Dissociating basal forebrain and medial temporal amnesic syndromes: Insights from classical conditioning

In humans, anterograde amnesia can result from damage to the medical temporal (MT) lobes (including hippocampus), as well as to other brain areas such as basal forebrain. Results from animal classical conditioning studies suggest that there may be qualitative differences in the memory impairment following MT vs. basal forebrain damage. Specifically, delay eyeblink conditioning is spared after MT damage in animals and humans, but impaired in animals with basal forebrain damage. Recently, we have likewise shown delay eyeblink conditioning impairment in humans with amnesia following anterior communicating artery (ACoA) aneurysm rupture, which damages the basal forebrain. Another associative learning task, a computer-based concurrent visual discrimination, also appears to be spared in MT amnesia while ACoA amnesics are slower to learn the discriminations. Conversely, animal and computational models suggest that, even though MT amnesics may learn quickly, they may learn qualitatively differently from controls, and these differences may result in impaired transfer when familiar information is presented in novel combinations. Our initial data suggests such a two-phase learning and transfer task may provide a double dissociation between MT amnesics (spared initial learning but impaired transfer) and ACoA amnesics (slow initial learning but spared transfer). Together, these merging data suggest that there are subtle but dissociable differences in the amnesic syndrome following damage to the MT lobes vs. basal forebrain, and that these differences may be most visible in non-declarative tasks such as eyeblink classical conditioning and simple associative learning.     

Dissociating Medial Temporal and Striatal Memory Systems With a Same/Different Matching Task: Evidence for Two Neural Systems in Human Recognition

The medial temporal lobe and striatum have both been implicated as brain substrates of memory and learning. Here, we show dissociation between these two memory systems using a same/different matching task, in which subjects judged whether four-letter strings were the same or different. Different RT was determined by the left-to-right location of the first letter different between the study and test string, consistent with a left-to-right comparison of the study and test strings, terminating when a difference was found. This comparison process results in same responses being slower than different responses. Nevertheless, same responses were faster than different responses. Same responses were associated with hippocampus activation. Different responses were associated with both caudate and hippocampus activation. These findings are consistent with the dual-system hypothesis of mammalian memory and extend the model to human visual recognition.     

Classical Eyeblink Conditioning: Clinical Models and Applications

In this paper, we argue that the main reason that classical eyeblink conditioning has proven so useful when applied to clinical situations, is that a great deal of information is known about the behavioral and neural correlates of this form of associative learning. Presented here is a summary of three lines of research that have used classical eyeblink conditioning to study three different clinical conditions; autism, fetal alcohol syndrome, and obsessive-compulsive disorder. While seemingly very different clinical conditions, classical eyeblink conditioning has proven very useful for advancing our understanding of these clinical pathologies and the neural conditions that may underlie them.     

Hippocampal Theta Oscillations and Classical Conditioning

Studies are reviewed that support a hypothesized role for hippocampal theta oscillations in the neural plasticity underlying behavioral learning. Begun in Richard F. Thompson's laboratory in the 1970s, these experiments have documented a relationship between free-running 3- to 7-Hz hippocampal slow waves (theta) and rates of acquisition in rabbit classical nictitating membrane (NM) conditioning. Lesion and drug manipulations of septohippocampal projections have affected NM and jaw movement conditioning in ways consistent with a theta-related brain state being an important modulator of behavioral acquisition. These findings provide essential empirical support for the recently developed neurobiological and computational models that posit an important role for rhythmic oscillations (such as theta) in cellular plasticity and behavioral learning.     

Eyeblink Classical Conditioning Differentiates Normal Aging from Alzheimer's Disease

Eyeblink classical conditioning is a useful paradigm for the study of the neurobiology of learning, memory, and aging, which also has application in the differential diagnosis of neurodegenerative diseases expressed in advancing age. Converging evidence from studies of eyeblink conditioning in neurological patients and brain imaging in normal adults document parallels in the neural substrates of this form of associative learning in humans and non-human mammals. Age differences in the short-delay procedure (400 ms CS-US interval) appear in middle age in humans and may be caused at least in part by cerebellar cortical changes such as loss of Purkinje cells. Whereas the hippocampus is not essential for conditioning in the delay procedure, disruption of hippocampal cholinergic neurotransmission impairs acquisition and slows the rate of learning. Alzheimer's disease (AD) profoundly disrupts the hippocampaL cholinergic system, and patients with AD consistently perform poorly in eyeblink conditioning. We hypothesize that disruption of hippocampal cholinergic pathways in AD in addition to age-associated Purkinje cell loss results in severely impaired eyeblink conditioning. The earliest pathology in AD occurs in entorhinal cortical input to hippocampus, and eyeblink conditioning may detect this early disruption before declarative learning and memory circuits become impaired. A case study is presented in which eyeblink conditioning detected impending dementia six years before changes on other screening tests indicated impairment. Because eyeblink conditioning is simple, non-threatening, and non-invasive, it may become a useful addition to test batteries designed to differentiate normal aging from mild cognitive impairment that progresses to AD and AD from other types of dementia.     

