Giulio Pergola

Altered Error Processing following Vascular Thalamic Damage: Evidence from an Antisaccade Task

Event-related potentials (ERP) research has identified a negative deflection within about 100 to 150 ms after an erroneous response – the error-related negativity (ERN) - as a correlate of awareness-independent error processing. The short latency suggests an internal error monitoring system acting rapidly based on central information such as an efference copy signal. Studies on monkeys and humans have identified the thalamus as an important relay station for efference copy signals of ongoing saccades. The present study investigated error processing on an antisaccade task with ERPs in six patients with focal vascular damage to the thalamus and 28 control subjects. ERN amplitudes were significantly reduced in the patients, with the strongest ERN attenuation being observed in two patients with right mediodorsal and ventrolateral and bilateral ventrolateral damage, respectively. Although the number of errors was significantly higher in the thalamic lesion patients, the degree of ERN attenuation did not correlate with the error rate in the patients. The present data underline the role of the thalamus for the online monitoring of saccadic eye movements, albeit not providing unequivocal evidence in favour of an exclusive role of a particular thalamic site being involved in performance monitoring. By relaying saccade-related efference copy signals, the thalamus appears to enable fast error processing. Furthermore early error processing based on internal information may contribute to error awareness which was reduced in the patients.

Recall deficits in stroke patients with thalamic lesions covary with damage to the parvocellular mediodorsal nucleus of the thalamus

The functional role of the mediodorsal thalamic nucleus (MD) and its cortical network in memory processes is discussed controversially. While Aggleton and Brown (1999) suggested a role for recognition and not recall, Van der Werf et al. (2003) suggested that this nucleus is functionally related to executive function and strategic retrieval, based on its connections to the prefrontal cortices (PFC). The present study used a lesion approach including patients with focal thalamic lesions to examine the functions of the MD, the intralaminar nuclei and the midline nuclei in memory processing. A newly designed pair association task was used, which allowed the assessment of recognition and cued recall performance. Volume loss in thalamic nuclei was estimated as a predictor for alterations in memory performance. Patients performed poorer than healthy controls on recognition accuracy and cued recall. Furthermore, patients responded slower than controls specifically on recognition trials followed by successful cued recall of the paired associate. Reduced recall of picture pairs and increased response times during recognition followed by cued recall covaried with the volume loss in the parvocellular MD. This pattern suggests a role of this thalamic region in recall and thus recollection, which does not fit the framework proposed by Aggleton and Brown (1999). The functional specialization of the parvocellular MD accords with its connectivity to the dorsolateral PFC, highlighting the role of this thalamocortical network in explicit memory (Van der Werf et al., 2003).

Associative Learning Beyond the Medial Temporal Lobe: Many Actors on the Memory Stage

Decades of research have established a model that includes the medial temporal lobe, and particularly the hippocampus, as a critical node for episodic memory. Neuroimaging and clinical studies have shown the involvement of additional cortical and subcortical regions. Among these areas, the thalamus, the retrosplenial cortex, and the prefrontal cortices have been consistently related to episodic memory performance. This article provides evidences that these areas are in different forms and degrees critical for human memory function rather than playing only an ancillary role. First we briefly summarize the functional architecture of the medial temporal lobe with respect to recognition memory and recall. We then focus on the clinical and neuroimaging evidence available on thalamo-prefrontal and thalamo-retrosplenial networks. The role of these networks in episodic memory has been considered secondary, partly because disruption of these areas does not always lead to severe impairments; to account for this evidence, we discuss methodological issues related to the investigation of these regions. We propose that these networks contribute differently to recognition memory and recall, and also that the memory stage of their contribution shows specificity to encoding or retrieval in recall tasks. We note that the same mechanisms may be in force when humans perform non-episodic tasks, e.g., semantic retrieval and mental time travel. Functional disturbance of these networks is related to cognitive impairments not only in neurological disorders, but also in psychiatric medical conditions, such as schizophrenia. Finally we discuss possible mechanisms for the contribution of these areas to memory, including regulation of oscillatory rhythms and long-term potentiation. We conclude that integrity of the thalamo-frontal and the thalamo-retrosplenial networks is necessary for the manifold features of episodic memory.

