr: Mann–Whitney U, p = .007). There was no significant difference between control patients and healthy controls and between clinical subgroups (Mann–Whitney U, both ps > .05).

Figure 4. 

Median performances of target patients, control patients, and healthy controls in the semantic tasks. An asterisk marks significant differences between groups (Mann–Whitney U, p < .05).

Figure 4. 

Median performances of target patients, control patients, and healthy controls in the semantic tasks. An asterisk marks significant differences between groups (Mann–Whitney U, p < .05).

On the basis of these results, we asked which types of error (no activation, i.e., misses, false activations, or false alarms, i.e., activation to distracters) caused the difference between target patients and healthy controls. Mann–Whitney U comparisons on the types of errors revealed that the lower number of correct responses to target items in the patients was caused especially by a significantly increased number of false responses (i.e., the pair was correctly identified as target, but the activated object was incorrect; median target patients = 2.5, median healthy controls = 1; p = .022). A trend was found toward an increased number of misses (i.e., the participant did not correctly endorse a pair as a target; median target patients = 2, median healthy controls = 0; p = .073). No significant difference between the groups was observed for the number of responses to the distracters (false alarms; p > .05). In none of the tasks did groups differ in the Br (all ps > .05), which measures in how far responses are conservative.

Individual Patients' Performances

Table 3 shows the performances of individual patients in the aphasia battery and in the semantic retrieval task and also displays the normalized volume of the lesions and the percentage of volume lost in the MD and in the CM–Pf because of ischemia (only for those six patients for which we obtained high-resolution images). Figures 5 and 6 show the individual performances of patients in the semantic retrieval task and the types of errors they committed, expressed as z scores with respect to healthy controls' distribution. Note that we used z scores in this case because we tested 10 controls, and therefore, the concerns expressed in the Participants section about the reliability of the standard deviation with small samples do not apply. The z scores are intended to improve the description of the performance of individual patients. Only group tests allow inferences at the group level.

Table 3. 

Performances of Individual Patients and Quantitative Lesion Data

Patient
AAT Score
Performance (z Score of Hit Rate)
Performance (z Score of Pr)
Volume Loss in the MD
Volume Loss in the CM–Pf Complex
Normalized Lesion Volume
P1 120 −1.30 −.09 37.2 18.4 359 
P2 114 −2.23 −1.00    
P3 114 −3.16 −2.82    
P4 117 −2.23 −.09 11.2 26.2 453 
P5 118 −3.16 −6.45    
P6 119 1.49 1.73 .00 1.02 73 
P7 119 −3.16 −4.64 10.0 59.7 321 
P8 120 −1.30 −5.54 22.6 9.13 179 
P9 117 −2.23 −4.64    
P10 116 −1.30 −3.73 5.55 23.2 75 
Patient
AAT Score
Performance (z Score of Hit Rate)
Performance (z Score of Pr)
Volume Loss in the MD
Volume Loss in the CM–Pf Complex
Normalized Lesion Volume
P1 120 −1.30 −.09 37.2 18.4 359 
P2 114 −2.23 −1.00    
P3 114 −3.16 −2.82    
P4 117 −2.23 −.09 11.2 26.2 453 
P5 118 −3.16 −6.45    
P6 119 1.49 1.73 .00 1.02 73 
P7 119 −3.16 −4.64 10.0 59.7 321 
P8 120 −1.30 −5.54 22.6 9.13 179 
P9 117 −2.23 −4.64    
P10 116 −1.30 −3.73 5.55 23.2 75 

Volume loss is expressed as percentage of the putative territory of the nucleus falling into the lacuna. Normalized lesion volume is expressed in mm3.

Figure 5. 

Performances of target and control patients standardized based on healthy controls' distribution. Target patients' performances are shown on the left (vertical pattern); control patients' performances are shown on the right (horizontal pattern). z = 2.58 corresponds to p = .005. This threshold was selected to take into account multiple comparisons.

Figure 5. 

Performances of target and control patients standardized based on healthy controls' distribution. Target patients' performances are shown on the left (vertical pattern); control patients' performances are shown on the right (horizontal pattern). z = 2.58 corresponds to p = .005. This threshold was selected to take into account multiple comparisons.

Figure 6. 

Errors of target and control patients standardized on healthy controls' distribution. Target patients' errors are shown on the left (vertical pattern); control patients' performances are shown on the right (horizontal pattern). z = 2.58 corresponds to p = .005. This threshold was selected to take into account multiple comparisons.

Figure 6. 

