The temporal lobes and memory.

Since the first description of the case of H.M. in the mid-1950s, the debate over the contribution of the mesial temporal lobe (MTL) to human memory functioning has not ceased to stimulate new experimental work and the development of new theoretical models. The early demonstration that despite their devastating memory loss patients with hippocampal damage are still able to learn a number of visuo-motor and visuo-perceptual skills at a normal rate and to be normally primed by verbal and visual material suggested that the term "memory" is actually an umbrella concept that includes very different brain plasticity phenomena and that MTL damage actually impairs only one of these. Subsequent research, which capitalized on a detailed anatomical description of MTL structures and on the close analysis of memory-related phenomena, tried to define the unique role of the MTL structures in brain plasticity and in the government of human behavior. A first hypothesis identified this role in the conscious forms of memory as opposed to implicit ones. In the last two decades, the emphasis has moved to the relational role of the hippocampus in binding together different pieces of unimodal information to provide unitary, multimodal representations of personal experiences.

Subjective clustering in patients with fronto-temporal dementia.

In the behavioral variant of frontotemporal dementia (bvFTD) memory deficits have been traditionally considered as due to difficulties in encoding/retrieval frontal strategies. However, the frontal origin of memory deficits in bvFTD has been questioned and hippocampal dysfunction has been also proposed. Here we analyzed bvFTD patients' proficiency in subjectively organizing memories without an external criterion. Twenty bvFTD patients and 20 healthy individuals were assessed with memory and executive tasks. The ability to subjectively organize memories in the immediate recall of a 15 unrelated word list was measured by calculating the index of subjective clustering (ISC) based on the constancies in response order across the five consecutive free recall trials. Results revealed reduced ISC in bvFTD patients with respect to normal controls. In the bvFTD group, the ISC score correlated with the Corsi span backward score and the number of categories achieved on the Modified Card Sorting Test. The bvFTD patients' reduced ISC and its correlation with executive performance suggest that executive deficits underlie their defective strategic organization of memories. However, as ISC did not predict memory accuracy in these patients, the memory deficit may not be the mere expression of their executive difficulties.

Articulatory suppression delays processing of abstract words: The role of inner speech.

Compared to concrete concepts, like "book," abstract concepts expressed by words like "justice" are more detached from sensorial experiences, even though they are also grounded in sensorial modalities. Abstract concepts lack a single object as referent and are characterised by higher variability both within and across participants. According to the Word as Social Tool (WAT) proposal, owing to their complexity, abstract concepts need to be processed with the help of inner language. Inner language can namely help participants to re-explain to themselves the meaning of the word, to keep information active in working memory, and to prepare themselves to ask information from more competent people. While previous studies have demonstrated that the mouth is involved during abstract concepts' processing, both the functional role and the mechanisms underlying this involvement still need to be clarified. We report an experiment in which participants were required to evaluate whether 78 words were abstract or concrete by pressing two different pedals. During the judgement task, they were submitted, in different blocks, to a baseline, an articulatory suppression, and a manipulation condition. In the last two conditions, they had to repeat a syllable continually and to manipulate a softball with their dominant hand. Results showed that articulatory suppression slowed down the processing of abstract more than that of concrete words. Overall results confirm the WAT proposal's hypothesis that abstract concepts processing involves the mouth motor system and specifically inner speech. We discuss the implications for current theories of conceptual representation.

Memory for public events in amnestic mild cognitive impairment: The role of hippocampus and ventro-medial prefrontal cortex.

