Does Ventromedial Prefrontal Cortex Damage Really Increase Impulsiveness? Delay and Probability Discounting in Patients with Focal Lesions.

If the tendency to discount rewards reflects individuals' general level of impulsiveness, then the discounting of delayed and probabilistic rewards should be negatively correlated: The less a person is able to wait for delayed rewards, the more they should take chances on receiving probabilistic rewards. It has been suggested that damage to the ventromedial prefrontal cortex (vMPFC) increases individuals' impulsiveness, but both intertemporal choice and risky choice have only recently been assayed in the same patients with vMPFC damage. Here, we assess both delay and probability discounting in individuals with vMPFC damage (n = 8) or with medial temporal lobe (MTL) damage (n = 10), and in age- and education-matched controls (n = 30). On average, MTL-lesioned individuals discounted delayed rewards at normal rates but discounted probabilistic rewards more shallowly than controls. In contrast, vMPFC-lesioned individuals discounted delayed rewards more steeply but probabilistic rewards more shallowly than controls. These results suggest that vMPFC lesions affect the weighting of reward amount relative to delay and certainty in opposite ways. Moreover, whereas MTL-lesioned individuals and controls showed typical, nonsignificant correlations between the discounting of delayed and probabilistic rewards, vMPFC-lesioned individuals showed a significant negative correlation, as would be expected if vMPFC damage increases impulsiveness more in some patients than in others. Although these results are consistent with the hypothesis that vMPFC plays a role in impulsiveness, it is unclear how they could be explained by a single mechanism governing valuation of both delayed and probabilistic rewards.

A method for estimating coherence of molecular mechanisms in major human disease and traits.

BACKGROUND: Phenotypes such as height and intelligence, are thought to be a product of the collective effects of multiple phenotype-associated genes and interactions among their protein products. High/low degree of interactions is suggestive of coherent/random molecular mechanisms, respectively. Comparing the degree of interactions may help to better understand the coherence of phenotype-specific molecular mechanisms and the potential for therapeutic intervention. However, direct comparison of the degree of interactions is difficult due to different sizes and configurations of phenotype-associated gene networks. METHODS: We introduce a metric for measuring coherence of molecular-interaction networks as a slope of internal versus external distributions of the degree of interactions. The internal degree distribution is defined by interaction counts within a phenotype-specific gene network, while the external degree distribution counts interactions with other genes in the whole protein-protein interaction (PPI) network. We present a novel method for normalizing the coherence estimates, making them directly comparable. RESULTS: Using STRING and BioGrid PPI databases, we compared the coherence of 116 phenotype-associated gene sets from GWAScatalog against size-matched KEGG pathways (the reference for high coherence) and random networks (the lower limit of coherence). We observed a range of coherence estimates for each category of phenotypes. Metabolic traits and diseases were the most coherent, while psychiatric disorders and intelligence-related traits were the least coherent. We demonstrate that coherence and modularity measures capture distinct network properties. CONCLUSIONS: We present a general-purpose method for estimating and comparing the coherence of molecular-interaction gene networks that accounts for the network size and shape differences. Our results highlight gaps in our current knowledge of genetics and molecular mechanisms of complex phenotypes and suggest priorities for future GWASs.

The Coherence Problem: Finding Meaning in GWAS Complexity.

Genome wide association studies (GWAS) for behavioral traits and psychiatric disorders have inspired both confident optimism and withering criticism. Although many recent findings from well powered GWAS have been replicated in independent data sets, the genes identified have pinned down few if any underlying causal mechanisms. Therefore, a key issue is whether or not the genes implicated by GWAS form a coherent story on their own and thus could in principle lead to insight into the biological mechanisms underlying the trait or disorder. We sketch here four scenarios for how genes may contribute to traits and disorders; genetic studies may help elucidate mechanisms under only two of our scenarios. We also describe here an approach to characterize, in an unbiased fashion, the molecular coherence of the gene sets implicated by GWAS of various behavioral and psychiatric phenotypes and we sketch how the four scenarios may be reflected in our molecular coherence measure.

Episodic memory and the witness trump card.

We accept Mahr & Csibra's (M&C's) causal claim that episodic memory provides humans with the means for evaluating the veracity of reports about non-occurrent events. We reject their evolutionary argument that this is the proper function of episodic memory. We explore three intriguing implications of the causal claim, for cognitive neuropsychology, comparative psychology, and philosophy.

The directionality of distinctively mathematical explanations.