The FoodCast research image database (FRIDa)

In recent years we have witnessed an increasing interest in food processing and eating behaviors. This is probably due to several reasons. The biological relevance of food choices, the complexity of the food-rich environment in which we presently live (making food-intake regulation difficult), and the increasing health care cost due to illness associated with food (food hazards, food contamination, and aberrant food-intake). Despite the importance of the issues and the relevance of this research, comprehensive and validated databases of stimuli are rather limited, outdated, or not available for non-commercial purposes to independent researchers who aim at developing their own research program. The FoodCast Research Image Database (FRIDa) we present here includes 877 images belonging to eight different categories: natural-food (e.g., strawberry), transformed-food (e.g., french fries), rotten-food (e.g., moldy banana), natural-non-food items (e.g., pinecone), artificial food-related objects (e.g., teacup), artificial objects (e.g., guitar), animals (e.g., camel), and scenes (e.g., airport). FRIDa has been validated on a sample of healthy participants (N = 73) on standard variables (e.g., valence, familiarity, etc.) as well as on other variables specifically related to food items (e.g., perceived calorie content); it also includes data on the visual features of the stimuli (e.g., brightness, high frequency power, etc.). FRIDa is a well-controlled, flexible, validated, and freely available (http://foodcast.sissa.it/neuroscience/) tool for researchers in a wide range of academic fields and industry.

The role of the thalamus in schizophrenia from a neuroimaging perspective.

The thalamus is a crucial node for brain physiology and part of functional and structural pathways relevant for schizophrenia. Relatively few imaging studies on schizophrenia have focused on this brain region, yet extant evidence supports the association between this brain disorder and thalamic anomalies. Nevertheless, the mechanisms underlying this association remain largely conjectural. Here, we review imaging literature on the relationship between the thalamus and schizophrenia, focusing on critical challenges for future studies, in particular: (i) the anatomical and functional organization of the thalamus in separate nuclei, which are also differently connected with the cortex; (ii) state-dependent variables, which do not allow firm conclusions on the relevance of thalamic correlates as core phenotypes of schizophrenia and (iii) genetic variation, which affects thalamic physiology and may lead to variability of structural and functional patterns. Current evidence from the studies reviewed does not appear conclusive, although the relevance of thalamo-prefrontal interactions clearly emerges. Results from imaging genetics are beginning to cast insight on possible mechanisms of the involvement of the thalamus in schizophrenia.

The role of the thalamic nuclei in recognition memory accompanied by recall during encoding and retrieval: An fMRI study

The present functional imaging study aimed at investigating the contribution of the mediodorsal nucleus and the anterior nuclei of the thalamus with their related cortical networks to recognition memory and recall. Eighteen subjects performed associative picture encoding followed by a single item recognition test during the functional magnetic resonance imaging session. After scanning, subjects performed a cued recall test using the formerly recognized pictures as cues. This post-scanning test served to classify recognition trials according to subsequent recall performance. In general, single item recognition accompanied by successful recall of the associations elicited stronger activation in the mediodorsal nucleus of the thalamus and in the prefrontal cortices both during encoding and retrieval compared to recognition without recall. In contrast, the anterior nuclei of the thalamus were selectively active during the retrieval phase of recognition followed by recall. A correlational analysis showed that activation of the anterior thalamus during retrieval as assessed by measuring the percent signal changes predicted lower rates of recognition without recall. These findings show that the thalamus is critical for recognition accompanied by recall, and provide the first evidence of a functional segregation of the thalamic nuclei with respect to the memory retrieval phase. In particular, the mediodorsal thalamic-prefrontal cortical network is activated during successful encoding and retrieval of associations, which suggests a role of this system in recall and recollection. The activity of the anterior thalamic-temporal network selectively during retrieval predicts better memory performances across subjects and this confirms the paramount role of this network in recall and recollection.

The involvement of the thalamus in semantic retrieval: A clinical group study

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.