BACKGROUND: Current theories assume that retrograde memory deficits for semantic information in amnestic mild cognitive impairment (aMCI) are temporally graded and partially sparing most remote memories. Moreover, these models assume a prevalent role of the hippocampus in early phases of memory consolidation and of the prefrontal mesial neocortical areas in permanent consolidation of traces. PURPOSE: To explore the relationship between hippocampus and memory accuracy for the most recent public events and between the ventro-medial prefrontal cortex (vmPFC) and memory accuracy irrespective of the memory age, we investigated in aMCI patients the retrograde memory for public events and its relationship with grey matter volume reductions in the hippocampus and vmPFC. METHODS: 18 aMCI patients and 13 healthy subjects (HS) underwent a modified version of the Famous Events questionnaire (FEq) to assess their memory performance for public events. Patients underwent 3T-MRI scanning to assess correlations between FEq's scores and grey matter volumes. RESULTS: aMCI showed significantly reduced performances on FEq compared to HS in the recollection of most recent events, while no significant difference was observed for more remote memories, thus demonstrating a temporal gradient. Moreover, hippocampal volumes predicted accuracy scores for most recent, but not older, public events. Finally, an area in the subcallosal portion of the vmPFC, corresponding to BA32, predicted accuracy scores on FEq irrespective of the period examined. CONCLUSIONS: Pathological changes in a neural circuit linking hippocampal to medial prefrontal cortical regions are responsible for impaired recollection of retrograde memories in aMCI.

The role of hippocampus in the retrieval of autobiographical memories in patients with amnestic Mild Cognitive Impairment due to Alzheimer's disease.

The role of the hippocampus and neocortical areas in the retrieval of past memories in pre-dementia Alzheimer's disease (AD) patients was investigated. The aim was to assess whether the hippocampus has a temporary role in memory trace formation, according to the Cortical Reallocation Theory (CRT), or whether it continuously updates and enriches memories, according to the Multiple Trace Theory. According to the former theory, hippocampal damage should affect more recent memories, whereas the association cortex is expected to affect memories of the entire lifespan. In the second case, damage to either the hippocampus or the association cortices should affect memories of the entire lifespan. Seventeen patients with amnestic Mild Cognitive Impairment due to AD were submitted to autobiographical (i.e., episodic and semantic personal) memory assessment. Patients underwent MRI for the acquisition of T1-weighted brain volumes. Voxel-based morphometry was used to assess correlations between grey matter (GM) volumes and autobiographical memory. Correlation analyses revealed a strict association between GM volumes in the hippocampus and patients' ability to retrieve the most recent but not the oldest autobiographical memories in both aspects, episodic and semantic. Moreover, patients' GM volumes in the pre-frontal and temporal polar areas were associated with recollection of episodic and semantic events, respectively. Finally, GM volumes in the precuneus and occipital cortex were associated with retrieval of the most recent episodic events. These findings indicate that the hippocampus has a specific time-dependent role; thus, they support the CRT.

Influence of controlled encoding and retrieval facilitation on memory performance of patients with subcortical ischemic vascular dementia and Alzheimer's disease.

Patients with subcortical ischemic vascular dementia (SIVD) perform better than Alzheimer's disease patients (AD) on the Free and Cued Recall Selective Reminding test (FCSRT). In this test, SIVD are able to overcome their strategic retrieval deficit, whereas AD patients, whose memory impairment is due to a hippocampal storage deficit, are not. However, the FCSRT does not assess the advantage passing from free to assisted learning, which is expected to be different in frontal and hippocampal damage. We compared SIVD, AD and healthy subjects on the free recall of a 15-word list not assisted at encoding and on the free and cued recall of the FCRST. Indexes of Encoding, Cueing and Total (measuring the advantage passing from the 15-word list free recall to the free and cued recall of the FCRST) were computed. The two groups performed comparably poorly on the free recall of the 15-word list, but SIVD outperformed AD patients in the free and cued recall of the FCSRT and took greater advantage than AD patients on both learning and recall when passing from the unassisted to the assisted paradigms. All indexes significantly predicted diagnostic group membership, but the Total Index showed the larger classification accuracy with 80% of AD and 71% of SIVD correctly classified. These results confirm that the FCRST is able to differentiate AD and SIVD patients with a good level of accuracy. However, the evaluation of memory performance variation as a function of support to encoding provides additional data able to increase diagnostic reliability.

The Regulatory Role of the Human Mediodorsal Thalamus.

The function of the human mediodorsal thalamic nucleus (MD) has so far eluded a clear definition in terms of specific cognitive processes and tasks. Although it was at first proposed to play a role in long-term memory, a set of recent studies in animals and humans has revealed a more complex, and broader, role in several cognitive functions. The MD seems to play a multifaceted role in higher cognitive functions together with the prefrontal cortex and other cortical and subcortical brain areas. Specifically, we propose that the MD is involved in the regulation of cortical networks especially when the maintenance and temporal extension of persistent activity patterns in the frontal lobe areas are required.