In "What Makes a Scientific Explanation Distinctively Mathematical?" (2013b), Lange uses several compelling examples to argue that certain explanations for natural phenomena appeal primarily to mathematical, rather than natural, facts. In such explanations, the core explanatory facts are modally stronger than facts about causation, regularity, and other natural relations. We show that Lange's account of distinctively mathematical explanation is flawed in that it fails to account for the implicit directionality in each of his examples. This inadequacy is remediable in each case by appeal to ontic facts that account for why the explanation is acceptable in one direction and unacceptable in the other direction. The mathematics involved in these examples cannot play this crucial normative role. While Lange's examples fail to demonstrate the existence of distinctively mathematical explanations, they help to emphasize that many superficially natural scientific explanations rely for their explanatory force on relations of stronger-than-natural necessity. These are not opposing kinds of scientific explanations; they are different aspects of scientific explanation.

Moral judgment in episodic amnesia.

To investigate the role of episodic thought about the past and future in moral judgment, we administered a well-established moral judgment battery to individuals with hippocampal damage and deficits in episodic thought (insert Greene et al. 2001). Healthy controls select deontological answers in high-conflict moral scenarios more frequently when they vividly imagine themselves in the scenarios than when they imagine scenarios abstractly, at some personal remove. If this bias is mediated by episodic thought, individuals with deficits in episodic thought should not exhibit this effect. We report that individuals with deficits in episodic memory and future thought make moral judgments and exhibit the biasing effect of vivid, personal imaginings on moral judgment. These results strongly suggest that the biasing effect of vivid personal imagining on moral judgment is not due to episodic thought about the past and future. © 2016 Wiley Periodicals, Inc.

A registration problem for functional fingerprinting.

Functional fingerprints aggregate over heterogeneous tasks, protocols, and controls. The appearance of functional diversity might be explained by task heterogeneity and conceptual imprecision.

Cueing the personal future to reduce discounting in intertemporal choice: Is episodic prospection necessary?

How does the ability to imagine detailed future experiences (i.e., episodic prospection) contribute to choices between immediate and delayed rewards? Individuals with amnesia do not show abnormally steep discounting in intertemporal choice, suggesting that neither medial temporal lobe (MTL) integrity nor episodic prospection is required for the valuation of future rewards (Kwan et al. (), Hippocampus, 22:1215-1219; Kwan et al. (2013), J Exp Psychol, 142:1355-1369 2013). However, hippocampally mediated episodic prospection in healthy adults reduces the discounting of future rewards (Peters and Büchel (2010), Neuron, 66:138-148; Benoit et al. (2011), J Neurosci, 31:6771-6779), raising the possibility that MTL damage causes more subtle impairments to this form of decision-making than noted in previous patient studies. Intertemporal choice appears normal in amnesic populations, yet they may be unable to use episodic prospection to adaptively modulate the value assigned to future rewards. To investigate how the extended hippocampal system, including the hippocampus and related MTL structures, contributes to the valuation of future rewards, we compared the performance of six amnesic cases with impaired episodic prospection to that of 20 control participants on two versions of an intertemporal choice task: a standard discounting task, and a cued version in which cues prompted them to imagine specific personal future events temporally contiguous with the receipt of delayed rewards. Amnesic individuals' intertemporal choices in the standard condition were indistinguishable from those of controls, replicating previous findings. Surprisingly, performance of the amnesic cases in the cued condition indicates that amnesia does not preclude flexible modulation of choices in response to future event cues, even in the absence of episodic prospection. Cueing the personal future to modulate decisions appears to constitute a less demanding or a qualitatively different (e.g., personal semantic) form of prospection that is not as sensitive to MTL damage as prospective narrative generation.

An Allais paradox without mental time travel.

The capacity to anticipate future experiences of regret has been hypothesized to explain otherwise irrational aspects of human decision-making, including the certainty effect (Kahneman and Tversky (1979) Econometrica 47:263-291) and the common ratio effect (Allais (1953) Econometrica 21:503-546). The anticipated regret hypothesis predicts that individuals incapable of episodically imagining their personal futures, as has been reported for people with extensive damage to medial temporal lobe structures and resulting deficits in episodic thought, should be immune to these effects. We report that K.C., who has extensive bilateral damage to his hippocampus and adjacent medial temporal lobe structures and nearly complete deficits in his ability to episodically imagine his personal future, nonetheless displays both the certainty and the common ratio effects. These results suggest that the episodic anticipation of future regret does not explain the general human tendency to display the certainty and common ratio effects.

Future decision-making without episodic mental time travel.

