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.     

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.     

A Renewed Interest in Human Classical Eyeblink Conditioning

Abstract—Over the past few years, a number of publications have reported the results of a variety of human classical eyeblink conditioning experiments. This renewed interest in human classical eyeblink conditioning appears to be caused by several factors, including the preference by some researchers to observe and report on behavior directly, the discovery that eyeblink conditioning can be used to assess basic biological and psychological processes, recent success in using eyeblink conditioning to determine the cause and expression of brain pathologies, and the successful use of this simple behavioral procedure in human imaging and electrophysiological experiments.     

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.     

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.     

来源记忆中背景的情绪效价与唤醒对提取过程的影响

以往研究表明情绪背景对来源记忆存在影响,但背景的情绪效价和唤醒如何影响熟悉性及回想尚存争议。本研究以ERPs技术作为测量手段,采用来源记忆多键范式,操纵背景的情绪效价及唤醒强度,以探讨编码阶段背景情绪影响来源记忆提取的认知神经机制。学习阶段,呈现中性汉字及情绪图片（正性高唤醒、正性低唤醒、负性高唤醒、负性低唤醒）;测验阶段,仅呈现汉字,被试进行五键判断。行为结果发现：来源正确的比率比来源错误的比率更高,反应时更短;同时提取正性背景的辨别力更强,反应时更短;提取高唤醒背景反应时更短。脑电结果发现了分别代表熟悉性及回想的FN400及LPC新旧效应,且在500～700 ms,提取正性背景及高唤醒背景诱发显著更正的ERPs,但效价与唤醒没有交互作用。总体来说,来源记忆中背景效价及唤醒度对回想过程存在独立影响,体现为正性背景及高唤醒背景对来源提取的促进作用。     

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.     

The Interaction of Emotional Valence and Arousal on Attentional Breadth and Creative Task Performance

Within the literature, there are two opposing views regarding the influencing role of emotions on the creative process. The most commonly held view contends that positive emotions enhance creativity and negative emotions stifle it; yet, some studies show an opposite trend. These contradictory findings can be explained by examining two aspects of the emotions: attention and creativity relationship. First, emotional valence and arousal levels interact to affect attention. Second, creativity is not a unitary cognitive process and some stages rely more on focused attention but others are aided by diffused or broad attention. To test this proposition, two experiments were conducted. In Experiment 1, valence (positive vs. negative) and arousal (high vs. low) were manipulated and participants completed a series of attention and creativity tasks. Experiment 2 employed similar emotion induction procedure, but a different set of creative problems was used. The results of both experiments were consistent with the proposed explanation of the effects of emotions on creativity.     

情绪效价和唤醒对熟悉性和回想的不同影响

本研究检验了情绪的效价和唤醒对记忆提取阶段熟悉性过程和回想过程的影响及其心理机制。结果发现,编码阶段无分心任务时,积极图片的高、低自信再认准确率均高于消极图片,而唤醒对于高自信再认准确率的影响只限于消极图片;在编码阶段设置分心任务时,发现积极和消极的高唤醒图片的高自信再认准确率显著高于低唤醒图片。这些结果说明情绪的效价影响了熟悉性和回想两类记忆过程,而唤醒只影响回想过程,效价效应是编码阶段被试调用认知资源对积极图片进行精细加工的结果,而唤醒对回想过程的影响是自动编码高唤醒刺激细节的结果。     

Classical Delay Eyeblink Conditioning in in 4- and 5-Month-Old Human Infants

Abstract-Simple delay classical eyeblink conditioning, using a tone conditioned stimulus (CS) and airpuff unconditioned stimulus (US), was studied in cross-sectional samples of 4- and 5-month-old healthy, full-term infants. Infants received two identical training sessions, 1 week apart. At both ages, infants experiencing paired tones and air-puffs demonstrated successful conditioning over two sessions, relative to control subjects who had unpaired training. Conditioning was not evident, however, during the first session. Two additional groups of 5-month-olds received varied experiences during Session 1, either unpaired presentations of the CS and US or no stimulus exposure, fol-lowed by paired conditioning during Session 2. Results from these groups suggest that the higher level of conditioning observed following two sessions of paired conditioning was not the result of familiarity with the testing environment or the stimuli involved but, rather, the result of retention of associative learning not expressed during the first conditioning session.     