Errors of target and control patients standardized on healthy controls' distribution. Target patients' errors are shown on the left (vertical pattern); control patients' performances are shown on the right (horizontal pattern). z = 2.58 corresponds to p = .005. This threshold was selected to take into account multiple comparisons.

Object Representations

Neither control participants nor patients had any difficulty choosing the corresponding line drawing of a given object form. All groups reached, on average, the maximum score of 8. Similarly, healthy control participants reached the maximum score of 8 for the questions about object features. With a median score of 7.5, target patients scored a little bit lower. There was a significant general group difference on this measure (Kruskal–Wallis test, p = .02), but none of the post hoc pairwise tests between groups yielded significant results (Mann–Whitney U, all pairwise comparisons had p > .05).

DISCUSSION

This study aimed at testing the hypothesis that focal ischemic lesions in the left medial thalamus disrupt semantic retrieval. The evidence supports the hypothesis because patients showed impaired accuracy (measured by using the Pr) selectively on the semantic retrieval task. The deficit was explained by a reduced hit rate rather than by overly frequent responses to distracters. In particular, target patients with lesions in the left paramedian thalamus as a group mainly activated incorrect objects, after correctly endorsing a target pair as one that activated a third object. Four of the six target patients showed an even stronger tendency toward misses, that is, failures in object activation. The same pattern could not be consistently detected for control patients, who suffered from lesions in the thalamus outside the ROIs for this study.

Target patients were not impaired on control tasks used to assess patients' ability to categorize and perform semantic associations. No patient showed symptoms of aphasia, consistently with the literature on paramedian stroke (Carrera & Bogousslavsky, 2006; Schmahmann, 2003; Nadeau & Crosson, 1997). Also, target patients did not consistently show decreased IQ or impaired visual representation ability. The evidence accords with previous investigations (Calley et al., 2010; Assaf et al., 2006; Segal et al., 2003; Kraut et al., 2002) and suggests a role of the medial thalamus in semantic retrieval at least partially independent of aphasic symptoms.

Behavioral Results

The only significant impairment shown by target patients refers to semantic retrieval, without clinically relevant aphasic symptoms. Visual representation of the items was also intact. The decreased performance on semantic retrieval was motivated, at the group level, by significantly increased false activations in response to target pairs compared with healthy controls. However, for at least four of the six target patients, misses (i.e., “no activations”) represented a more striking source of error compared with false activations (Figure 6).

The pattern of results opens three possible interpretations of the behavioral data, which are not mutually exclusive. First, semantic retrieval is more effortful and requires more cognitive resources than categorization and semantic association. The difference in task complexity was also present in previous investigations (Assaf et al., 2006), but the imaging data showed that the tasks activate different brain networks, rather than activating the same brain network to different extents. Consistent with this observation, one patient (P6) whose lesion was markedly more lateral compared with other patients (see Figure 2, Table 3, and the Relationships between Lesion Localization and Behavioral Results section) did not show deficits in semantic retrieval. Therefore, deficits in semantic retrieval are not an unspecific consequence of thalamic lesions. Our detection power in the categorization and in the semantic association task might be hindered by ceiling effects. Whereas in the semantic retrieval task, ceiling effects were almost absent (only one patient, P6, and one control reached ceiling in this task), in the categorization task, five patients (P1, P2, P7, P8, and P10) and eight control participants reached ceiling. Ceiling effects are not an issue in the semantic association task, in which no patients and only two controls achieved perfect performance; the fact that target patients were not impaired in this task detracts from the plausibility of purely semantic deficits. The fact remains that the current data do not enable us to rule out subtle deficits on categorization in these patients. However, four of five patients who obtained perfect performance in the categorization task belonged to the target clinical group, which does not support the hypothesis that categorization deficits were the hallmark of the semantic impairment shown by this clinical sample. Furthermore, previous cases of semantic memory deficits secondary to medial thalamic ischemia also did not affect categorization per se (Raymer, Moberg, Crosson, Nadeau, & Gonzalez-Rothi, 1997; patient W. T.). We suggest that more than the difficulty factor alone is necessary to explain the present evidence.

