Prospective memory in thalamic amnesia

Neuropsychologia 49 (2011) 2199–2208

Contents lists available at ScienceDirect

Neuropsychologia journal homepage: www.elsevier.com/locate/neuropsychologia

Prospective memory in thalamic amnesia G.A. Carlesimo a,b,∗ , A. Costa b , L. Serra c , M. Bozzali c , L. Fadda a,b , C. Caltagirone a,b a

Neurology Clinic, Tor Vergata University, Rome, Italy Unit of Clinical and Behavioral Neurology, Santa Lucia Foundation, IRCCS, Rome, Italy c Neuroimaging Laboratory, Santa Lucia Foundation, IRCCS, Rome, Italy b

a r t i c l e

i n f o

Article history: Received 16 August 2010 Received in revised form 10 November 2010 Accepted 12 November 2010 Available online 27 November 2010 Keywords: Prospective memory Thalamus Amnesia Executive functions

a b s t r a c t The contribution of the thalamus to the functioning of prospective memory (PM) is currently unknown. Here we report an experimental investigation of the performance of two patients with bilateral infarcts in the anterior-mesial regions of the thalami on an event-based PM paradigm. One patient, G.P., had a pervasive declarative memory impairment but no significant executive deficit. The other patient, R.F., had a memory deficit limited to verbal material with associated behavioral abnormalities (inertia and apathy); she performed poorly on tests of executive functions. Although both patients performed poorly on the PM task, a qualitative analysis of performance revealed different mechanisms at the base of their impaired PM. G.P. had reduced declarative memory for target words compared with normal controls; but, unforgotten words were normally able to elicit his recall of the prospective intention. Conversely, R.F.’s declarative memory for target words was as accurate as that of normal controls, but she presented a dramatically reduced ratio between the number of target words she recalled and the number of times she activated the prospective intention on the PM task, suggesting that her deficit consisted of difficulty in activating the intention despite normal declarative memory for the target events. In conclusion, results of the present study demonstrate that thalamic structures have an important role in PM processes. They also document that damage to the anterior-mesial regions of the thalami affects PM abilities by two different mechanisms, respectively based on the relative disruption of declarative memory or executive processes functioning, which, in turn, is related to the specific intrathalamic structures involved by the lesions. Indeed, while G.P.’s pervasive declarative memory deficit was underlain by bilateral involvement of the mammillo-thalamic tract, R.F.’s executive and behavioral abnormalities were likely related to bilateral damage of the midline, intralaminar, and medio-dorsal nuclei. © 2010 Elsevier Ltd. All rights reserved.

1. Introduction Prospective memory (PM) is generally defined as the cognitive ability (or set of cognitive abilities) that enables an individual to carry out a previously planned action at the appropriate time (Einstein & McDaniel, 1996; Ellis & Kvavilashvili, 2000). Over the last few years, there has been an increasing interest in PM among neuropsychologists. Both observational and experimental studies in clinical populations have reported that PM is particularly vulnerable to brain damage. In fact, it has been found impaired in a variety of neurological and psychiatric conditions, such as closed head injury (Carlesimo, Casadio, & Caltagirone, 2004; Fleming et al., 2008; Groot, Wilson, Evans, & Watson, 2002), Parkinson’s disease (Costa, Peppe, Caltagirone, & Carlesimo, 2008; Kliegel, Phillips, Lemke, & Kopp, 2005), preclinical (Kazui et al., 2005; Troyer &

∗ Corresponding author at: IRCCS S. Lucia, V. Ardeatina, 306, 00179 Rome, Italy. Tel.: +39 06 51501517; fax: +39 06 51501388. E-mail address: [email protected] (G.A. Carlesimo). 0028-3932/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropsychologia.2010.11.013

Murphy, 2007) and early Alzheimer’s disease (Huppert & Beardsall, 1993), and schizophrenia (Wang et al., 2009). Many different experimental paradigms have been proposed for laboratory-based investigations of PM. According to Burgess, Scott, and Frith (2003), an experimental paradigm suitable for PM investigation should fulfill the following criteria: (i) subjects under assessment should be first informed that at the occurrence of a specific event (event-based task) or at the expiration of a given time (time-based task) they are expected to carry out some action; (ii) the delay period between creating the intention and occurrence of the appropriate time to act (the socalled “retention interval”) is filled with activities known as the “ongoing task”, which prevents continuous, conscious rehearsal of the intention over the entire delay period; and (iii) the retrieval context (time expiration or event occurrence) does not interfere with, or directly interrupt, performance of the ongoing task; under these conditions, intention enactment is self-initiated. It is still being debated whether and to what extent the cognitive abilities involved in remembering to perform a previously planned action overlap with or differ from those implicated in more

2200

G.A. Carlesimo et al. / Neuropsychologia 49 (2011) 2199–2208

traditional assessments of retrospective memory (which assess the ability to remember previous events or previously acquired information). In fact, PM tasks share with retrospective memory tasks the need to encode, maintaining over time and successively retrieving some new information (e.g., a word list in a retrospective memory task or the trigger time or event in a PM paradigm, and the specific actions to be performed). However, a critical difference between these two experimental conditions is that, unlike retrospective memory tasks in which the examiner prompts the experimental subjects to initiate retrieval of studied items, in a typical PM task subjects have to rely exclusively on their own initiative to start an intended action in response to a trigger time or event. This implies that two cognitive components are critical for the correct delayed execution of planned actions: (i) a more typical prospective component, which allows subjects to reactivate the intention at the appropriate time or when the cue event occurs, without any explicit external prompt and (ii) a retrospective memory component, which allows subjects to effectively encode and remember the cue event or time together with the particular actions to be performed (Ellis, 1996; Kvavilashvili, 1987). It is generally acknowledged that the retrospective component of a PM task relies on the same declarative memory system also involved in the encoding and successive retrieval of past events. Conversely, a number of cognitive abilities (some of which are still underspecified) contribute to the effective functioning of the prospective component (Burgess & Shallice, 1997; Guynn, McDaniel, & Einstein, 1998; Kvavilashvili, 1987; Marsh, Hicks, & Landau, 1998). Planning, attentional, time monitoring, and set-shifting abilities, as well as motivational factors, are all implicated in reactivating the prospective intention at the appropriate time. Some of these abilities are considered part of the executive system. The role of executive or declarative memory abilities in mediating PM processes has been confirmed by neuropsychological studies of both healthy elderly subjects and patients with brain damage. For example, in a study by McDaniel, Glisky, Rubin, Guynn and Routhieaux (1999), a group of 41 healthy elderly individuals, divided into 4 experimental groups on the basis of their performance on tests of executive functions and declarative memory, were submitted to an event-based PM task. The authors found that subjects with higher functioning executive abilities showed better prospective remembering than those with lower functioning executive abilities. Conversely, they found no significant difference in performance on the PM task which could be attributed to reduced declarative memory functioning (see McFarland & Glisky, 2009, for analogous results). Instead, the hypothesis that performance on the prospective and retrospective components of a PM task mainly relies on executive functions and declarative memory abilities, respectively, is supported by the results of a previous study by our group involving 16 patients suffering from chronic sequelae of severe closed head injuries (Carlesimo et al., 2004). In that study, we reported a strict association between accuracy in the spontaneous retrieval of intention (i.e., the prospective component of the PM task) and performance on the Wisconsin Card Sorting Test. Conversely, accuracy in remembering the specific actions to be performed (i.e., the retrospective component) was related to performance on tests of anterograde declarative memory, such as free recall of a word list and a short story. The different reliance of retrospective and prospective components of PM on declarative and executive abilities suggests that the same brain regions that subserve these cognitive abilities are also directly implicated in PM. In this perspective, it has been suggested that the mesial areas of the temporal lobes, whose role in declarative memory is well established, might support the retrospective component of memory, whereas the frontal lobes, more involved in executive functions, might support its prospective component (Adda, Castro, Além-Mar e Silva, de Manreza, & Kashiara, 2008;