Associative Agreement as a Predictor of Naming Ability in Alzheimer's Disease: A Case for the Semantic Nature of Associative Links.

We aimed to address the long-standing issue of the nature of the relationships that link a cue word to words associated with it. In keeping with a recently proposed neuropsychological model of semantic memory (Zannino et al., 2015), we provide support for the hypothesis that associative links are semantic in nature and not lexical. In support of this hypothesis, we demonstrate a relationship in healthy subjects between the probability of producing word X in response to cue word Y in a free association task and the probability of using word X to describe the meaning of word Y. Furthermore, we provide evidence that associative measures are altered in people suffering from Alzheimer's disease (AD) and predict their level of performance in a picture-naming task. We provide a parsimonious account of the experimental data gathered form these different sources of evidence according to the hypothesis that the links between a cue word and its associates can be viewed as binding a concept (the cue) to pieces of information regarding its meaning (the associates).

Exploring classical conditioning for strengthening the links between semantic and lexical representations in pure anomia: Preliminary findings from a single case study.

The same language symptom might arise at different functional loci in people with aphasia. Therefore, it is plausible that different therapeutic interventions should be adopted to approach the same difficulties in different patients. Although this point of view is still widely accepted, recently the focus has shifted from the functional locus of a rehabilitative intervention to the mechanisms of action underlying the relearning process. We maintain that both aspects should be taken into account when programming a rehabilitative intervention; furthermore, investigating relearning mechanisms might shed new light on the functional architecture of the disrupted processes. Here, we investigated, in a single case study, whether classical conditioning was a suitable relearning paradigm for targeting word-finding difficulties in pure anomia, that is in a patient with an impairment in accessing intact output lexical representations from a spared semantic system. Using a word-repetition task on picture presentation, we contrasted a condition in which the stimulus onset asynchrony between word and picture stimuli was well suited to produce classical conditioning with a condition in which repetition training could not benefit from this learning mechanism. Only classical conditioning training exerted a significant, long-lasting effect on our patient's naming skill. Tentative implications of our results for the functional architecture of single-word processing are discussed.

The contribution of neurodegenerative diseases to the modelling of semantic memory: A new proposal and a review of the literature.

This paper provides a focused review of the literature on semantic impairment in semantic dementia (SD) and Alzheimer's disease (AD). An attempt is made to interpret the most relevant phenomena in the light of a new model of semantic memory. This model comprises a language-based component (disrupted in SD and AD), which supports our ability to establish reliable token vs. type relationships in the service of propositional thinking, and a philogenetically older sensorimotor component, which is needed to categorize our environment in a more implicit way. Extant neuropsychological models of semantic memory are also reviewed and compared with the new model in terms of their ability to explain the observed phenomena and to deal with the problem of establishing token vs. type relationships starting from inconsistent cross modal input representations and arbitrary category boundaries.

A pilot study on the effect of cognitive training on BDNF serum levels in individuals with Parkinson's disease.

Parkinson's disease (PD) patients, besides motor dysfunctions, may also display mild cognitive deficits (MCI) which increase with disease progression. The neurotrophin brain-derived neurotrophic factor (BDNF) plays a role in the survival of dopaminergic neurons and in the regulation of synaptic connectivity. Moreover, the brain and peripheral level of this protein may be significantly reduced in PD patients. These data suggest that a cognitive rehabilitation protocol aimed at restoring cognitive deficits in PD patients may also involve changes in this neurotrophin. Thus, in this pilot study we evaluated the effect of a cognitive rehabilitation protocol focused on the training of executive functioning and measured BDNF serum levels in a group of PD patients with mild cognitive impairment, as compared to the effect of a placebo treatment (n = 7/8 group). The results showed that PD patients undergoing the cognitive rehabilitation, besides improving their cognitive performance as measured with the Zoo Map Test, also displayed increased serum BDNF levels as compared to the placebo group. These findings suggest that BDNF serum levels may represent a biomarker of the effects of cognitive rehabilitation in PD patients affected by MCI. However, the functional significance of this increase in PD as well as other neuropathological conditions remains to be determined.