A second interpretation stems from the additional requirements of recalling and naming a third object in the semantic retrieval task but not in categorization and semantic association. Some target patients showed more misses compared with controls, that is, they failed to activate the object (most notably, P2, P4, P5, and P7). Given the sample size of the target group (six patients), the fact that misses were not significantly increased at the group level can hardly lead to conclude that this source of error was of minor importance. On the contrary, whereas four of six target patients displayed increased misses (with patients performing several standard deviations above healthy controls), only one of four control patients showed a similar pattern (Figure 6). Hence, recognizing a pair as a target and activating the third object was problematic for target patients. Misses might have been motivated by a lexical deficit (anomia), that is, failure to engage in phonological representations from semantics (Raymer et al., 1997); alternatively, misses could be because of failure to activate a representation of the third object based on semantic knowledge. Given the absence of semantic association deficits (Figure 4B), anomia was likely the origin of the deficits in semantic retrieval. Notably, selective anomia for nonliving items could have disproportionately affected performance in the semantic retrieval task, because there was imbalance between living and nonliving items in the target stimuli of this task (Table 2). However, no such pattern was apparent in the aphasia battery. It remains to be ascertained whether this sort of impairments consequent to thalamic lesions applies to taxonomic semantics—the semantic retrieval task employed here mainly taps associative semantics.

A third interpretation considers the increased number of incorrect responses to targets. The significant effect of group on false recall rate raises the possibility of a mild semantic deficit (phonology is accessible from semantics, but the semantic space is distorted) that could contribute to explain the poor performance on semantic retrieval. Patients did not show increased distractibility, that is, they did not respond to distracters more frequently than controls, hence there is no evidence of general attention deficits. Incorrect activations to targets may also suggest a failure in monitoring the responses. This interpretation would be consistent with evidence pointing to executive deficits in patients with thalamic lesions (Moscovitch & Melo, 1997; reviewed by Van der Werf et al., 2003; Kopelman, 2002). Impaired thalamo-cortical coordination might blunt concepts definition, resulting in inaccurate responses particularly in tasks that require unambiguous activation and selection of a response (Raymer et al., 1997), such as the semantic retrieval task. However, the task employed in the current study required naming; thus, it does not allow a clear conclusion in favor of a conceptual—rather than lexical—deficit. The same argument applies to the marginally significant difference found in the similarities subtest of the Wechsler Adult Intelligence Scale. This test shares some features of the semantic retrieval task, but there are also important differences. First, participants are required at least in some instances to retrieve superordinate concepts (e.g., “animal” from “dog” and “lion”) that are expected to be more resistant to concept distortion. Second, there is a wide range of correct responses, which is not the case for the semantic retrieval task. Again, however, anomia could play a role in this marginal difference, so that using a nonverbal control task might provide more stringent evidence in future studies.

In summary, multiple factors likely contribute to the observed deficits, possibly because of damage to different thalamo-cortical networks. Current results suggest a lexical deficit (anomia) in participants who did not show clinically relevant aphasia. Given that anomia showed some heterogeneity in the target clinical sample (Figure 6) in spite of similar lesion localization, it is also possible that mild conceptual (e.g., semantic) deficits played a role in originating the impairments detected on semantic retrieval, as suggested by the increased rate of false activations.

Relationships between Lesion Localization and Behavioral Results

Lesions were assessed at the time of testing by using routine diagnostic scans showing damage to the MD and the VL as a consequence of ischemia. Importantly, lesions to the anterior and laterodorsal nuclei which play a major role in episodic memory (Aggleton et al., 2011) were negligible. The follow-up assessment confirmed that, in five of the six patients reassessed, the MD suffered the greatest damage, whereas in patient P6, it remained unaffected. There is a clear separation between the medial lesions of patients P1, P4, P7, P8, and P10 and the lesion of patient P6. Interestingly, patient P6 performed at ceiling on hit rate in the semantic retrieval task (Figure 5). It should be noted that, although the lesion of patient P6 was quite small, its size was comparable with the size of the other lesions. Patient P10, for instance, was a right-handed man in the same age range of patient P6, with the same years of education; the volume of the lesion was comparable in these two patients, but in P10, it almost exclusively affected the Pf and the MD. The accuracy achieved by patient P10 on Pr for semantic retrieval was 4 SD below the controls' mean. Notably, P10 showed increased false alarms and false activations (Figure 6), a behavioral pattern that could be expected in a patient with damage to the CM–Pf. In general, inspection of the data shown in Table 3 suggests that the lesion localization was critical in affecting behavioral performance, because patients with similar lesion volumes performed differently. In Figure 6, it can be seen that target patients were all above controls' mean with respect to false activations. This explains why, by running a group analysis, we found a significant effect of group (Categorization, Semantic Association, and Semantic Retrieval section). This was not the case for “no activations”: Two target patients performed below controls' mean, resulting in a marginal difference at the group level (Categorization, Semantic Association, and Semantic Retrieval section), although the effect size of this deficit was clearly larger for some of the target patients (Figure 6).