Carlesimo et al., 2004; Poppenk, Moscovitch, McIntosh, Ozcelik, & Craik, 2010). The contribution of neuropsychology to the search for the anatomical basis of PM has thus far been rather scanty. In a study by Burgess, Veitch, de Lacy Costello, and Shallice (2000), 60 patients with circumscribed cerebral lesions were administered a multitasking procedure that included the assessment of eventbased PM functioning. On the basis of structural equation modeling, these authors concluded that the left anterior and posterior cingulate gyri are both implicated in retrospective memory demands, whereas left BA 8, 9, and 10, together with the right dorso-lateral prefrontal cortex, support processes of PM and planning functions. Involvement of the mesio-temporal regions in PM functioning was, instead, supported by a study comparing performances on event-based and time-based PM tasks of 26 patients with right hippocampal sclerosis, 22 patients with left hippocampal sclerosis, and 26 matched controls (Adda et al., 2008). Overall, the patients performed significantly worse than the healthy controls on both PM tasks. Moreover, the patients with left-sided hippocampal sclerosis performed worse than those with right-sided involvement on the event-based task. No doubt richer has been the contribution of functional neuroimaging at clarifying the neural substrates of PM. Using PET, Okuda et al. (1998) found that the rostral, dorso-lateral, and mesial regions of the frontal lobes were more activated when subjects performed an event-based PM task than when they were involved in a verbal span task. Although these authors identified a specific region of activation in the left parahippocampus, they did not speculate on the potentially different roles of frontal and mesiotemporal circuits in the processing of prospective and retrospective components of the PM task. Subsequent studies emphasized the role of the most rostral region of the frontal lobes (broadly corresponding to BA 10) in maintaining the delayed intention during a PM task (e.g., Burgess, Quayle, & Frith, 2001; Burgess et al., 2003). In the most recent functional imaging study on this topic, Poppenk et al. (2010) reported that activations in left prefrontal BA 10 and in the right parahippocampal gyrus were directly correlated with subjects’ performances on an event-based PM task. These authors explicitly acknowledged the crucial contribution of these cortical areas involved in executive and declarative memory functions in supporting the prospective and retrospective components of PM. In this paper, we report the results of a study investigating the role of the human thalamus in PM functioning. A role of the thalamus in PM can be hypothesized based on the above mentioned roles of declarative memory and executive functions in normal PM functioning, Indeed, in the context of a complex and multifaceted contribution of the thalamus to cognition, the domains in which the role of the thalamus is most documented are declarative memory and executive functions. In a series of papers, Van der Werf, Witter, Uylings, and Jolles (2000) and Van der Werf et al. (2003) established that a clear relationship exists between deficits of these two main cognitive domains and well localized lesions of the thalamus. Concerning declarative memory, these authors demonstrated unequivocally that a focal thalamic lesion can produce a hippocampal-like amnesic syndrome only when the mammillo-thalamic tract (MTT) is involved. In fact, in a review of the literature (Van der Werf et al., 2000) they documented that the MTT was lesioned in virtually all reported cases of individuals who became amnesic following a thalamic infarct. In another study, which reported the results of a neuropsychological investigation of 22 new cases with focal thalamic lesions, the overlap and subtraction image analysis revealed a close association between the presence of an amnesic syndrome and damage in an area of the ventral anterior region of the left thalamus, coinciding with the location of the MTT (Van der Werf et al., 2003). It is widely accepted that a lesion to the MTT, which directly connects the mammillary bodies to the anterior thalamic nuclei, may produce an amnesic syndrome because of its critical position in the declarative mem-

G.A. Carlesimo et al. / Neuropsychologia 49 (2011) 2199–2208

ory circuit. What remains less clear is the relationship between focal lesions of the thalamus and impairment of executive functions. In the review cited above, Van der Werf et al. (2000) suggest that damage localized in the midline, intralaminar, and MD nuclei may impair executive functions. According to this view, an isolated lesion of one of these structures is not sufficient to produce clinical deficits that would require the concomitant involvement of at least two of them. In the study mentioned above, based on overlap and subtraction image analysis in patients with thalamic infarction (Van der Werf et al., 2003), the medial ventral part of the thalamus (especially on the left side) was significantly more associated with deficits of executive functions than other thalamic regions. This part of the thalamus includes the ventral MD nucleus, the midline, and the medial intralaminar nuclei. Theoretically, this is consistent with the notion that all these nuclei have diffuse projections to the frontal lobes (e.g., Behrens et al., 2003; Johansen-Berg et al., 2005; see also Aggleton and Brown (1999) for a discussion of functional dissociations in cognition within the thalamic nuclei). Some clues about the involvement of the thalamus in PM functioning come from functional neuroimaging investigations. In two different studies conducted by Burgess et al. (2001, 2003), increased activity in the frontopolar cortex during performance of an eventbased PM task was associated with increased activity in the medial part of the right thalamus, roughly corresponding to the mediodorsal (MD) nucleus. In the only neuropsychological investigation published thus far on involvement of the thalamus in PM, Cheng, Tian, Hu, Wang, Wang (2010) compared the performance of a group of patients with thalamic stroke and a group of matched healthy controls on tests of event-based and time-based PM. Compared with healthy controls, the thalamic patients were impaired on the time-based but not the event-based task. Unfortunately, as the intrathalamic localization of the lesions in these patients was not reported, no conclusions could be drawn from these data about the relative role played by specific thalamic structures in PM. Here we report the results of an experimental investigation of PM functioning in two patients with bilateral lacunar infarcts of the thalamus. The patients, who presented with different neuropsychological profiles, were also characterized by different anatomical involvements of the thalami. In reporting these two patients, our aims were the following: (i) to characterize the pattern of their PM deficits (focusing especially on the distinction between prospective and retrospective components) in relation with those of declarative memory and executive functions and (ii) to assess whether there is an association between anatomical location of thalamic lesions and different patterns of PM impairment. 2. Case report Case 1. This patient (G.P.) was described in a previous paper (Carlesimo et al., 2007). Briefly, he was a 38-year-old, right-handed, highly educated (degree in law) man when he was first referred to our memory clinic for a deep amnesic syndrome. A radiological assessment revealed a bilateral infarct of the anterior-medial part of the thalami. An experimental investigation of his declarative memory deficit (reported in Carlesimo et al., 2007) revealed a clear dissociation between impaired recollection, but preserved familiarity, in recognition tests. Case 2. R.F., a 61-year-old, right-handed woman, with a high school degree, and occupied as a housewife, had an abrupt onset of a confusional state. On the following days, she was diagnosed as having severe memory deficits in association with behavioral inertia and apathy. A formal neuropsychological examination revealed deficits on tests of verbal episodic memory and executive functions. A cerebral MRI scan, performed 30 days after clinical onset, showed the presence of two roughly symmetrical ischemic lesions