Arousal and Valence in the Direct Scaling of Emotional Response to Film Clips

Contributions of differential attention to valence versus arousal (Feldman, 1995) in self-reported emotional response may be difficult to observe due to (1)confounding of valence and arousal in the labeling of rating scales, and (2) the assumption of an interval scale type. Ratings of emotional response to film clips (Ekman, Friesen, & Ancoli, 1980) were reanalyzed as categorical (nominal) in scale type using consensus analysis. Consensus emerged for valence-related scales but not for arousal scales. Scales labeled Interest and Arousal produced a distribution of idiosyncratic responses across the scale, whereas scales labeled Happiness, Anger, Sadness, Fear, Disgust, Surprise, and Pain, produced consensual response. Magnitude of valenced response varied with both stimulus properties and self-reported arousal.     

身体攻击行为学生自主神经活动的情绪唤醒特点

运用情绪生理学的方法,以31名具有身体攻击行为的初中工读学生和30名普通初中生为研究对象,研究了身体攻击行为学生与普通学生在基线生理唤醒和情绪生理唤醒的方面不同特点。结果发现,在生理唤醒的基线水平上,身体攻击行为学生与普通学生在指温、R-R间期、心率、指脉率方面差异显著,身体攻击行为学生的指温、心率、指脉率比普通学生低,身体攻击行为学生的R-R间期比普通学生R-R间期长。在愤怒刺激条件下,身体攻击行为学生报告的愤怒体验水平比普通学生高;愤怒诱发刺激引起身体攻击行为学生R-R间期、心率变化显著,而普通学生R-R间期、心率变化不显著。厌恶与恐惧、悲伤、愉快诱发刺激引起普通学生皮肤电变化显著,而身体攻击行为学生皮肤电变化不显著     

诱发及个体自发认知重评对情绪唤醒反应及情绪记忆的影响

为了明确诱发（IRE）及个体习惯化的自发（SRE）认知重评策略对情绪唤醒反应及情绪记忆的影响,在测量被试SRE水平的基础上,先呈现一系列中性与负性情绪图片,要求被试对图片内容进行自然观看或认知重评,同时记录被试的主观与生理唤醒水平,之后对图片进行自由回忆及再认测试。发现IRE显著降低了情绪唤醒水平及再认正确率,但只对情绪唤醒反应较高的LR（SRE水平较低）被试有效。结果提示,IRE对情绪唤醒反应与情绪记忆的调控受到SRE的影响。     

Fear Develops to the Conditioned Stimulus and to the Context during Classical Eyeblink Conditioning in Rats

In classical eyeblink conditioning, non-specific emotional responses to the aversive shock unconditioned stimulus (US), which are presumed to coincide with the development of fear, occur early in conditioning and precede the emergence of eyeblink responses. This two-process learning model was examined by concurrently measuring fear and eyeblink conditioning in the freely moving rat. Freezing served as an index of fear in animals and was measured during the inter-trial intervals in the training context and during a tone conditioned stimulus (CS) presented in a novel context. Animals that received CS-US pairings exhibited elevated levels of fear to the context and CS early in training that decreased over sessions, while eyeblink conditioned responses (CRs) developed gradually during acquisition and decreased during extinction. Random CS-US presentations produced a similar pattern of fear responses to the context and CS as paired presentations despite low eyeblink CR percentages, indicating that fear responding was decreased independent of high levels of learned eyeblink responding. The results of paired training were consistent with two-process models of conditioning that postulate that early emotional responding facilitates subsequent motor learning, but measures from random control animals demonstrate that partial CS-US contingencies produce decrements in fear despite low levels of eyeblink CRs. These findings suggest a relationship between CS-US contingency and fear levels during eyeblink conditioning, and may serve to clarify further the role that fear conditioning plays in this simple paradigm.     

Attentional Capture by Emotional Stimuli: Manipulation of Emotional Valence by the Sample Pre‐rating Method

Eye movements directed at emotional and neutral pictures were investigated. Participants were instructed to fixate on a target and avoid looking at a non‐target. Results of trials consisting of emotional and neutral pictures were analyzed based on participants’ evaluations of the stimuli before the experiment. Results indicated that the number and duration of fixations were larger and longer for targets than for non‐targets. Further, the probability of first fixation was less for neutral targets than for emotional targets. This suggests that unpleasant pictures capture visual attention and that the attentional orienting is subject to automatic response. The possibility that top‐down processes of visual attention may be involved in attentional capture was also discussed.     

The Effect of Scopolamine in Older Rabbits Tested in the 750 ms Delay Eyeblink Classical Conditioning Procedure

We investigated the effect of several doses of scopolamine in older rabbits that were trained for 20 days in the 750 ms delay eyeblink classical conditioning procedure. Our aim was to determine if the scopolamine-injected older rabbit would be a useful model for testing drugs for cognition enhancement in Alzheimer's disease (AD). A total of 39 rabbits with a mean age of 31 months received classical eyeblink conditioning with daily injections of 0.25, 0.75, or 1.5 mg/kg scopolamine hydrobromide or sterile saline vehicle. Doses of 0.75 and 1.5 mg/kg scopolamine significantly impaired acquisition, whereas acquisition was not significantly impaired with 0.25 mg/kg scopolamine. Results exhibit parallels in performance on delay eyeblink classical conditioning between scopolamine-treated older rabbits and human patients diagnosed with AD.     

