Human Eyeblink Classical Conditioning Research Articles

Erratum to: "Functional MRI of Human Eyeblink Classical Conditioning in Children with Fetal Alcohol Spectrum Disorders".

Erratum to: "Functional MRI of Human Eyeblink Classical Conditioning in Children with Fetal Alcohol Spectrum Disorders".

Functional MRI of Human Eyeblink Classical Conditioning in Children with Fetal Alcohol Spectrum Disorders.

Prenatal alcohol exposure has been linked to a broad range of developmental deficits, with eyeblink classical conditioning (EBC) among the most sensitive endpoints. This fMRI study compared EBC-related brain activity in 47 children with fetal alcohol syndrome (FAS), partial FAS (PFAS), heavily exposed (HE) non-syndromal children, and healthy controls. All of the children had previously participated in two EBC studies conducted as part of our longitudinal study of fetal alcohol spectrum disorders. Although learning-related behavioral differences were seen in all groups during the scans, controls showed more conditioned responses (CR) than the alcohol-exposed groups. Despite lower conditioning levels relative to controls, the exposed groups exhibited extensive cerebellar activations. Specifically, children with FAS/PFAS showed increased activation of cerebellar lobule VI in session 2, while HE children showed increased activation in session 1. Continuous measures of prenatal alcohol use correlated with learning-related activations in cerebellum and frontal cortices. Only controls showed significant cerebellar activation-CR correlations in the deep nuclei and lateral lobule VI, suggesting that these key regions supporting EBC may be functionally disorganized in alcohol-exposed children. These findings are the first to characterize abnormalities in brain function associated with the behavioral conditioning deficits seen in children with prenatal alcohol exposure.

Model-Driven Analysis of Eyeblink Classical Conditioning Reveals the Underlying Structure of Cerebellar Plasticity and Neuronal Activity.

The cerebellum plays a critical role in sensorimotor control. However, how the specific circuits and plastic mechanisms of the cerebellum are engaged in closed-loop processing is still unclear. We developed an artificial sensorimotor control system embedding a detailed spiking cerebellar microcircuit with three bidirectional plasticity sites. This proved able to reproduce a cerebellar-driven associative paradigm, the eyeblink classical conditioning (EBCC), in which a precise time relationship between an unconditioned stimulus (US) and a conditioned stimulus (CS) is established. We challenged the spiking model to fit an experimental data set from human subjects. Two subsequent sessions of EBCC acquisition and extinction were recorded and transcranial magnetic stimulation (TMS) was applied on the cerebellum to alter circuit function and plasticity. Evolutionary algorithms were used to find the near-optimal model parameters to reproduce the behaviors of subjects in the different sessions of the protocol. The main finding is that the optimized cerebellar model was able to learn to anticipate (predict) conditioned responses with accurate timing and success rate, demonstrating fast acquisition, memory stabilization, rapid extinction, and faster reacquisition as in EBCC in humans. The firing of Purkinje cells (PCs) and deep cerebellar nuclei (DCN) changed during learning under the control of synaptic plasticity, which evolved at different rates, with a faster acquisition in the cerebellar cortex than in DCN synapses. Eventually, a reduced PC activity released DCN discharge just after the CS, precisely anticipating the US and causing the eyeblink. Moreover, a specific alteration in cortical plasticity explained the EBCC changes induced by cerebellar TMS in humans. In this paper, for the first time, it is shown how closed-loop simulations, using detailed cerebellar microcircuit models, can be successfully used to fit real experimental data sets. Thus, the changes of the model parameters in the different sessions of the protocol unveil how implicit microcircuit mechanisms can generate normal and altered associative behaviors.The cerebellum plays a critical role in sensorimotor control. However, how the specific circuits and plastic mechanisms of the cerebellum are engaged in closed-loop processing is still unclear. We developed an artificial sensorimotor control system embedding a detailed spiking cerebellar microcircuit with three bidirectional plasticity sites. This proved able to reproduce a cerebellar-driven associative paradigm, the eyeblink classical conditioning (EBCC), in which a precise time relationship between an unconditioned stimulus (US) and a conditioned stimulus (CS) is established. We challenged the spiking model to fit an experimental data set from human subjects. Two subsequent sessions of EBCC acquisition and extinction were recorded and transcranial magnetic stimulation (TMS) was applied on the cerebellum to alter circuit function and plasticity. Evolutionary algorithms were used to find the near-optimal model parameters to reproduce the behaviors of subjects in the different sessions of the protocol. The main finding is that the optimized cerebellar model was able to learn to anticipate (predict) conditioned responses with accurate timing and success rate, demonstrating fast acquisition, memory stabilization, rapid extinction, and faster reacquisition as in EBCC in humans. The firing of Purkinje cells (PCs) and deep cerebellar nuclei (DCN) changed during learning under the control of synaptic plasticity, which evolved at different rates, with a faster acquisition in the cerebellar cortex than in DCN synapses. Eventually, a reduced PC activity released DCN discharge just after the CS, precisely anticipating the US and causing the eyeblink. Moreover, a specific alteration in cortical plasticity explained the EBCC changes induced by cerebellar TMS in humans. In this paper, for the first time, it is shown how closed-loop simulations, using detailed cerebellar microcircuit models, can be successfully used to fit real experimental data sets. Thus, the changes of the model parameters in the different sessions of the protocol unveil how implicit microcircuit mechanisms can generate normal and altered associative behaviors.