2201

in the anterior-medial portion of the right and left thalamus in the absence of any other macroscopic damage. We first observed R.F. three months after clinical onset. At that time, her general behavior was dominated by inertia, apathy, lack of initiative, and a general loss of insight. Although her neurological examination was substantially unremarkable, her relatives reported that she had significant memory problems and great difficulty in doing housework that had been routine before her illness. Basic cultural knowledge and remote memory for public events and familiar people were apparently preserved. 2.1. Neuropsychological examination The neuropsychological investigation was aimed at evaluating G.P.’s and R.F.’s performance on tests of general intelligence, executive functions, visual-spatial abilities, short-term memory, and declarative episodic memory. The patients’ scores on all tests were first adjusted for age and education according to published norms. Normalized scores were then compared to the score distribution in the normative population. As shown in Table 1, both patients performed normally on tests of general intelligence, although probably somewhat lower than expected based on their high educational level and social status. Note, however, that a significant discrepancy emerged in G.P. between high verbal but less than normal performance IQ on the Wechsler Intelligence scale. The patient’s particularly poor performance on the visual-constructive subtests of the WAIS (Block Design and Object Assembly) was confirmed by low scores on tests of copying drawings. As already noted in Carlesimo et al. (2007), the larger extension of the ischemic lesion in the right thalamus might explain G.P.’s poor performance on tests requiring high-level integration between visual-spatial perception and praxic abilities (Vogel, Bowers, & Vogel, 2003). Note, however, that G.P. obtained normal scores on Raven’s Progressive Matrices, which assess nonverbal intelligence but require no praxic ability. On tests of executive functions, G.P. performed consistently in the normal range. Conversely, R.F. scored below the 5‰ on the Modified Card Sorting Test, and below the 10‰ on the Phonological Verbal Fluency Test. On the Trail Making Test, R.F.’s performance was within the normal range, but was definitely poorer than G.P.’s. On all tests assessing declarative episodic memory for verbal material (regardless of whether they were based on free recall or recognition procedures), both patients were remarkably impaired. Conversely, they performed differently when assessed on tests of visual and spatial memory. Here G.P. performed poorly on all tests, whereas R.F. scored consistently within the normal range (Table 2). To summarize, there are several common features together with some significant discrepancies in the cognitive profiles of the two cases presented here. Both patients have normal intelligence and a remarkable deficit of episodic verbal memory. However, R.F., but not G.P., has some “frontal” features, as demonstrated by her behavioral abnormalities (inertia and apathy) and poor performance on tests of executive functions. Moreover, G.P., but not R.F., suffers from a declarative memory deficit for visual-spatial material that is as severe as that for verbal material. 2.2. Neuroradiological investigation Both patients underwent an MRI brain scan at 3.0 T (Siemens, Medical Solutions, Erlangen, Germany). In a single session, the following pulse sequences were collected: (a) dual-echo spin echo (DE-SE) (TR = 5000 ms, TE = 20/100 ms) and (b) 3D T1weighted turbo-flash magnetization-prepared rapid-acquisition gradient echo (MPRAGE) (TR = 7.92 ms; TE = 2.4 ms, TI = 210 ms, flip

2202

G.A. Carlesimo et al. / Neuropsychologia 49 (2011) 2199–2208

Table 1 G.P.’s and R.F.’s performance scores on tests of general intelligence, executive functions and visuo-perceptual abilities. For the WAIS subtests, scaled scores are reported. For the other tests, the scores reported are adjusted for age, education, and gender according to published normative data. References from which normative data and, when available, percentile scores were derived are also reported. Test

G.P.

General intelligence WAIS-R (Wechsler, 1981) Information 12 Digit span 13 16 Vocabulary 15 Arithmetic Comprehension 19 13 Similarities 9 Picture completion 10 Picture arrangement 4 Block design 2 Object assembly 9 Digit symbol 133 Verbal IQ 76 Performance IQ 110 Full-scale IQ 26.2 (>30‰) Raven’s Coloured Matrices (Carlesimo et al., 1996) Executive functions Modified Card Sorting Test (Nocentini, Di Vincenzo, Panella, Pasqualetti, & Caltagirone, 2002) 6 (=100‰) Criteria achieved 2.6 (>50‰) Perseverative errors 47.3 (>50‰) Phonological Verbal Fluency (Carlesimo, Caltagirone, Gainotti, 1996) Trail Making Test (Giovagnoli et al., 1997) 48 s (>40‰) A B 79 s (>50‰) A–B 32 s (>50‰) Visual-spatial abilities 7.7 (<10‰) Copy of Drawings (Carlesimo et al., 1996) Copy of Drawings with Landmarks (Carlesimo et al., 1996) 65.1 (=10‰) Rey’s Figure Copy (Carlesimo et al., 2002) 25.0 (<10‰)

angle = 15◦ ). For the dual-echo sequence, 52 contiguous interleaved axial slices were acquired with a 2 mm slice thickness, with a 192 × 256 matrix over a 256 mm × 256 mm field of view, covering the whole brain. The MPRAGE sequence was acquired in a single slab, with a sagittal orientation, a 224 × 256 matrix size over a 256 × 256 mm2 field of view, with an effective slice thickness of 1 mm. MRI scans were first assessed visually. In both patients, thalamic damage was compatible with the presence of ischemic lesions. In G.P., thalamic involvement was asymmetrical, with the right lesion considerably larger than the left one (Fig. 1A). Conversely,

R.F.