Comparison of Single Unit Responses to Tone, Light, and Compound Conditioned Stimuli during Rabbit Classical Eyeblink Conditioning

Unit recordings and lesion studies have implicated the cerebellum as an essential site for the acquisition and maintenance of the conditioned eyeblink response. The current study looked at the neural characteristics of conditioned stimulus (CS) processing in the interpositus nucleus of the cerebellum after training New Zealand white rabbits (Oryctolagus cuniculus) in one of two conditioning paradigms: (a) compound conditioning (CMP), a compound CS consisting of light and tone paired with an air puff unconditioned stimulus (US); or (b) stimulus compounding (ALT), alternating blocks of tone CS and light CS trials paired with the air puff US. Single unit responses were recorded during five sessions after the animals had reached an asymptotic level of responding. Animals were tested for behavioral and neural responses to CS alone trials that included tone alone, light alone, and compound tone-light trials. For the CMP group, the compound CS elicited 80 to 90% conditioned eyeblink responses (CRs), whereas the individual tone and light CSs elicited only 40 to 50% CRs. For the ALT group, all three CSs (tone, light, and compound) elicited very high levels of responding of at least 80% CRs. For the CMP group, there were roughly equal numbers of cells responding to all of the CSs. This includes cells that responded exclusively to one, and only one, of the three stimuli and also those cells that responded to combinations of two or more. Cells from the ALT group were far more likely to respond exclusively to only one of the CSs. Both the behavioral and physiological results suggest that the compound tone-light stimulus was processed as a distinct stimulus, separate from the component tone and light. These results are discussed in the context of multisensory processing.     

Effects of Early Hippocampal Lesions on Trace, Delay, and Long-Delay Eyeblink Conditioning in Developing Rats

The effects of bilateral hippocampal aspiration lesions on later acquisition of eyeblink conditioning were examined in developing Long-Evans rat pups. Lesions on postnatal day (PND) 10 were followed by evaluation of trace eyeblink conditioning (Experiment 1) and delay eyeblink conditioning (Experiment 2) on PND 25. Pairings of a tone conditioned stimulus (CS) and periocular shock unconditioned stimulus (US, 100 ms) were presented in one of three conditioning paradigms: trace (380 ms CS, 500 ms trace interval, 880 ms interstimulus interval [ISI]), standard delay (380 ms CS, 280 ms ISI), or long delay (980 ms CS, 880 ms ISI). The results of two experiments indicated that hippocampal lesions impaired trace eyeblink conditioning more than either type of delay conditioning. In light of our previous work on the ontogeny of trace, delay, and long-delay eyeblink conditioning (Ivkovich, Paczkowski, & Stanton, 2000) showing that trace and long-delay eyeblink conditioning had similar ontogenetic profiles, the current data suggest that during ontogeny hippocampal maturation may be more important for the short-term memory component than for the long-ISI component of trace eyeblink conditioning. The late development of conditioning over long ISIs may depend on a separate process such as protracted development of cerebellar cortex.     

Using Eyeblink Classical Conditioning as a Test of the Functional Consequences of Exposure of the Developing Cerebellum to Alcohol

Exposure of the developing brain to alcohol produces profound Purkinje cell loss in the cerebellum, and deficits in tests of motor coordination. However, the precise relationship between these two sets of findings has been difficult to determine. Eyeblink classical conditioning is known to engage a discrete brainstem-cerebellar circuit, making it an ideal test of cerebellar functional integrity after developmental alcohol exposure. In eyeblink conditioning, one of the deep cerebellar nuclei, the interpositus nucleus, as well as specific Purkinje cell populations, are sites of convergence for CS and US information. A series of studies have shown that eyeblink conditioning is impaired in both weanling and adult rats given binge-like exposure to alcohol as neonates, and that these deficits can be traced, at least in part, to impaired activation of cerebellar interpositus nucleus neurons and to an overall reduction in the deep cerebellar nuclear cell population. Because particular cerebellar cell populations are utilized in well-defined ways during eyeblink conditioning, conclusions regarding specific changes in the mediation of behavior by these cell populations are greatly strengthened. Further studies will be directed towards the impact of early exposure to alcohol on the functionality of specific Purkinje cell populations, as well as towards brainstem areas that process the tone CS and the somatosensory US.