Unfortunately, it was not possible to reassess the lesions of patients P5 and P9, who, similar to patient P6, displayed more lateral lacunae (Figure 1; see Participants section). In patient P5, the large deficits detected depend particularly on increased misses and increased false alarms. In this patient, damage to the VL could have been accompanied by pulvinar damage, given the posterior lesion location (Figure 2). The performance of patient P9, who was assigned to the control clinical sample, is also interesting because it markedly differed from the perfect performance of patient P6. This patient showed increased false alarms and greatly increased false activations compared with healthy controls, which might suggest undetected additional thalamic damage. It cannot be excluded that intralaminar lesions in these patients have been overlooked during the first low-resolution assessment.

The present data nevertheless involve the MD and the CM–Pf in semantic retrieval (Figure 2). The MD is part of a thalamo-frontal network thought to underlie some aspects of executive function (Van der Werf et al., 2003; Kopelman, 2002; Markowitsch, 1982). In particular, its parvocellular portion is reciprocally connected with the dorsolateral pFC (Barbas, Garcìa-Cabezas, & Zikopoulos, 2012; Ray & Price, 1993; Preuss & Goldman-Rakic, 1987; Russchen, Amaral, & Price, 1987), which is crucial for semantic memory (Hayama & Rugg, 2009; Martin & Chao, 2001). The parvocellular MD has been recently related to episodic recall (which involves activation of an episodic representation) but not nonassociative recognition (which does not involve episodic activation) in a clinical study involving patients with medial thalamic lesions (Pergola, Güntürkün, et al., 2012). Clinical conditions such as schizophrenia also show striking relationships with the MD. Schizophrenia implies dysfunction in the dorsolateral pFC and is characterized by impaired semantic memory and executive function (reviewed by Kuperberg, 2008). Postmortem studies found specific cell loss in the MD of schizophrenic patients (Byne et al., 2002; Young, Manaye, Liang, Hicks, & German, 2000) and especially of its parvocellular portion (Popken, Bunney, Potkin, & Jones, 2000). The MD might be required for activation of accurate item representations (including phonological representations; for a review, see Barbas et al., 2012) from semantic and episodic memory (Van der Werf et al., 2003; Nadeau & Crosson, 1997), consistent with recent proposals on the importance of structured knowledge for episodic memory (Greenberg & Verfaellie, 2010).

The CM–Pf complex, on the other hand, is strongly connected with the pallidum (Sadikot, Parent, & Francois, 1992) and may be involved in gaze control (reviewed by Jones, 2007), attention (Van der Werf, Witter, & Groenegen, 2002), and performance monitoring (Peterburs et al., 2011; Bellebaum, Hoffmann, Koch, Schwarz, & Daum, 2006; Bellebaum, Daum, Koch, Schwarz, & Hoffmann, 2005; Versino, Beltrami, Uggetti, & Cosi, 2000; Gaymard, Rivaud, & Pierrot-Deseilligny, 1994). The role of the BG in lexical decisions and response control has been highlighted by Barbas et al. (2012) and Wallesch and Papagno (1988). The intralaminar thalamic nuclei also show altered metabolism in schizophrenic patients (Hazlett et al., 2004). Additionally, Nadeau and Crosson (1997) assigned a paramount role in semantic memory to these thalamic nuclei based on their relationship with the prefrontal cortices and the cortical control of the activity of the thalamic reticular nucleus.

From the current data, it is unclear whether the ventral MD, which in paramedian stroke is more likely damaged compared with its dorsal aspects, may yield greater importance for semantic memory compared with the dorsal MD. It has recently been shown that the MD is rather heterogeneous with respect to its connectivity pattern (Rovò, Ulbert, & Acsa'dy, 2012).

Conclusions

Thalamic activity might regulate activation of semantic and phonological representations based on cues, hence semantic retrieval, possibly relying on high-frequency electrophysiological thalamo-cortical oscillations (Huguenard & McCormick, 2007; Kraut et al., 2002; Slotnick, Moo, Kraut, Lesser, & Hart, 2002). We could show that lesion to the medial thalamus specifically impairs semantic retrieval, possibly by disrupting the MD pFC and/or the intralaminar BG frontal network. The behavioral pattern shown by target patients points to anomic deficits as the basis of the impairment on semantic retrieval.

Further evidence may shed light on the mild conceptual deficits detected in the current investigation through the significantly increased false recall rate. Crucial steps in this path include precise mapping of the functional activations and investigation of patients with selective MD versus selective intralaminar lesions.

Reprint requests should be sent to Giulio Pergola, Department of Cognitive Neuroscience, International School for Advanced Studies (SISSA), via Bonomea 265, I-34136 Trieste, Italy, or via e-mail: giuliopergola@yahoo.it.

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