Maximum score

10 7 8 9 6 6 5 4 4 3 4 96 87 92 24.9 (>20‰)

19 19 19 19 19 19 19 19 19 19 19

2 (<5‰) 15.4 (<5‰) 19.4 (<10‰)

6 0

36

81 (<10‰) 139 (>30‰) 58 (>25‰) 10.2 (>25‰) 68.1 (> 25‰) 29.7 (>50‰)

12 70 36

R.F. showed more symmetrical thalamic involvement, showing lesions with a similar location and extension between hemispheres (Fig. 1B). Moreover, R.F.’s lesions were more posterior than G.P.’s. Neither patient showed additional brain abnormalities in DE-SE or in T1 weighted scans. T1 weighted scans were also used to obtain a more quantitative assessment of the thalamic damage. To reduce the between subjects variability in gross brain size and to circumvent the errorprone collection of an index of brain size, T1-weighted images were first transferred into normalized space using a 9-parameter reg-

Table 2 G.P.’s and R.F.’s performance on tests of short-term and declarative episodic memory. For all tests (except for the subtests of the Camden Memory battery), reported scores are adjusted for age, education, and gender according to published normative data. References from which normative data and percentile scores were derived are also reported. Test Short-term memory Digit span (Orsini et al., 1987) Corsi span (Orsini et al., 1987) Immediate Visual Memory (Carlesimo et al., 1996) Declarative verbal memory 15-word learning task (Carlesimo et al., 1996) Immediate recall 15 min delayed recall Prose recall (Mauri et al., 1997) Immediate recall 20 min delayed recall Camden Memory test (Warrington, 1996) Paired associate learning Words Declarative visual-spatial memory Rey’s Figure (Carlesimo et al., 2002) Immediate reproduction 15 min delayed reproduction Supraspan spatial sequence learning (Spinnler & Tognoni, 1987) Camden Memory test (Warrington, 1996) Pictorial Topographical Faces

G.P.

R.F.

Maximum score

7.2 (>50‰) 6.2 (>50‰) 18.8 (>25‰)

5.7 (>50‰) 4.0 (>25‰) 17.6 (>25‰)

9 9 22

30.4 (<10‰) 0 (<1‰)

17.9 (<5‰) 0 (<5‰)

75 15

6 (>25‰) 2.3 (<5‰)

0 (<5‰) 0 (<5‰)

4 (<1‰) 23 (=15‰)

12 (<5‰) 17 (<5‰)

30 25

4.9 (<5‰) 1.7 (<5‰) 4.2 (<5‰)

9.4 (<10‰) 8.8 (<10‰) 19.4 (>50‰)

36 36 30.8

27 (<5‰) 17 (<5‰) 25 (>50‰)

29 (>30‰) 20 (>15‰) 24 (>70‰)

30 30 25

8 8

G.A. Carlesimo et al. / Neuropsychologia 49 (2011) 2199–2208

2203

Fig. 1. Bilateral thalamic damage detectable on T1-weighted images in the two patients as shown in sagittal (top), coronal (middle), and axial view (bottom). In G.P., involvement of the thalamus was more asymmetrical, with the right lesion considerably larger than the left one (left). Conversely, R.F. presented with more symmetrical thalamic involvement, showing lesions with a similar location and extension between hemispheres (right).

istration algorithm (Collins, Neelin, Peters, & Evans, 1994). Then, for each patient, involvement of thalamic nuclei and fibers was assessed using the interactive program DISPLAY (Brain Imaging Center, Montreal Neurological Institute, McGill University) and comparing the distribution of tissue damage with Mai, Assheuer, and Paxinos’s human brain atlas (2004). In light of the different neuropsychological characteristics observed in G.P. and R.F., the principal aim of this image analysis was to assess whether the MTT, the MD, and the intralaminar and midline nuclei were differently involved in the two patients. As mentioned in the introduction, differential damage to these thalamic structures was previously associated with specific deficits in declarative memory (MTT) and executive functions (MD, intralaminar and midline nuclei). As shown in Fig. 2, G.P.’s ischemic lesions were mainly confined to the MTT bilaterally and only marginally involved the reuniens nucleus, which is part of the midline nuclei. The intralaminar and MD nuclei appeared completely preserved in this patient. Conversely, R.F.’s brain damage involved the MTT only on the left side and strongly affected the reuniens nucleus (in the midline group), the parafascicularis and central-median nuclei (in the intralaminar group), and the ventral part of the MD nucleus. In summary, G.P.’s damage seems to be more critically associated with thalamic control of memory functions, which accounts for his amnesic syndrome for both verbal and visual-spatial material. R.F.’s damage includes the left but not the right MTT, which accounts for the dissociation between impaired verbal memory and normal visual-spatial memory. Moreover, the bilateral damage of the midline, intralaminar and MD nuclei observed in R.F. (but not in G.P.) fits well with her executive deficits and behavioral abnormalities.

2.3. Experimental investigation In both patients, PM was investigated with a modified version of an event-based experimental paradigm frequently used with healthy individuals in the experimental literature (Einstein, Holland, McDaniel, & Guynn, 1992). Consistent with the criteria established by Burgess et al. (2003) for a PM task, this procedure included an encoding phase, in which experimental subjects are informed that, at the occurrence of a specific event (i.e., the presentation of a specific word) they had to carry out a specific action (in this case, press a button). The retention interval between creating the intention and occurrence of the trigger event was filled by an “ongoing task” (i.e., a verbal span task with forward or backward instructions to repeat), which prevented continuous, conscious rehearsal of the intention over the delay period. Finally, to evaluate declarative memory for the event triggering intention recall, at the end of each block the patients were requested to recall the target word(s). 2.3.1. Material Experiments were conducted in a soundproof, dimly lit room. The patients sat comfortably in an armchair placed approximately 50 cm away from the computer monitor, whose center was aligned with their eyes. The experimental material consisted of 54 bisyllabic words. All 54 words were used for the ongoing task, but only 10 of them were also used as PM target stimuli. This 10-word subset did not differ from the overall 54-word set for frequency of occurrence in the Italian language (Bortolini, Tagliavini, & Zampulli, 1971). Four experimental blocks were created; each block consisted

2204

G.A. Carlesimo et al. / Neuropsychologia 49 (2011) 2199–2208

Fig. 2. Details of distribution of thalamic damage in the two patients. For each one, the selective involvement of specific thalamic structures is reported. G.P.’s damage is mainly confined to the MTT bilaterally (red areas). Conversely, R.F.’s damage includes the MTT on the left side only, with extensive bilateral damage of the midline, intralaminar, and MD nuclei (green areas). These lesion distributions fit with the cognitive deficits observed in the patients. See text for further details. Legend: 3V: third ventricle; AD: anterodorsal nucleus; AV: anteroventral nucleus; CeMe: central medial thalamic nucleus; Co: commissural nucleus; iml: internal medullary lamina; ithp: inferior thalamic peduncle; LD: lateral dorsal nucleus; MD: medial dorsal nucleus; mt: mammillo-thalamic tract; mtg: mammillo-tegmental tract; PT: paratenial nucleus; PV: paraventricular nucleus; Re: reuniens nucleus; Rt: reticular nucleus; VA: ventroanterior thalamic nucleus; VL: ventral lateral nucleus.