Lexical-semantic deficits in processing food and non-food items

The study of category specific deficits in brain-damaged patients has been instrumental in explaining how knowledge about different types of objects is organized in the brain. Much of this research focused on testing putative semantic sensory/functional subsystems that could explain the observed dissociations in performance between living things (e.g., animals and fruits/vegetables) and non-living things (e.g., tools). As neuropsychological patterns that did not fit the original living/non-living distinction were observed, an alternative organization of semantic memory in domains constrained by evolutionary pressure was hypothesized. However, the category of food, that contains both living-natural items, such as an apple, and nonliving-manufactured items as in the case of a hamburger, has never been systematically investigated. As such, food category could turn out to be very useful to test whether the brain organizes the knowledge about food in sensory/functional subsystems, in a specific domain, or whether both approaches might need to be integrated. In the present study we tested the ability of patients with Alzheimer dementia (AD) and with Primary Progressive Aphasias (PPA) as well as healthy controls to perform a confrontation naming task, a categorization task, and a comprehension of edible (natural and manufactured food) and non edible items (tools and non-edible natural things) task (Tasks 1-3). The same photographs of natural and manufactured food were presented together with a description of foods sensory or functional property that could be either congruent or incongruent with that particular food (Task 4). Patients were overall less accurate than healthy individuals, and PPA patients were generally more impaired than AD patients, especially on the naming task. Food tended to be processed better than non-food in two out of three tasks (categorization and comprehension tasks). Patient groups showed no difference in naming food and non-food items, while controls were more accurate with non-food than food (controlling for the linguistic variables and calorie content). AD patients named manufactured food more accurately than natural food (with PPA and controls showing no difference). Recognition of food and, to some extent, of manufactured food seems to be more resilient to brain damage, possibly by virtue of its survival relevance. Furthermore, on Task 4 patients showed an advantage for the sensory-natural pairs over sensory-manufactured combination. Overall, findings do not fit an existing model of semantic memory and suggest that properties intrinsic to the food items (such as the level of transformation and the calorie content) or even to the participants like the Body Mass Index (as shown in another study reviewed here) should be considered.

Cerebellar volume and cerebellocerebral structural covariance in schizophrenia: a multisite mega-analysis of 983 patients and 1349 healthy controls

Although cerebellar involvement across a wide range of cognitive and neuropsychiatric phenotypes is increasingly being recognized, previous large-scale studies in schizophrenia (SZ) have primarily focused on supratentorial structures. Hence, the across-sample reproducibility, regional distribution, associations with cerebrocortical morphology and effect sizes of cerebellar relative to cerebral morphological differences in SZ are unknown. We addressed these questions in 983 patients with SZ spectrum disorders and 1349 healthy controls (HCs) from 14 international samples, using state-of-the-art image analysis pipelines optimized for both the cerebellum and the cerebrum. Results showed that total cerebellar grey matter volume was robustly reduced in SZ relative to HCs (Cohens’s d=−0.35), with the strongest effects in cerebellar regions showing functional connectivity with frontoparietal cortices (d=−0.40). Effect sizes for cerebellar volumes were similar to the most consistently reported cerebral structural changes in SZ (e.g., hippocampus volume and frontotemporal cortical thickness), and were highly consistent across samples. Within groups, we further observed positive correlations between cerebellar volume and cerebral cortical thickness in frontotemporal regions (i.e., overlapping with areas that also showed reductions in SZ). This cerebellocerebral structural covariance was strongest in SZ, suggesting common underlying disease processes jointly affecting the cerebellum and the cerebrum. Finally, cerebellar volume reduction in SZ was highly consistent across the included age span (16–66 years) and present already in the youngest patients, a finding that is more consistent with neurodevelopmental than neurodegenerative etiology. Taken together, these novel findings establish the cerebellum as a key node in the distributed brain networks underlying SZ.

DRD2 co-expression network and a related polygenic index predict imaging, behavioral and clinical phenotypes linked to schizophrenia

Genetic risk for schizophrenia (SCZ) is determined by many genetic loci whose compound biological effects are difficult to determine. We hypothesized that co-expression pathways of SCZ risk genes are associated with system-level brain function and clinical phenotypes of SCZ. We examined genetic variants related to the dopamine D2 receptor gene DRD2 co-expression pathway and associated them with working memory (WM) behavior, the related brain activity and treatment response. Using two independent post-mortem prefrontal messenger RNA (mRNA) data sets (total N=249), we identified a DRD2 co-expression pathway enriched for SCZ risk genes. Next, we identified non-coding single-nucleotide polymorphisms (SNPs) associated with co-expression of this pathway. These SNPs were associated with regulatory genetic loci in the dorsolateral prefrontal cortex (P<0.05). We summarized their compound effect on co-expression into a Polygenic Co-expression Index (PCI), which predicted DRD2 pathway co-expression in both mRNA data sets (all P<0.05). We associated the PCI with brain activity during WM performance in two independent samples of healthy individuals (total N=368) and 29 patients with SCZ who performed the n-back task. Greater predicted DRD2 pathway prefrontal co-expression was associated with greater prefrontal activity and longer WM reaction times (all corrected P<0.05), thus indicating inefficient WM processing. Blind prediction of treatment response to antipsychotics in two independent samples of patients with SCZ suggested better clinical course of patientswith greater PCI (total N=87; P<0.05). The findings on this DRD2 co-expression pathway are a proof of concept that gene co-expression can parse SCZ risk genes into biological pathways associated with intermediate phenotypes as well as with clinically meaningful information.