Botallo's error, or the quandaries of the universality assumption.

One of the founding principles of human cognitive neuroscience is the so-called universality assumption, the postulate that neurocognitive mechanisms do not show major differences among individuals. Without negating the importance of the universality assumption for the development of cognitive neuroscience, or the importance of single-case studies, here we aim at stressing the potential dangers of interpreting the pattern of performance of single patients as conclusive evidence concerning the architecture of the intact neurocognitive system. We take example from the case of Leonardo Botallo, an Italian surgeon of the Renaissance period, who claimed to have discovered a new anatomical structure of the adult human heart. Unfortunately, Botallo's discovery was erroneous, because what he saw in the few samples he examined was in fact the anomalous persistence of a fetal structure. Botallo's error is a reminder of the necessity to always strive for replication, despite the major hindrance of a publication system heavily biased towards novelty. In the present paper, we briefly discuss variations and anomalies in human brain anatomy and introduce the issue of variability in cognitive neuroscience. We then review some examples of the impact on cognition of individual variations in (1) brain structure, (2) brain functional organization and (3) brain damage. We finally discuss the importance and limits of single case studies in the neuroimaging era, outline potential ways to deal with individual variability, and draw some general conclusions.

Space-related confabulations after right hemisphere damage.

Confabulations usually refer to memory distortions, characterized by the production of verbal statements or actions that are inconsistent with the patient's history and present situation. However, behavioral patterns reminiscent of memory confabulations can also occur in patients with right hemisphere damage, in relation to their personal, peripersonal or extrapersonal space. Thus, such patients may be unaware of their left hemiplegia and confabulate about it (anosognosia), deny the ownership of their left limbs (somatoparaphrenia), insult and hit them (misoplegia), or experience a "third", supernumerary left limb. Right brain-damaged patients can also sometimes confabulate about the left, neglected part of images presented in their peripersonal space, or believe to be in another place (reduplicative paramnesia). We review here these instances of confabulation occurring after right hemisphere damage, and propose that they might reflect, at least partially, the attempts of the left hemisphere to make sense of inappropriate input received from the damaged right hemisphere.

Lithium limits trimethyltin-induced cytotoxicity and proinflammatory response in microglia without affecting the concurrent autophagy impairment.

Trimethyltin (TMT) is a highly toxic molecule present as an environmental contaminant causing neurodegeneration particularly of the limbic system both in humans and in rodents. We recently described the occurrence of impairment in the late stages of autophagy in TMT-intoxicated astrocytes. Here we show that similarly to astrocytes also in microglia, TMT induces the precocious block of autophagy indicated by the accumulation of the autophagosome marker, microtubule associated protein light chain 3. Consistent with autophagy impairment we observe in TMT-treated microglia the accumulation of p62/SQSTM1, a protein specifically degraded through this pathway. Lithium has been proved effective in limiting neurodegenerations and, in particular, in ameliorating symptoms of TMT intoxication in rodents. In our in vitro model, lithium displays a pro-survival and anti-inflammatory action reducing both cell death and the proinflammatory response of TMT-treated microglia. In particular, lithium exerts these activities without reducing TMT-induced accumulation of light chain 3 protein. In fact, the autophagic block imposed by TMT is unaffected by lithium administration. These results are of interest as defects in the execution of autophagy are frequently observed in neurodegenerative diseases and lithium is considered a promising therapeutic agent for these pathologies. Thus, it is relevant that this cation can still maintain its pro-survival and anti-inflammatory role in conditions of autophagy block. Copyright © 2016 John Wiley & Sons, Ltd.

Effects of self-generated versus experimenter-provided cues on the representation of future events.

Most experimental studies of prospection focused on episodic forms of future events prompted by means of verbal cues. However, there is evidence suggesting that future events differ considerably according to whether they are produced in response to external, experimenter-provided verbal cues or they are self-generated. In the present study, we compared the quality, the phenomenal characteristics, the temporal distribution, and the content of imagined events prompted by experimenter-provided cues (i.e., cue-words and short verbal sentences) or elicited by means of verbal cues that were self-generated in an autobiographical fluency task. The results showed that future events prompted by means of self-generated cues contained fewer event-specific details than future events prompted by experimenter-provided cues. However, future events elicited by means of self-generated and by experimenter-provided cues did not differ with respect to their phenomenal characteristics. The temporal distribution and the thematic content of future representations were also affected by the type of cue used to elicit prospection. These results offer a holistic view of the properties of future thinking and suggest that the content and the characteristics of envisioned future events may be affected by the method used to elicit prospection.