of 48 trials of an ongoing task. In half of the blocks, the patients had to repeat the four-word sequence in the same order it was administered (forward modality); in the other half, the word sequences had to be repeated in reverse order (backward modality). In half of the blocks, the same target word was presented four times; in the other half, four different target words were presented once. In each block, the position of the target words was pseudo random, that is, the 48 trials were virtually divided into four parts, each one consisting of 12 trials; the target word could appear randomly in each of the 12 trials and in any of the four positions of the word sequence. In summary, two variables of interest were manipulated across four experimental blocks: (i) number of target words, which was one in half of the blocks and four in the other half; (ii) the instruction to repeat during the ongoing task, which was forward in half of the blocks and backward in the other half. The order of administration of the four blocks was randomized across subjects. 2.3.2. Procedure The experiment was preceded by a training phase in which the patients were given instructions about the PM procedure and were requested to practice on a shortened version of the task. Following this phase, and at the beginning of each experimental block, the examiner informed them that they had to execute the ongoing task in either the forward or the backward modality. He also read the target word(s) the patients had to repeat aloud immediately and after a delay interval of about 1 min and informed them that both ongoing and prospective tasks were equally import to obtain a high level of performance. Then, after a rest interval of about 2 min, the patients were required to repeat what they were required to do

during the task and to recall the target word(s). Following this preliminary session, the experimental PM procedure began. In each of 48 trials per block, the patients were presented with a sequence of four words; each word appeared for 1.5 s in white characters at the center of a black screen. Each trial ended when a cross appeared for 0.5 s at the center of the screen, followed by a 3-s interval during which the subjects had to repeat the four-word sequence in forward or backward order, according to specific instructions. If one of the words in the sequence was a target item, the patients had to press a button on the keyboard immediately (prospective task). At the end of each block, declarative memory for the target word(s) was assessed using a free recall procedure. The dependent variable for the ongoing task was the total number of four-word sequences repeated correctly. Performance on the PM task was evaluated on the basis of three different dependent variables: (i) number of target words that elicited the expected action (pressing the key button), which gave an overall index of PM functioning; (ii) number of target words recalled at the end of each block, which provided an index of functionality of the retrospective component of PM; and (iii) proportion of recalled words that elicited or did not elicit a correct response on the PM task (i.e., pressing the key button). This index, which quantifies the ability to activate the intention at the occurrence of a target event, posed that the declarative memory of the target event is available, represents a measure of the prospective component of the PM task. We predicted that if reduced declarative memory for the target words (i.e., retrospective component of PM) was the sole factor accounting for the two patients’ poor accuracy on the PM task, then the correspondence between accuracy on the PM and recall tasks should

G.A. Carlesimo et al. / Neuropsychologia 49 (2011) 2199–2208

2205

Table 3 Performance of G.P., R.F., and relative control groups on the ongoing task. Results of t tests (one-tailed) in accordance with ) are also reported.

Forward ongoing task 1 target word 4 target words Backward ongoing task 1 target word 4 target words

G.P.

Healthy controls (N = 8)

t

p

R.F.

Healthy controls (N = 14)

t

p

46 40

43.0 (5.1) 40.8 (6.5)

0.6 0.1

>0.20 >0.20

36 32

23.5 (9.8) 24.1 (10.4)

1.2 0.7

>0.10 >0.20

45 42

39.4 (9.5) 36.2 (10.6)

0.6 0.5

>0.20 >0.20

13 12

8.4 (10.8) 7.3 (9.7)

0.4 0.5

>0.20 >0.20

not differ from that of NCs. Conversely, if failure to press the button at the appearance of the target word was at least partially independent from the retrospective memory impairment, then reduced correspondence should be observed in the patients compared with the NC. 3. Results G.P.’s and R.F.’s performances were, respectively, compared with those of two different matched control groups. One group included 8 healthy men (mean age = 37.5 years; SD = 4.2; mean years of education = 18.2 years; SD = 2.1), and the other group 14 healthy women (mean age = 62.5 years; SD = 5.4; mean years of education = 12.4; SD = 3.1). Statistical comparisons between patients and controls were performed using Crawford and Garthwaite’s (2002) one-tailed significance test on the difference between the individual patient’s scores and those of the control sample. 3.1. Ongoing task As shown in Table 3, both patients performed the ongoing task similarly to their relative control groups, irrespective of whether the instruction to repeat was in the same or reversed order. Although this result was expected in G.P., it was somewhat surprising in R.F. due to her less than normal performances on tests of executive functions. Indeed, this finding suggests that R.F.’s working memory was relatively well preserved, at least for verbal material.

3.2. PM task Performance accuracy on the PM task of the two patients (G.P. and R.F.) and their relative control groups is reported in Table 4. Across the four blocks of the experimental task, both patients performed worse than controls in signaling the appearance of the target words. Indeed, R.F. was particularly impaired when there was one target word, whereas G.P. was impaired when there were four target words but not when there was one. Collapsing performance in the forward and backward conditions, G.P. correctly signaled the appearance of the target word all eight times it occurred in the one-word blocks (NCs: mean = 7.75; SD = 0.46; t = 0.5; p > 0.10) but only twice in the four-word blocks (NCs: mean = 6.10; SD = 2.11; t = 1.8; p = 0.05). Conversely, R.F. never signaled the appearance of the target word in the one-word blocks (NCs: mean = 6.79; SD = 1.89; t = 3.5; p = 0.002) and she signaled the occurrence of the target word only once in the four-word blocks; in this case, however, the difference was non significant (t = 0.9; p > 0.10) because of the low average performance and large SD in the NC group (mean = 3.71; SD = 2.89). G.P. was significantly impaired in the free recall of target words in the four-word blocks. Indeed, collapsing performances on the forward and backward conditions, he was perfectly accurate in recalling the single target word in the one-word blocks; conversely, in the four-word blocks he recalled only two out of eight words, which was significantly less that the NCs’ average (mean = 6.23; SD = 2.23; t = 1.79; p < 0.05). R.F. was as accurate as her matched controls in performing this task. Indeed, she recalled the two words

Table 4 Performance of G.P., R.F., and relative groups of healthy controls on the PM task. Results of t tests (one-tailed) are also reported in accordance with ). G.P.

NCs (N = 8)

t

p

Number of target words signaled during each block Forward ongoing task 4 4.0 (0) 0.0 0.50 1 target word 4 target words 1 3.0 (0.8) 2.4 0.02* Backward ongoing task 4 3.7 (0.5) 0.6 0.30 1 target word 4 target words 1 2.9 (1.4) 1.3 0.12 13.6 (1.8) 1.9 0.05* Total 10 Number of target words recalled at the end of each block Forward ongoing task 1 1.0 (0) 0.0 0.50 1 target word 1 3.5 (1.1) 1.8 0.03* 4 target words Backward ongoing task 1 1.0 (0) 0 0.50 1 target word 1 2.7 (1.3) 1.2 0.12 4 target words 4 8.2 (2.1) 1.8 0.05* Total Ratio of the number of words signaled over the number of words recalled at the end of each block Forward ongoing task 1 1.0 (0) 0.0 0.50 1 target word 4 target words 1 0.9 (0.1) 0.9 0.19 Backward ongoing task 1 0.9 (0.1) 0.9 0.19 1 target word 4 target words 1 0.9 (0.4) 0.2 0.41 Mean 1 0.9 (0.2) 0.3 0.39 *

R.F.