内侧颞叶与来源记忆

来源记忆不同于项目记忆。早期的研究认为来源记忆的神经基础主要是前额叶,但近几年的相关研究发现内侧颞叶在来源记忆中的作用也是相当重要的,健康被试的功能神经成像研究和内侧颞叶损伤病人研究都为内侧颞叶在来源记忆中的作用提供了可靠证据。     

Insights into Moral Injury and Soul Repair from Classical Jewish Texts

Pastoral Psychology - This article explores how Jewish biblical, rabbinic, and liturgical texts can be used to broaden and deepen an understanding of moral injury. To date, the literature on moral...     

Timing in Eyeblink Classical Conditioning and Timed-Interval Tapping

Abstract—The cerebellum is implicated in interval timing for diverse tasks including eyeblink classical conditioning (EBCC) and repetitive tapping. We examined performance on both tasks across identical intervals ranging from 325 to 550 ms. In five weekly sessions, 23 participants used a different interval each week, both as the target for tapping and as the delay interval in EBCC. Changes in variability as a function of the tapping or delay interval were assessed using regression analyses. The slope for repetitive tapping was comparable to two measures of temporal acuity in EBCC, onset and peak latency of the conditioned response. Each of 80 additional participants was assessed in one session at one of four tapping and delay intervals. Results were similar to those observed in the repeated measures group. These findings provide further evidence that EBCC and repetitive tapping utilize common mechanisms for representing temporal information.     

Basal Ganglia and Thalamic Contributions to Language Function: Insights from A Parallel Distributed Processing Perspective

Neuropsychology Review - Cerebral representations are encoded as patterns of activity involving billions of neurons. Parallel distributed processing (PDP) across these neuronal populations provides...     

New Directions for a Classical Paradigm: Human Eyeblink Conditioning

Abstract—The knowledge base on neural substrates an mechanisms involved in classical eyeblink conditioning makes it an ideal paradigm for investigating fundamental issues in learning and memory. New applications for the model system presented here include its use in (a) assessment to evaluate neurocognitive development in infancy, (b) theory building in abnormal psychology to test relationships between obsessive-compulsive behavior and learning rate, (c) evaluation of hypotheses about brain memory systems, and (d) exploration of the role of brain structures such as the cerebellum in learning and timing. Human eyeblink conditioning is a prototype of the utility of a model system that has become well characterized at both the behavioral and the neurobiological levels.     

Temporal Coding in Pavlovian Conditioning: Hall-Pearce Negative Transfer

The Hall-Pearce (1979) negative transfer effect in rats was used to examine whether temporal relationships are coded as part of the informational content of associations that result from CS-US pairings. The transfer effect consists of adeficit in conditioned responding following CS-US pairings in Phase 2 that results from prior CS-US pairings in Phase 1. strong weak Using conditioned bar-press suppression, we found that gaps of different duration between CS termination and US onset in the two training phases resulted in less of a Hall-Pearce negative transfer effect than did an equivalent gap in the twotraining phases. The results are discussed with respect tothe temporal coding hypothesis (Matzel, Held, &Miller, 1988), the Pearce and Hall (1980) model, and Bouton's (1993) interference model.     

The Critical Role of Cholinergic Basal Forebrain Neurons in Morphological Change and Memory Encoding: A Hypothesis

It has been known for a long time that cholinergic basal forebrain neurons which project to the cerebral cortex play a role in learning and memory. Behavioral studies following lesions, for example, repeatedly have suggested multiple learning-related roles for these neurons. Apart from behavioral studies, cholinergic neurons have been shown to possess extraordinarily plastic axons. This plasticity has not been related comprehensively to mnemonic devises, even though morphological changes in the CNS are prime candidates for the neural engram. In this paper, I propose a hypothesis that relates these two characteristics of cholinergic neurons. This hypothesis is that plastic cholinergic axon terminals induce structural reorganization in their targets during memory storage. Possible intracellular mechanisms are examined, whereby acetylcholine release in the cerebral cortex could cause postsynaptic structural changes. Finally, the characteristics of the overall cholinergic–cholinoceptive cell “engram” are elaborated with particular attention paid to the encoding of the stimulus properties along with the context and meaning of the stimulus.     

A Possible Role for Cholinergic Neurons of the Basal Forebrain and Pontomesencephalon in Consciousness