Impairment of the autophagic flux in astrocytes intoxicated by trimethyltin.

Autophagy is a lysosomal catabolic route for protein aggregates and damaged organelles which in different stress conditions, such as starvation, generally improves cell survival. An impairment of this degradation pathway has been reported to occur in many neurodegenerative processes. Trimethyltin (TMT) is a potent neurotoxin present as an environmental contaminant causing tremors, seizures and learning impairment in intoxicated subjects. The present data show that in rat primary astrocytes autophagic vesicles (AVs) appeared after few hours of TMT treatment. The analysis of the autophagic flux in TMT-treated astrocytes was consistent with a block of the late stages of autophagy and was accompanied by a progressive accumulation of the microtubule associated protein light chain 3 (LC3) and of p62/SQSTM1. Interestingly, an increased immunoreactivity for p62/SQSTM1 was also observed in hippocampal astrocytes detected in brain slices of TMT-intoxicated rats. The time-lapse recordings of AVs in EGFP-mCherry-LC3B transfected astrocytes demonstrated a reduced mobility of autophagosomes after TMT exposure respect to control cells. The observed block of the autophagic flux cannot be overcome by known autophagy inducers such as rapamycin or 0.5mM lithium. Although ineffective when used at 0.5mM, lithium at higher concentrations (2mM) was able to protect astrocyte cultures from TMT toxicity. This effect correlated well with its ability to determine the phosphorylation/inactivation of glycogen kinase synthase-3ß (GSK-3ß).

When brain damage "improves" perception: neglect patients can localize motion-shifted probes better than controls.

When we look at bars flashed against a moving background, we see them displaced in the direction of the upcoming motion (flash-grab illusion). It is still debated whether these motion-induced position shifts are low-level, reflexive consequences of stimulus motion or high-level compensation engaged only when the stimulus is tracked with attention. To investigate whether attention is a causal factor for this striking illusory position shift, we evaluated the flash-grab illusion in six patients with damaged attentional networks in the right hemisphere and signs of left visual neglect and six age-matched controls. With stimuli in the top, right, and bottom visual fields, neglect patients experienced the same amount of illusion as controls. However, patients showed no significant shift when the test was presented in their left hemifield, despite having equally precise judgments. Thus, paradoxically, neglect patients perceived the position of the flash more veridically in their neglected hemifield. These results suggest that impaired attentional processes can reduce the interaction between a moving background and a superimposed stationary flash, and indicate that attention is a critical factor in generating the illusory motion-induced shifts of location.

Potential regulatory molecules in the human trabecular meshwork of patients with glaucoma: immunohistochemical profile of a number of inflammatory cytokines.

Glaucoma occurs when there are imbalances between the production and the drainage of the eye liquid. The vast majority of the aqueous humor leaves the eye through the trabecular meshwork (TM). The cause of hypertonicity may be due to an alteration in the thickness of the TM. In the majority of cases the molecular changes that determine primary open­angle glaucoma (POAG) are unclear. However, it has been hypothesized that the significant increase in the extracellular matrix (ECM) of the fibrillary bands in the TM is associated with possible inflammatory conditions. In this study the tissue distribution of interleukin (IL)­6, IL­1ß, transforming growth factor-ß1 (TGF­ß1), vascular endothelial growth factor (VEGF) and tumor necrosis factor α (TNF­α) was analyzed in TM samples from patients with POAG by immunohistochemistry. Seven specimens from patients with POAG and three control tissues were analyzed by immunohistochemistry using specific antibodies against these cytokines. Morphological changes in the TM, such as increased cell content, macrophages, fibrosis and accumulation of neutrophils, were observed by transmission electron microscopy. In human TM tissues, an evident immunoreactivity for IL­6, IL­1ß and TNF­α was observed in patients with POAG when compared with the control subjects, indicating that these cytokines may be correlated with disease activity. TM endothelial cells secrete a number of factors and cytokines that modulate the functions of the cells and the ECM of the conventional outflow pathway. In the TM in glaucoma, macrophages produce cytokines, including IL­6, IL­1ß and TNF­α, leading to an acute inflammatory response and recruitment of other immune cells, including T lymphocytes. In addition, TGF­ß1 regulates and induces the expression of IL­6 in TM that indirectly induces angiogenesis by stimulating VEGF expression. The present results support previous evidence that suggests that growth factors and cytokines can induce ECM remodelling and alter cytoskeletal interactions in the TM.