NCs (N = 14)

t

p

0 1

3.3 (1.2) 2.0 (1.6)

2.6 0.6

0.02* 0.29

0 0 1

3.5 (0.9) 1.7 (1.6) 10.5 (3.9)

3.7 1.0 2.3

0.004* 0.17 0.02*

1 1

1.0 (0) 1.5 (1.2)

0.0 0.4

0.50 0.35

1 2 5

1.0 (0) 1.5 (1.2) 5.0 (2.2)

0 0.4 0.0

0.50 0.35 0.50

0 1

0.8 (0.3) 0.9 (0.2)

2.5 0.5

0.02* 0.33

0 0 0.25

0.9 (0.2) 0.8 (0.3) 0.8 (0.3)

4.2 2.5 2.2

0.002* 0.02* 0.03*

Indicates a statistical significance (p < 0.05) for the comparisons between each single case and his own control group.

2206

G.A. Carlesimo et al. / Neuropsychologia 49 (2011) 2199–2208

in the one-word blocks (NCs: mean = 2.0; SD = 0.0) and three out of eight words in the four-word blocks (NCs: mean = 3.0; SD = 2.25; t = 0.0; p = 0.50). Finally, regarding the correspondence index between the number of target words that elicited a correct PM response and the number of words that were recalled at the end of each block, G.P. was consistently at ceiling, whereas R.F. was consistently impaired, except in the block with four different target words and a forward ongoing task. This means that to the extent to which G.P. did not forget the words, he was normally able to signal them during the PM task. R.F., instead, almost never signaled the appearance of a target word despite her normal recall of these same words at the end of each block. Results of the experimental procedure for assessing event-based PM can be summarized as follows: (i) both patients performed poorly on the PM task; (ii) G.P., but not R.F., was impaired in the recall of target words at the end of the four-word blocks; (iii) R.F. presented a dramatically reduced correspondence between the number of target words she recalled in the declarative memory task and the number of times she activated the prospective intention at the appearance of the same target words during the PM task. By contrast, in G.P. this correspondence index was fully normal, thus demonstrating that unforgotten words were normally able to elicit his recall of the prospective intention. 4. Discussion The main finding of this study is that the thalamic structures have an important role in PM processes. In fact, both of our patients, who suffered from cognitive impairment due to an isolated bilateral infarction of the anterior-mesial regions of the thalamus, showed severe deficits in an experimental paradigm devised to assess event-based PM functioning. Our data also show that thalamic damage can affect PM abilities by two different mechanisms, respectively, based on the relative disruption of declarative memory or executive processes functioning, which, in turn, is related to the specific intrathalamic structures involved in the lesions. Before discussing the implications of these results regarding the role of the thalamic structures in PM, we have to acknowledge the intrinsic limits of any neuroradiological attempt to precisely locate the specific thalamic structures damaged or spared by a focal lesion. Considering that these structures cannot be directly observed on a structural MRI scan, their exact location within the thalamus can only be inferred by comparison with images in anatomical atlases and this procedure can result in errors deriving from even small deviations/errors in the normalization procedure and/or individual differences in this relatively small and tightly packed structure. Although this is a limit of virtually all the current literature devoted to ascertaining the functional–anatomical relationships within the thalamus, it should be acknowledged that the overall picture is consistent enough to encourage this kind of attempt. For example, in a review of neuropsychological deficits following focal lesions of the anterior thalamus, Van der Werf et al. (2000) only reported patients with CT or MRI scan localization of thalamic damage. Nevertheless, the results of this investigation were highly consistent in describing a differential role for the MTT-anterior nuclei axis vs. the MD and intralaminar nuclear group with respect to declarative memory and executive functions. Future research in this field should take advantage from the work with groups of patients and should use advanced neuroimaging approaches (e.g., tractographic investigation of MTT on high resolution MR images; e.g., see Cipolotti et al., 2008) to increase confidence in identifying structures affected or spared by lesions. The interpretation of G.P.’s PM deficit seems quite straightforward. He presented a severe deficit of declarative memory for both verbal and visuo-spatial material as a result of bilateral damage to

the MTT. By contrast, consistent with substantial sparing of midline, intralaminar, and MD nuclei, he revealed no significant executive deficit. Accordingly, the PM deficit in G.P. was closely related to his difficulty in remembering target events that triggered recollection of the prospective intention. Indeed, he was as accurate as NCs in performing the intended actions at the occurrence of target words he was able to remember in the recall task. However, since in the four-word blocks he recalled significantly less words than NCs, he turned out to be less accurate than NCs also on the PM task. Previous studies in healthy elderly subjects and patients with cognitive impairments are inconsistent in highlighting a relationship between deficits in PM and declarative memory functioning (e.g., Burgess & Shallice, 1997; McDaniel et al., 1999). According to some authors (e.g., Burgess & Shallice, 1997), this could depend on the specific tasks used to investigate PM. Typically, these tasks make low demands on declarative memory resources; thus, they also allow individuals with mild to moderate memory deficits to cope with the required memory loads. As mentioned above, however, other studies in individuals with more remarkable memory deficits (e.g., Adda et al., 2008; Carlesimo et al., 2004) revealed a significant association between severity of impairment in declarative memory and ability to recall the intended actions. The case of G.P. further confirms that when deficits in declarative memory are severe enough to impair the long-term retention of even a few informative units (e.g., the four target words in our experiment), they significantly interfere with normal PM functioning. R.F.’s pattern of PM impairment was qualitatively different from that of G.P. Indeed, her reduced ability to comply with the prospective intention was not due to deficits in remembering the target words. Rather, her extremely poor performance on the PM task was due to selective failure to initiate the action (pressing the button) when the target event occurred. We interpret this pattern of PM impairment as an expression of her global neuropsychological and behavioral abnormalities. Indeed, consistently with bilateral damage of midline, intralaminar and MD nuclei, R.F. presented with a dysexecutive syndrome characterized by mental rigidity, reduced shifting abilities, and deficits in concept formation, which were associated with lack of self-initiative and apathetic mood. Conversely, consistent with the sparing of her right MTT, R.F.’s memory deficit was confined to verbal material. Building upon her relatively preserved memory functions, R.F. was as accurate as healthy controls in the recall test administered at the end of each experimental block. But, she was almost never able to rely on her preserved memory of the target words to produce the prospective intention when they appeared during the PM task. It should be acknowledged that although R.F.’s case confirmed a close association between executive dysfunctions and impaired PM (e.g., Burgess & Shallice, 1997; Carlesimo, Formisano, Bivona, Barba, & Caltagirone, 2009; Fleming et al., 2008), the exact mechanisms underlying her deficit in complying with the intended actions remain largely underspecified. Indeed, executive dysfunctions may interfere with timely activation of the prospective intention for many reasons, including (i) deficits in encoding the functional relationship between target events and intended action; (ii) deficits in monitoring the environment to detect the appearance of target events; (iii) deficits in probing memory for the intended action once the target event has been identified; (iv) deficits of attentional resources that might interfere with execution of a dual task; (v) deficits in set shifting that interfere with the switch from the ongoing to the PM task; and (vi) general inertia interfering with compliance with previously planned intentions. R.F. may have failed on our PM paradigm because of a deficit at the level of one or more of these processes, all of which are necessary for the correct fulfillment of a delayed intention. Unfortunately, we could not further investigate this patient and therefore did not have the opportunity of manipulating critical experimental variables (such