Deficits in episodic memory are associated with deficits in the ability to imagine future experiences (i.e., mental time travel). We show that K.C., a person with episodic amnesia and an inability to imagine future experiences, nonetheless systematically discounts the value of future rewards, and his discounting is within the range of controls in terms of both rate and consistency. Because K.C. is neither able to imagine personal uses for the rewards nor provide a rationale for selecting larger future rewards over smaller current rewards, this study demonstrates a dissociation between imagining and making decisions involving the future. Thus, although those capable of mental time travel may use it in making decisions about future rewards, these results demonstrate that it is not required for such decisions.

The role of ventromedial prefrontal cortex in reward valuation and future thinking during intertemporal choice.

Intertemporal choices require trade-offs between short-term and long-term outcomes. Ventromedial prefrontal cortex (vmPFC) damage causes steep discounting of future rewards (delay discounting [DD]) and impoverished episodic future thinking (EFT). The role of vmPFC in reward valuation, EFT, and their interaction during intertemporal choice is still unclear. Here, 12 patients with lesions to vmPFC and 41 healthy controls chose between smaller-immediate and larger-delayed hypothetical monetary rewards while we manipulated reward magnitude and the availability of EFT cues. In the EFT condition, participants imagined personal events to occur at the delays associated with the larger-delayed rewards. We found that DD was steeper in vmPFC patients compared to controls, and not modulated by reward magnitude. However, EFT cues downregulated DD in vmPFC patients as well as controls. These findings indicate that vmPFC integrity is critical for the valuation of (future) rewards, but not to instill EFT in intertemporal choice.

Is it time? Episodic imagining and the discounting of delayed and probabilistic rewards in young and older adults.

Remembering and imagining specific, personal experiences can help shape our decisions. For example, cues to imagine future events can reduce delay discounting (i.e., increase the subjective value of future rewards). It is not known, however, whether such cues can also modulate other forms of reward discounting, such as probability discounting (i.e., the decrease in the subjective value of a possible reward as the odds against its occurrence increase). In addition, it is unclear whether there are age-related differences in the effects of cueing on either delay or probability discounting. Accordingly, young and older adult participants were administered delay and probability discounting tasks both with and without cues to imagine specific, personally meaningful events. As expected, cued episodic imagining decreased the discounting of delayed rewards. Notably, however, this effect was significantly less pronounced in older adults. In contrast to the effects of cueing on delay discounting, personally relevant event cues had little or no effect on the discounting of probabilistic rewards in either young or older adults; Bayesian analysis revealed compelling support for the null hypothesis that event cues do not modulate the subjective value of probabilistic rewards. In sum, imagining future events appears only to affect decisions involving delayed rewards. Although the cueing effect is smaller in older adults, nevertheless, it likely contributes to how adults of all ages evaluate delayed rewards and thus, it is, in fact, about time.

Narrative construction is intact in episodic amnesia.

Autobiographical remembering and future imagining overlap in their underlying psychological and neurological mechanisms. The hippocampus and surrounding regions within the medial temporal lobes (MTL), known for their role in forming and maintaining autobiographical episodic memories, are also thought to play an essential role in fictitious and future constructions. Amnesic individuals with bilateral hippocampal damage cannot reconstruct their past personal experiences and also have severe deficits in the ability to construct coherent fictitious or future narratives. However, it is not known whether this impairment reflects a failure to generate details from autobiographical episodic memory to populate personal narratives or an inability to bind such details into coherent narratives. We show that four individuals with hippocampal damage and episodic amnesia can construct narratives when the relevant details of the story are provided in a picture book and that their narratives maintain overall coherence on several measures. These findings indicate that individuals with hippocampal damage can bind details into coherent narratives when details are available to them. We conclude that the hippocampal system instead likely plays a role in the generation of details from which narratives are constructed.

Beyond reduction: mechanisms, multifield integration and the unity of neuroscience.

Philosophers of neuroscience have traditionally described interfield integration using reduction models. Such models describe formal inferential relations between theories at different levels. I argue against reduction and for a mechanistic model of interfield integration. According to the mechanistic model, different fields integrate their research by adding constraints on a multilevel description of a mechanism. Mechanistic integration may occur at a given level or in the effort to build a theory that oscillates among several levels. I develop this alternative model using a putative exemplar of reduction in contemporary neuroscience: the relationship between the psychological phenomena of learning and memory and the electrophysiological phenomenon known as Long-Term Potentiation. A new look at this historical episode reveals the relative virtues of the mechanistic model over reduction as an account of interfield integration.

The spine problem: finding a function for dendritic spines.