Excitation at widely dispersed loci in the cerebral cortex may represent a neural correlate of consciousness. Accordingly, each unique combination of excited neurons would determine the content of a conscious moment. This conceptualization would be strengthened if we could identify what orchestrates the various combinations of excited neurons. In the present paper, cholinergic afferents to the cerebral cortex are hypothesized to enhance activity at specific cortical circuits and determine the content of a conscious moment by activating certain combinations of postsynaptic sites in select cortical modules. It is proposed that these selections are enabled by learning-related restructuring that simultaneously adjusts the cytoskeletal matrix at specific constellations of postsynaptic sites giving all a similar geometry. The underlying mechanism of conscious awareness hypothetically involves cholinergic mediation of linkages between microtubules and microtubule-associated protein-2 (MAP-2). The first reason for proposing this mechanism is that previous studies indicate cognitive-related changes in MAP-2 occur in cholinoceptive cells within discrete cortical modules. These cortical modules are found throughout the cerebral cortex, measure 1–2 mm², and contain approximately 10³–10⁴cholinoceptive cells that are enriched with MAP-2. The subsectors of the hippocampus may function similarly to cortical modules. The second reason for proposing the current mechanism is that the MAP-2 rich cells throughout the cerebral cortex correspond almost exactly with the cortical cells containing muscarinic receptors. Many of these cholinoceptive, MAP-2 rich cells are large pyramidal cell types, but some are also small pyramidal cells and nonpyramidal types. The third reason for proposing the current mechanism is that cholinergic afferents are module-specific; cholinergic axons terminate wholly within individual cortical modules. The cholinergic afferents may be unique in this regard. Finally, the tapering apical dendrites of pyramidal cells are proposed as primary sites for cholinergic mediation of linkages between MAP-2 and microtubules because especially high amounts of MAP-2 are found here. Also, the possibility is raised that muscarinic actions on MAP-2 could modulate microtubular coherence and self-collapse, phenomena that have been suggested to underlie consciousness.     

Parallel Neural Systems for Classical Conditioning: Support From Computational Modeling

Classical conditioning has been explained by two main types of theories that postulate different learning mechanisms. Rescorla and Wagner (1972) put forth a theory in which conditioning is based on the ability of the US to drive learning through error correction. Alternatively, Mackintosh (1973) put forth a theory in which the ability of the CS to be associated with the unconditioned stimulus is modulated. We have proposed a reconciliation of these two mechanisms as working in parallel within different neural systems: a cerebellar system for US modulation and a hippocampal system for CS modulation. We developed a computational model of cerebellar function in eyeblink conditioning based on the error correction mechanism of the Rescorla-Wagner rule in which learning-related activity from the cerebellum inhibits the inferior olive, which is the US input pathway to the cerebellum (Gluck et al., 1994). We developed a computational model of the hippocampal region that forms altered representations of conditioned stimuli based on their behavioral outcomes (Gluck & Myers, 1993; Myers et al., 1995). Overall, computational modeling and empirical findings support the idea that, at least in the case of eyeblink conditioning, there may be two different neural systems: the cerebellum which mediates US-based error correction and hippocampus which alters representations of CSs.     

The Effects of Selective Cholinergic Basal Forebrain Lesions and Aging upon Expectancy in the Rat

The effects of selective cholinergic cell loss within the basal forebrain (BF) were determined using a task that requires shifting of attention between two visual stimuli. Discriminability between two stimuli and response bias were determined in young and old F-344 rats given BF injections of IgG-192 saporin (100 ng). The lesion reduced ChAT activity in the frontal and parietal cortices, hippocampus, and olfactory bulbs. The lesion did not significantly alter Na⁺/K⁺-ATPase activity in cortex, hippocampus, or olfactory bulbs, or endogenous levels of neuropeptide Y and neurokinin B within the BF. The BF lesions impaired both stimulus discriminability and response bias in young and old rats. The BF lesions had a significantly greater effect upon stimulus discriminability and response bias in aged rats, compared to young rats, only when the stimulus duration was very brief, i.e., when the task was most difficult to solve. At longer stimulus durations, aging and lesions showed no interaction. The results suggest that the selective loss of cholinergic cells in the BF, but not normal aging, impairs the ability to discriminate between independent sensory stimuli. The loss of these cells confers a response bias in simple operant tasks involving motor responses to reward-related visual stimuli.     

The McCollough effect: Dissociating retinal from spatial coordinates

Three experiments were conducted to dissociate the perceived orientation of a stimulus from its orientation on the retina while inducing the McCollough effect. In the first experiment, the typical contingency between color and retinal orientation was eliminated by having subjects tilt their head 90° for half of the induction trials while the stimuli remained the same. The only relation remaining was that between color and the perceived or spatial orientation, which led to only a small contingent aftereffect. In contrast, when the spatial contingency was eliminated in the second experiment, the aftereffect was as large as when both contingencies were present. Finally, a third experiment determined that part of the small spatial effect obtained in the first experiment could be traced to hidden higher order retinal contingencies. The study suggested that even under optimal conditions the McCollough effect is not concerned with real-world properties of objects or events. Implications for several classes of theories are discussed.     

Human Eyeblink Classical Conditioning: Effects of Manipulating Awareness of the Stimulus Contingencies

Obsessive-compulsive disorder (OCD) is an intrusive and debilitating condition in which the individual experiences uncontrollable thoughts, compulsions, and urges. Successful treatments for OCD are based on Mowrer's theory of fear and avoidance behavior, which predicts that OCD subjects should show accelerated associative conditioning. This prediction was tested in two experiments that com-pared the classical eyeblink conditioning of OCD-like and control college students. OCD and control subjects learned normally and similarly when the conditioning procedure was accompanied by an active visual search background task (Experiment 1). However, when the background task was changed so that subjects passively viewed neutral pictures, OCD subjects conditioned significantly faster than control subjects (Experiment 2). Overall, the performance of all subjects in Experiment 1 was superior to the performance of subjects in Experiemnt 2.