G.A. Carlesimo et al. / Neuropsychologia 49 (2011) 2199–2208

as salience of target events and their functional relationship with the intended action), which could have shed some light on the basic mechanisms of her PM deficit. Future work in this field should be aimed at better defining the precise step in the processes underlying the accurate fulfillment of delayed intentions that is altered in patients with executive deficits due to thalamic lesions or direct damage to the prefrontal cortex. In conclusion, we would like to return to the central question of this paper: what is the role of the thalamus in PM? More specifically, what is the role in this domain of different nuclei and lesioned structures in our two patients? In this regard, it might be useful to consider the role ascribed to the anterior nuclei, the MD, the midline and the intralaminar nuclei in memory functioning. According to Van der Werf et al. (2003), the anterior nuclei are involved in the selection of material for subsequent memory storage, consistently with their close connection to the hippocampal system. Damage to this mechanism would clearly interfere with creating and consolidating the memory trace of the target event and associated actions to be performed in a PM task. This is probably why G.P., who presented with bilateral damage to the MTT, failed to recollect the target words that should have triggered performance of the intended actions from his declarative memory stores. Instead, the MD, midline, and intralaminar nuclei play a more crucial role at the time of memory retrieval and, therefore, their lesioning should mainly interfere with the prospective component of a PM task. The MD nucleus, which has strong reciprocal connections with the prefrontal cortex, would be involved in governing the processes of active retrieval efforts. In particular, it should play a critical role in adjusting the prefrontal executive processes in memory depending on the plans and intentions, the emotional state, and the physical priorities of the organism. Moreover, according to Aggleton and Brown’s model (1999) of the role of the thalamus in declarative memory, the MD nucleus should play a specific role in the familiarity processes of retrieval (as opposed to the recollection processes mainly mediated by the anterior thalamic nuclei). Even though any conclusion about a possible differential role of recollection and familiarity in PM retrieval would be premature based on the presently reported data, a suggestion worthy of further investigation is that reduced familiarity processes (which should be expected following bilateral MD damage in R.F.) might interfere with the retrieval of the prospective intention because of a failure to signal the detection of the target event. The intralaminar and midline nuclei are considered critical in controlling the allocation of activation in the cortex. An example of the latter would lie in alerting mechanisms (Steriade, Jones, & McCormick, 1997), in instances where a sudden stimulus in the environment arises that needs to be attended to. In these instances, the system of intralaminar and midline nuclei should act to temporarily suppress the performance of an ongoing process to pay attention to salient stimuli. The performance of R.F., who did not self-activate to perform the intended action even though she was usually able to recollect the target words when the prompt to remember them was provided by the examiner, fits well with this hypothesis.

References Adda, C. C., Castro, L. H., Além-Mar e Silva, L. C., de Manreza, M. L., & Kashiara, R. (2008). Prospective memory and mesial temporal epilepsy associated with hippocampal sclerosis. Neuropsychologia, 46, 1954–1964. Aggleton, J. P., & Brown, M. W. (1999). Episodic memory, amnesia and the hippocampal – anterior thalamic axis. Behavioral and Brain Sciences, 22, 425–444. Behrens, T. E., Johansen-Berg, H., Woolrich, M. W., Smith, S. M., Wheeler-Kingshott, C. A., Boulby, P. A., et al. (2003). Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging. Nature Neuroscience, 6, 750–757. Bortolini, V., Tagliavini, C., & Zampilli, A. (1971). [Frequency of words in contemporary Italian language] Lessico di frequenze della lingua italiana contemporanea. Milano, Italy: Garzanti.