Why do neurons have dendritic spines? This question-the heart of what Yuste calls "the spine problem"-presupposes that why-questions of this sort have scientific answers: that empirical findings can favor or count against claims about why neurons have spines. Here we show how such questions can receive empirical answers. We construe such why-questions as questions about how spines make a difference to the behavior of some mechanism that we take to be significant. Why-questions are driven fundamentally by the effort to understand how some item, such as the dendritic spine, is situated in the causal structure of the world (the causal nexus). They ask for a filter on that busy world that allows us to see a part's individual contribution to a mechanism, independent of everything else going on. So understood, answers to why-questions can be assessed by testing the claims these answers make about the causal structure of a mechanism. We distinguish four ways of making a difference to a mechanism (necessary, modulatory, component, background condition), and we sketch their evidential requirements. One consequence of our analysis is that there are many spine problems and that any given spine problem might have many acceptable answers.

Remembering Mr B.

In the accompanying translation and film, Gustav Störring describes the psychological profile of Mr. B. (Franz Breundl), a victim of carbon monoxide poisoning with a nearly complete short-term memory deficit. Störring diagnoses Mr. B. as lacking entirely the capacity to register or retain any information in consciousness for longer than two seconds. Here we introduce these historical documents, describe their historical context, summarize and discuss the central features of the case, and consider the potential significance of the case for contemporary theories of working memory, the self, and personal identity.

Individuals with episodic amnesia are not stuck in time.

The metaphor that individuals with episodic amnesia due to hippocampal damage are "stuck in time" persists in science, philosophy, and everyday life despite mounting evidence that episodic amnesia can spare many central aspects of temporal consciousness. Here we describe some of this evidence, focusing specifically on KC, one of the most thoroughly documented and severe cases of episodic amnesia on record. KC understands the concept of time, knows that it passes, and can orient himself with respect to his personal past and future. He expresses typical attitudes toward his past and future, and he is able to make future-regarding decisions. Theories claiming that the hippocampus plays an essential role in temporal consciousness need to be revised in light of these findings.

Dissociations in future thinking following hippocampal damage: evidence from discounting and time perspective in episodic amnesia.

Recollecting past experiences and imagining future experiences activate a common set of brain regions that includes the hippocampus (Schacter, Addis, & Buckner, 2007), and both functions are impaired in people with compromised hippocampal function (Klein, Loftus, & Kihlstrom, 2002; Tulving, 1985). These findings indicate a role for the hippocampus that extends beyond declarative memory. However, a case study revealed that a person with extensive medial temporal lobe (MTL) damage and episodic amnesia was able to forgo smaller, immediate rewards for a larger future payoff to a degree similar to control participants (Kwan et al., 2012). This finding suggests that typical regard for the future does not depend on hippocampal integrity. To test this hypothesis, the current study examined the nature and limits of the role of the hippocampus in future thinking and decision making in amnesic individuals with hippocampal damage and associated impairments in episodic memory and future imagining. The amnesic individuals were administered a delay discounting task to assess valuation of future rewards, a probability discounting task to assess risk taking, and the Zimbardo Time Perspective Inventory to assess personal orientation toward the past, present, and future. Comparisons with demographically matched controls indicated that aspects of temporal thought and future-oriented decision making are preserved in individuals with hippocampal amnesia despite their inability to imagine themselves in detailed future events. Thus, even extensive MTL damage and the resulting episodic amnesia do not preclude prudent decision making, including consideration of future financial outcomes and personal identification with the past and future.

The making of a memory mechanism.

Long-Term Publication (LTP) is a kind of synaptic plasticity that many contemporary neuroscientists believe is a component in mechanisms of memory. This essay describes the discovery of LTP and the development of the LTP research program. The story begins in the 1950's with the discovery of synaptic plasticity in the hippocampus (a medial temporal lobe structure now associated with memory), and it ends in 1973 with the publication of three papers sketching the future course of the LTP research program. The making of LTP was a protracted affair. Hippocampal synaptic plasticity was initially encountered as an experimental tool, then reported as a curiosity, and finally included in the ontic store of the neurosciences. Early researchers were not investigating the hippocampus in search of a memory mechanism; rather, they saw the hippocampus as a useful experimental model or as a structure implicated in the etiology of epilepsy. The link between hippocampal synaptic plasticity and learning or memory was a separate conceptual achievement. That link was formulated in at least three different ways at different times: reductively (claiming that plasticity is identical to learning), analogically (claiming that plasticity is an example or model of learning(, and mechanistically (claiming that plasticity is a component in learning or memory mechanisms). The hypothesized link with learning or memory, coupled with developments in experimental techniques and preparations, shaped how researchers understood LTP itself. By 1973, the mechanistic formulation of the link between LTP and memory provided an abstract framework around which findings from multiple perspectives could be integrated into a multifield research program.