Eye movements disrupt episodic future thinking.

Remembering the past and imagining the future both rely on complex mental imagery. We considered the possibility that constructing a future scene might tap a component of mental imagery that is not as critical for remembering past scenes. Whereas visual imagery plays an important role in remembering the past, we predicted that spatial imagery plays a crucial role in imagining the future. For the purpose of teasing apart the different components underpinning scene construction in the two experiences of recalling episodic memories and shaping novel future events, we used a paradigm that might selectively affect one of these components (i.e., the spatial). Participants performed concurrent eye movements while remembering the past and imagining the future. These concurrent eye movements selectively interfere with spatial imagery, while sparing visual imagery. Eye movements prevented participants from imagining complex and detailed future scenes, but had no comparable effect on the recollection of past scenes. Similarities between remembering the past and imagining the future are coupled with some differences. The present findings uncover another fundamental divergence between the two processes.

Eye movements disrupt spatial but not visual mental imagery.

It has long been known that eye movements are functionally involved in the generation and maintenance of mental images. Indeed, a number of studies demonstrated that voluntary eye movements interfere with mental imagery tasks (e.g., Laeng and Teodorescu in Cogn Sci 26:207-231, 2002). However, mental imagery is conceived as a multifarious cognitive function with at least two components, a spatial component and a visual component. The present study investigated the question of whether eye movements disrupt mental imagery in general or only its spatial component. We present data on healthy young adults, who performed visual and spatial imagery tasks concurrently with a smooth pursuit. In line with previous literature, results revealed that eye movements had a strong disruptive effect on spatial imagery. Moreover, we crucially demonstrated that eye movements had no disruptive effect when participants visualized the depictive aspects of an object. Therefore, we suggest that eye movements serve to a greater extent the spatial than the visual component of mental imagery.

Lithium improves survival of PC12 pheochromocytoma cells in high-density cultures and after exposure to toxic compounds.

Autophagy is an evolutionary conserved mechanism that allows for the degradation of long-lived proteins and entire organelles which are driven to lysosomes for digestion. Different kinds of stressful conditions such as starvation are able to induce autophagy. Lithium and rapamycin are potent autophagy inducers with different molecular targets. Lithium stimulates autophagy by decreasing the intracellular myo-inositol-1,4,5-triphosphate levels, while rapamycin acts through the inhibition of the mammalian target of rapamycin (mTOR). The correlation between autophagy and cell death is still a matter of debate especially in transformed cells. In fact, the execution of autophagy can protect cells from death by promptly removing damaged organelles such as mitochondria. Nevertheless, an excessive use of the autophagic machinery can drive cells to death via a sort of self-cannibalism. Our data show that lithium (used within its therapeutic window) stimulates the overgrowth of the rat Pheochromocytoma cell line PC12. Besides, lithium and rapamycin protect PC12 cells from toxic compounds such as thapsigargin and trimethyltin. Taken together these data indicate that pharmacological activation of autophagy allows for the survival of Pheochromocytoma cells in stressful conditions such as high-density cultures and exposure to toxins.

People believe each other to be selfish hedonic maximizers.

Current computational models of theory of mind typically assume that humans believe each other to selfishly maximize utility, for a conception of utility that makes it indistinguishable from personal gains. We argue that this conception is at odds with established facts about human altruism, as well as the altruism that humans expect from each other. We report two experiments showing that people expect other agents to selfishly maximize their pleasure, even when these other agents behave altruistically. Accordingly, defining utility as pleasure permits us to reconcile the assumption that humans expect each other to selfishly maximize utility with the fact that humans expect each other to behave altruistically.

Congenital asymptomatic diaphragmatic hernias in adults: a case series.