Influence of controlled encoding and retrieval facilitation on memory performance in patients with different profiles of mild cognitive impairment.

Memory tests able to differentiate encoding and retrieval processes from the memoranda storing ones should be used to differentiate patients in a very early phase of AD. In fact, individuals with mild cognitive impairment (MCI) can be characterized by two different memory profiles: a pure amnestic one (with poor learning and retrieval and poor improvement when encoding is assisted and retrieval is facilitated) and a dysexecutive one (with inefficient encoding and/or poor retrieval strategies and improvement with assisted encoding and retrieval). The amnestic profile characterizes subjects affected by medio-temporal atrophy typical of AD. In this study, a Grober-Buschke memory procedure was used to evaluate normal controls and MCI patients with different cognitive profiles: pure amnestic (aMCIsd), amnestic plus other cognitive impairments (aMCImd) and non-amnestic (naMCI). An index of sensitivity of cueing (ISC) measured the advantage passing from free to cued recall. Results showed that both strategic and consolidation abilities were impaired in the aMCIsd and aMCImd groups and were preserved in the naMCI group. aMCImd, however, compensated the memory deficit with assisted encoding and retrieval, but aMCIsd performed very poorly. When MCI subjects were defined according to the ISC value, subjects with poor ISC were primarily in the aMCIsd group and, to a lesser extent, in the aMCImd group and the naMCI group. Finally, patients with a poor ISC showed cerebral atrophy documented in the precocious phase of AD and the retrosplenial cerebral areas seemed to be the most useful areas for identifying patients in the early phase of AD.

Atrophy of presubiculum and subiculum is the earliest hippocampal anatomical marker of Alzheimer's disease.

BACKGROUND: There is no consensus about which hippocampal subfields become atrophic earliest in the course of Alzheimer's disease (AD). METHODS: Thirty AD patients, 41 mild cognitive impairment (MCI) patients, and 38 healthy controls (HCs) underwent cerebral magnetic resonance imaging (with an automated segmentation protocol for the volumetric analysis of hippocampal subfields) and a test of immediate and delayed recall of a 15-word list. RESULTS: The volumes of the presubiculum and subiculum presented the most remarkable reduction in the patient's groups. In the MCI group, only the volumes of presubiculum and subiculum predicted performance on the memory tests. In AD patients, the volumes of all hippocampal subfields (with the notable exception of the CA1) predicted memory scores. CONCLUSIONS: Our data point to a prevalent atrophy of the presubicular-subicular complex from the early phases of AD. This finding is consistent with neuropathological observations in AD patients and probably reflects the severe degeneration of the perforant pathway while penetrating the hippocampus through the subicular field in its course from the entorhinal cortex to the dentate gyrus.

Prospective memory impairment and executive dysfunction in prefrontal lobe damaged patients: is there a causal relationship?

BACKGROUND: The prospective memory (PM) construct is aimed at capturing cognitive operations involved in the successful accomplishment of delayed intentions. It is generally agreed that PM impairment occurs in patients with prefrontal lobes damage. OBJECTIVE: To evaluate if there is a causal role of a deficit of executive abilities (failures of planning, set-shifting, selective attention, or working memory) over the PM impairment. METHODS: We report a detailed investigation of PM and executive abilities in two patients with posttraumatic damage to prefrontal lobes who complained from a reduced compliance with appointments and daily routines. RESULTS: Laboratory tests confirmed a difficulty in fulfilling delayed intentions in response to the occurrence of critical events and elapsed time. In one patient, PM impairment was associated with poor performance on tests investigating planning, working memory, and mental shifting. The other patient performed in the normal range on all executive tests. CONCLUSIONS: Despite the frequent claim of a dependence of PM deficits from executive dysfunction, the reported cases demonstrate that this is not necessarily the case. The results are discussed in the light of current hypotheses relating PM impairment to other deficits that commonly occur as a result of damage to the prefrontal lobes.