2207

Burgess, P. W., & Shallice, T. (1997). The relationship between prospective and retrospective memory: Neuropsychological evidence. In M. A. Conway (Ed.), Cognitive models of memory (pp. 247–272). Hove: Psychology Press. Burgess, P. W., Veitch, E., de Lacy Costello, A., & Shallice, T. (2000). The cognitive and neuroanatomical correlates of multitasking. Neuropsychologia, 38, 848– 863. Burgess, P. W., Quayle, A., & Frith, C. D. (2001). Brain regions involved in prospective memory as determined by positron emission tomography. Neuropsychologia, 39, 545–555. Burgess, P. W., Scott, S. K., & Frith, C. D. (2003). The role of the rostral frontal cortex (area 10) in prospective memory: A lateral versus medial dissociation. Neuropsychologia, 41, 906–918. Carlesimo, G. A., Buccione, I., Fadda, L., Graceffa, A., Mauri, M., Lo Russo, S., et al. (2002). Standardizzazione di due test di memoria per uso clinico: Breve racconto e figura di Rey. Nuova Rivista di Neurologia, 12, 1–13. Carlesimo, G. A., Casadio, P., & Caltagirone, C. (2004). Prospective and retrospective components in the memory for actions to be performed in patients with severe closed-head injury. Journal of the International Neuropsychological Society, 10, 679–688. Carlesimo, G. A., Caltagirone, C., Gainotti, G., & the Group for the Standardization of the Mental Deterioration Battery. (1996). The Mental Deterioration Battery: normative data, diagnostic reliability and qualitative analyses of cognitive impairment. European Neurology, 36, 378–384. Carlesimo, G. A., Serra, L., Fadda, L., Cherubini, A., Bozzali, M., & Caltagirone, C. (2007). Bilateral damage of the mammillo-thalamic tract impairs recollection but not familiarity in the recognition process: A single case investigation. Neuropsychologia, 45, 2467–2479. Carlesimo, G. A., Formisano, R., Bivona, U., Barba, L., & Caltagirone, C. (2009). Prospective memory in patients with severe closed-head injury: Role of concurrent activity and encoding instructions. Behavioral Neurology, 22, 101–110. Cheng, H., Tian, Y., Hu, P., Wang, J., & Wang, K. (2010). Time-based prospective memory impairment in patients with thalamic stroke. Behavioral Neuroscience, 124, 152–158. Cipolotti, L., Husain, M., Crinion, J., Bird, C. M., Khan, S. S., Losseff, N., Howard, R. S., & Leff, A. P. (2008). The role of the thalamus in amnesia: a tractography, highresolution MRI and neuropsychological study. Neuropsychologia, 46, 2745–2758. Collins, D. L., Neelin, P., Peters, T. M., & Evans, A. C. (1994). Automatic 3D intersubject registration of MR volumetric data into standardized Talairach space. Journal of Computer Assisted Tomography, 18, 192–205. Costa, A., Peppe, A., Caltagirone, C., & Carlesimo, G. A. (2008). Prospective memory impairment in individuals with Parkinson’s disease. Neuropsychology, 22, 283–292. Crawford, J. R., & Garthwaite, P. H. (2002). Investigation of the single case in neuropsychology: Confidence limits on the abnormality of test scores and test score differences. Neuropsychologia, 40, 1196–1208. Einstein, G. O., & McDaniel, M. A. (1996). Retrieval processes in prospective memory: Theoretical approaches and some new empirical findings. In M. Brandimonte, G. O. Einstein, & M. A. McDaniel (Eds.), Prospective memory: Theory and applications (pp. 115–141). Mahwah, NJ: Erlbaum. Einstein, G. O., Holland, L. J., McDaniel, M. A., & Guynn, M. J. (1992). Age-related deficits in prospective memory: The influence of task complexity. Psychology and Aging, 7, 471–478. Ellis, J. A. (1996). Prospective memory or the realization of delayed intentions: A conceptual framework for research. In M. Brandimonte, G. O. Einstein, & M. A. McDaniel (Eds.), Prospective memory: Theory and applications (pp. 1–22). Mahwah, NJ: Erlbaum. Ellis, J. A., & Kvavilashvili, L. (2000). Prospective memory in 2000: Past, present and future directions. Applied Cognitive Psychology, 14, S1–S9. Fleming, J., Riley, L., Gill, H., Gullo, M. J., Strong, J., & Shum, D. (2008). Predictors of prospective memory in adults with traumatic brain injury. Journal of the International Neuropsychological Society, 14, 823–831. Giovagnoli, A. R., Del Pesce, M., Mascheroni, S., Simoncelli, M., Laiacona, M., & Capitani, E. (1997). Trail making test: normative values from 287 normal adult controls. Italian Journal of Neurological Sciences, 17, 305–309. Groot, Y. C., Wilson, B. A., Evansand, J., & Watson, P. (2002). Prospective memory functioning in people with and without brain injury. Journal of the International Neuropsychological Society, 8, 645–654. Guynn, M. J., McDaniel, M. A., & Einstein, G. O. (1998). Prospective memory: When reminders fail. Memory and Cognition, 26, 287–298. Huppert, F. A., & Beardsall, L. (1993). Prospective memory impairment as an early indicator of dementia. Journal of Clinical and Experimental Neuropsychology, 15, 805–821. Johansen-Berg, H., Behrens, T. E., Sillery, E., Ciccarelli, O., Thompson, A. J., Smith, S. M., et al. (2005). Functional–anatomical validation and individual variation of diffusion tractography-based segmentation of the human thalamus. Cerebral Cortex, 15, 31–39. Kazui, H., Matsuda, A., Girono, N., Mori, E., Miyoshi, N., Ogino, A., et al. (2005). Everyday memory impairment of patients with mild cognitive impairment. Dementia and Geriatric Cognitive Disorders, 19, 331–337. Kliegel, M., Phillips, L. H., Lemke, U., & Kopp, U. A. (2005). Planning and realisation of complex intentions in patients with Parkinson’s disease. Journal of Neurology Neurosurgery and Psychiatry, 76, 1501–1505. Kvavilashvili, L. (1987). Remembering intention as a distinct form of memory. British Journal of Psychology, 78, 507–518. Mai, J. K., Assheuer, J., & Paxinos, G. (2004). Atlas of the human brain. San Diego: Academic Press.

2208

G.A. Carlesimo et al. / Neuropsychologia 49 (2011) 2199–2208

Marsh, R. L., Hicks, J. L., & Landau, J. D. (1998). An investigation of everyday prospective memory. Memory and Cognition, 26, 633–643. Mauri, M., Carlesimo, G. A., Graceffa, A. M. S., Loasses, A., Lo russo, S., Sinforiani, S., et al. (1997). Standardizzazione di due nuovi test di memoria: apprendimento di liste di parole correlate e non correlate semanticamente. Archivio di Psicologia, Neurologia e Psichiatria, 5–6, 621–645. McDaniel, M. A., Glisky, E. L., Rubin, S. R., Guynn, M. J., & Routhieaux, B. C. (1999). Prospective memory: A neuropsychological study. Neuropsychology, 13, 103–110. McFarland, C. P., & Glisky, E. L. (2009). Frontal lobe involvement in a task of timebased prospective memory. Neuropsychologia, 47, 1660–1669. Nocentini, U., Di Vincenzo, S., Panella, M., Pasqualetti, P., & Caltagirone, C. (2002). La valutazione delle funzioni esecutive nella pratica neuropsicologica; dal Modified Card Sorting Test al Modified Card Sorting Test-Roma Version. Dati di standardizzazione. Nuova Rivista di Neurologia, 12, 13–24. Okuda, J., Fujii, T., Yamadori, A., Kawashima, R., Tsukiura, T., Fukatsu, R., et al. (1998). Participation of the prefrontal cortices in prospective memory: Evidence from a PET study in humans. Neuroscience Letters, 253, 127–130. Poppenk, J., Moscovitch, M., McIntosh, A. R., Ozcelik, E., & Craik, F. I. (2010). Encoding the future: Successful processing of intentions engages predictive brain networks. Neuroimage, 49, 905–913.

Spinnler, H., & Tognoni, G. (1987). Standardizzazione e taratura italiana di test neuropsicologici. Italian Journal of Neurological Sciences, Suppl. 8, 35–38. Steriade, M., Jones, E. G., & McCormick, D. A. (1997). Thalamus, organisation and function Oxford: Elsevier. Troyer, A. M., & Murphy, K. J. (2007). Memory for intentions in amnestic mild cognitive impairment: Time- and event-based prospective memory. Journal of the International Neuropsychological Society, 13, 365–369. Van der Werf, Y. D., Witter, M. P., Uylings, H. B., & Jolles, J. (2000). Neuropsychology of infarctions in the thalamus: A review. Neuropsychologia, 38, 613– 627. 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, 1330–1344. Vogel, J. J., Bowers, C. A., & Vogel, D. S. (2003). Cerebral lateralization of spatial abilities: A meta-analysis. Brain and Cognition, 52, 197–204. Wang, Y., Cui, J., Chan, R. C., Deng, Y., Shi, H., Hong, X., et al. (2009). Metaanalysis of prospective memory in schizophrenia: Nature, extent, and correlates. Schizophrenia Research, 114, 64–70. Warrington, E. (1996). The Camden memory test. Erlbaum (UK): Psychology Press.