INTRODUCTION: Congenital diaphragmatic hernia is a major malformation occasionally found in newborns and babies. Congenital diaphragmatic hernia is defined by the presence of an orifice in the diaphragm, more often to the left and posterolateral, that permits the herniation of abdominal contents into the thorax. The aim of this case series is to provide information on the presentation, diagnosis and outcome of three patients with late-presenting congenital diaphragmatic hernias. The diagnosis of congenital diaphragmatic hernia is based on clinical investigation and is confirmed by plain X-ray films and computed tomography scans. CASE PRESENTATIONS: In the present report three cases of asymptomatic abdominal viscera herniation within the thorax are described. The first case concerns herniation of some loops of the large intestine into the left hemi-thorax in a 75-year-old Caucasian Italian woman. The second case concerns a rare type of herniation in the right side of the thorax of the right kidney with a part of the liver parenchyma in a 57-year-old Caucasian Italian woman. The third case concerns herniation of the stomach and bowel into the left side of the chest with compression of the left lung in a 32-year-old Caucasian Italian man. This type of hernia may appear later in life, because of concomitant respiratory or gastrointestinal disease, or it may be an incidental finding in asymptomatic adults, such as in the three cases featured here. CONCLUSIONS: Patients who present with late diaphragmatic hernias complain of a wide variety of symptoms, and diagnosis may be difficult. Additional investigation and research appear necessary to better explain the development and progression of this type of disease.

Future thinking in Parkinson's disease: an executive function?

Contrary to what was originally thought (Hassabis, Kumaran, Vann, & Maguire, 2007) recent data have shown that imagining the future is not entirely dependent on the hippocampus (Squire et al., 2010) and neuroimaging studies have demonstrated a frontopolar activation during future thinking tasks (Okuda et al., 2003). The present study investigated whether the performance of people with Parkinson's disease (PD) on future simulation tasks was dependent on memory or executive control. Thirty-one PD patients, asked to imagine possible future scenarios, generated fewer future episodic details than matched controls. The seven patients who clearly performed below the range of controls in future thinking, were also significantly poorer on the Frontal Assessment Battery (FAB), a battery assessing executive control, but showed no deficits in immediate or delayed memory tests. These results suggest that poor performance in the future thinking task is associated with poor executive control and less so with memory impairment. Flexible searching activities of past details might be crucial capacities for envisaging one's own future.

What differentiates episodic future thinking from complex scene imagery?

We investigated the contributions of familiarity of setting, self-relevance and self-projection in time to episodic future thinking. The role of familiarity of setting was assessed, in Experiment 1, by comparing episodic future thoughts to autobiographical future events supposed to occur in unfamiliar settings. The role of self-relevance was assessed, in Experiment 2, by comparing episodic future thoughts to future events involving familiar others. The role of self-projection in time was assessed, in both Experiments, by comparing episodic future thoughts to autobiographical events that were not temporal in nature. Results indicated that episodic future thoughts were more clearly represented than autobiographical future events occurring in unfamiliar setting and future events involving familiar others. Our results also revealed that episodic future thoughts were indistinguishable from autobiographical atemporal events with respect to both subjective and objective detail ratings. These results suggest that future and atemporal events are mentally represented in a similar way.

Episodic future thinking in amnesic mild cognitive impairment.

Results from behavioral studies of amnesic patients and neuroimaging studies of individuals with intact memory suggest that a brain system involving direct contributions from the medial temporal lobes supports both remembering the past and imagining the future (Episodic Future Thinking). In the present study, we investigated whether amnesic Mild Cognitive Impairment (aMCI) affects EFT. Amnesic MCI is a high-risk factor for Alzheimer's disease and is characterized by a selective impairment of episodic memory, likely reflecting hippocampal malfunctioning. The present study assessed, for the first time, whether the reduction of episodic specificity for past events, evident in aMCI patients, extends also to future events. We present data on 14 aMCI patients and 14 healthy controls, who mentally re-experienced and pre-experienced autobiographical episodes. Transcriptions were segmented into distinct details that were classified as either internal (episodic) or external (semantic). Results revealed that aMCI patients produced fewer episodic, event-specific details, and an increased number of semantic details for both past and future events, as compared to controls. These results are discussed with respect to the constructive episodic simulation hypothesis, which suggests that reminiscence and future thinking are the expression of the same neurocognitive system.

The role of past in the simulation of autobiographical future episodes.

Human beings' ability to envisage the future has been recently assumed to rely on the reconstructive nature of episodic memory (Schacter & Addis, 2007). In the present research, young adults mentally reexperienced and preexperienced temporally close and distant autobiographical episodes, and rated their phenomenal characteristics as well as their novelty. Additionally, they performed a delayed recognition task including remember-know judgments on new, old-remember, and old-imagine words. Results showed that past and future temporally close episodes included more phenomenal details than distant episodes, in line with earlier studies. However, future events were occasionally rated as already occurred in the past. Furthermore, in the recognition task, participants falsely attributed old-imagine words to remembered episodes. While partially in line with previous results, these findings call for a more subtle analysis in order to discriminate representations of past episodes from true future events simulations.