Dopamine treatment and cognitive functioning in individuals with Parkinson's disease: the "cognitive flexibility" hypothesis seems to work.

BACKGROUND: Previous data suggest that (i) dopamine modulates the ability to implement nonroutine schemata and update operations (flexibility processes) and that (ii) dopamine-related improvement may be related to baseline dopamine levels in target pathways (inverted U-shaped hypothesis). OBJECTIVE: To investigate above hypotheses in individuals with Parkinson's disease (PD). METHODS: Twenty PD patients were administered tasks varying as to flexibility load in two treatment conditions: (i) "off" condition, about 18 hours after dopamine dose and (ii) "on" condition, after dopamine administration. PD patients were separated into two groups: low performers (i.e., performance on Digit Span Backward below the sample mean) and high performers (i.e., performance above the mean). Twenty healthy individuals performed the tasks in two sessions without taking drugs. RESULTS: Passing from the "off" to the "on" state, only low performer PD patients significantly improved their performance on high-flexibility measures (interference condition of the Stroop test; P < 0.05); no significant effect was found on low-flexibility tasks. CONCLUSIONS: These findings document that high-flexibility processes are sensitive to dopamine neuromodulation in the early phases of PD. This is in line with the hypothesis that striatal dopamine pathways, affected early by PD, are precociously implicated in the expression of cognitive disorders in these individuals.

Free and cued recall memory in Parkinson's disease associated with amnestic mild cognitive impairment.

The hypothesis has been advanced that memory disorders in individuals with Parkinson's disease (PD) are related to either retrieval or consolidation failure. However, the characteristics of the memory impairments of PD patients with amnestic mild cognitive impairment have not been clarified. This study was aimed at investigating whether memory deficits in PD patients with amnestic mild cognitive impairment (PDaMCI) are due to failure of retrieval or consolidation processes. Sixteen individuals with PDaMCI, 20 with amnestic mild cognitive impairment without PD (aMCINPD), and 20 healthy controls were recruited. Participants were administered the Free and Cued Selective Reminding Test. An index of cueing was computed for each subject to capture the advantage in retrieval of cued compared to free recall. Individuals with PDaMCI performed worse than healthy controls on the free recall (p<0.01) but not the cued recall (p>0.10) task, and they performed better than aMCINPD subjects on both recall measures (p<0.01). The index of cueing of subjects with PD was comparable to that of healthy controls (p>0.10) but it was significantly higher than that of the aMCINPD sample (p<0.01). Moreover, PD patients' performance on free recall trials was significantly predicted by scores on a test investigating executive functions (i.e., the Modified Card Sorting Test; p = 0.042). Findings of the study document that, in subjects with amnestic mild cognitive impairment associated to PD, episodic memory impairment is related to retrieval rather than to consolidation failure. The same data suggest that, in these individuals, memory deficits might be due to altered frontal-related executive functioning.

Connectivity-based parcellation of the thalamus explains specific cognitive and behavioural symptoms in patients with bilateral thalamic infarct.

A novel approach based on diffusion tractography was used here to characterise the cortico-thalamic connectivity in two patients, both presenting with an isolated bilateral infarct in the thalamus, but exhibiting partially different cognitive and behavioural profiles. Both patients (G.P. and R.F.) had a pervasive deficit in episodic memory, but only one of them (R.F.) suffered also from a dysexecutive syndrome. Both patients had an MRI scan at 3T, including a T1-weighted volume. Their lesions were manually segmented. T1-volumes were normalised to standard space, and the same transformations were applied to the lesion masks. Nineteen healthy controls underwent a diffusion-tensor imaging (DTI) scan. Their DTI data were normalised to standard space and averaged. An atlas of Brodmann areas was used to parcellate the prefrontal cortex. Probabilistic tractography was used to assess the probability of connection between each voxel of the thalamus and a set of prefrontal areas. The resulting map of corticothalamic connections was superimposed onto the patients' lesion masks, to assess whether the location of the thalamic lesions in R.F. (but not in G. P.) implied connections with prefrontal areas involved in dysexecutive syndromes. In G.P., the lesion fell within areas of the thalamus poorly connected with prefrontal areas, showing only a modest probability of connection with the anterior cingulate cortex (ACC). Conversely, R.F.'s lesion fell within thalamic areas extensively connected with the ACC bilaterally, with the right dorsolateral prefrontal cortex, and with the left supplementary motor area. Despite a similar, bilateral involvement of the thalamus, the use of connectivity-based segmentation clarified that R.F.'s lesions only were located within nuclei highly connected with the prefrontal cortical areas, thus explaining the patient's frontal syndrome. This study confirms that DTI tractography is a useful tool to examine in vivo the effect of focal lesions on interconnectivity brain patterns.

Normative data for measuring performance change on parallel forms of a 15-word list recall test.

Declarative memory evaluation is an essential step in the clinical and neuropsychological assessment of a variety of neurological disorders. It typically addresses the issue of normality/abnormality of an individual's performance. Another clinical application of the neuropsychological assessment of declarative memory is the longitudinal evaluation of an individual's performance change. In fact, in a variety of neurological conditions repeated assessments are needed to evaluate the modifications of a memory disorder as a function of time or in response to a pharmacological or rehabilitation treatment. This study was aimed at collecting data for measuring and interpreting performance change on a memory test for verbal material. For this purpose, we administered to 100 healthy subjects (age range 20-80 years; years of formal education range 8-17 years) three parallel forms of a test requiring the immediate and delayed recall of a 15-word list. The subjects performed the recall test three times (each time with a different list) at least 1 week apart. The order of the lists was randomized across subjects. Results revealed that performance on the three lists was highly correlated and did not vary as a function of the order of presentation. However, accuracy of recall was slightly better on a list compared to the others. Based on a method devised by Payne and Jones (J Clin Psychol 13:115-121, 1957), we provide normative data for establishing whether a discrepancy in recall accuracy on two versions of the test exceeds the discrepancy expected based on the performance of normal controls.

The special status of verbal knowledge in semantic memory: evidence from performance of semantically impaired subjects on verbalizable and non-verbalizable versions of the object decision task.

According to the semantic hub hypothesis, a supramodal semantic hub is equally needed to deal with verbal and extraverbal "surface" representations. Damage to the supramodal hub is thought to underlie the crossmodal impairment observed in selective semantic deficits. In the present paper, we provide evidence supporting an alternative view: we hold that semantic impairment is not equal across domains but affects verbal behavior disproportionately. We investigated our hypothesis by manipulating the verbal load in an object decision task. Two pathological groups showing different levels of semantic impairment were enrolled together with their normal controls. The severe group included 10 subjects with semantic dementia and the mild group 10 subjects with Alzheimer's disease. In keeping with our hypothesis, when shifting from the low verbal load to the high verbal load condition, brain-damaged individuals, as compared to controls, showed a disproportionate impairment as a function of the severity of their semantic deficit.

Decreased event-based prospective memory functioning in individuals with Parkinson's disease.

The study was aimed at investigating the contribution of retrospective memory to prospective memory (PM) functioning in people with Parkinson's disease (PD). Twenty patients with PD without dementia and 20 normal controls were recruited. In the PM procedure, sequences of words were presented; in the inter-sequence delay, participants had to repeat sequence in the same or reverse order (ongoing task). At the occurrence of a target word, participants had to press a button on the keyboard (PM response). To evaluate the contribution of retrospective memory to PM performance, we manipulated the retrospective memory load of the target words (i.e., one vs. four words). The results show that patients with PD were poorer than controls in all PM conditions (p < .01). The memory load did not modulate differentially the PM performance of individuals in the two groups. Moreover, in PD patients, the ability to retrieve the target words in the episodic memory task was associated, at a lesser extent than in healthy controls, with the ability to activate the prospective intention at the occurrence of a target word. Our findings confirm PM decline in patients with PD without dementia. This flaw cannot be entirely explained by decreased retrospective memory. Altered self-retrieval processes might explain reduced PM performance of these individuals. This is a very relevant finding in the perspective of cognitive therapeutic intervention on PM that, in patients with PD, could be focused on mechanisms other than retrospective memory ones.