The effects of aging in delay and trace human eyeblink conditioning.

Normal aging has been shown to impact performance during human eyeblink classical conditioning, with older adults showing lower conditioning levels than younger adults. Previous findings showed younger adults can acquire both delay and trace conditioning concurrently, but it is not known whether older adults can learn under the same conditions. Present results indicated older adults did not produce a significantly greater number of conditioned responses during acquisition, but their ability to time eyeblink responses prior to the unconditioned stimulus was preserved. The decline in eyeblink conditioning that typically accompanies aging has been extended to concurrent presentations of delay and trace conditioning trials.

Neural substrates underlying human delay and trace eyeblink conditioning

Classical conditioning paradigms, such as trace conditioning, in which a silent period elapses between the offset of the conditioned stimulus (CS) and the delivery of the unconditioned stimulus (US), and delay conditioning, in which the CS and US coterminate, are widely used to study the neural substrates of associative learning. However, there are significant gaps in our knowledge of the neural systems underlying conditioning in humans. For example, evidence from animal and human patient research suggests that the hippocampus plays a critical role during trace eyeblink conditioning, but there is no evidence to date in humans that the hippocampus is active during trace eyeblink conditioning or is differentially responsive to delay and trace paradigms. The present work provides a direct comparison of the neural correlates of human delay and trace eyeblink conditioning by using functional MRI. Behavioral results showed that humans can learn both delay and trace conditioning in parallel. Comparable delay and trace activation was measured in the cerebellum, whereas greater hippocampal activity was detected during trace compared with delay conditioning. These findings further support the position that the cerebellum is involved in both delay and trace eyeblink conditioning whereas the hippocampus is critical for trace eyeblink conditioning. These results also suggest that the neural circuitry supporting delay and trace eyeblink classical conditioning in humans and laboratory animals may be functionally similar.

Conditioning in identical twins with ataxia-telangiectasia

Evidence has accumulated to indicate an essential role for the cerebellum in eyeblink classical conditioning, with normal acquisition impaired by lesions in the cerebellar cortex. For this reason, eyeblink conditioning was studied in a pair of 16-year-old identical twin females with ataxia-telangiectasia (AT), a disorder with onset in early childhood characterized by diffuse, almost selective, degeneration of the cerebellar cortex with extensive loss of Purkinje cells. We also tested a pair of 16-year-old identical twin female normal control subjects. Twins with AT produced significantly fewer conditioned responses (CRs). The mean percentages of CRs over 144 trials for each eye were 23.0% (left eye) and 10.2% (right eye) in patients with AT, and 45.9% (left eye) and 45.3% (right eye) in normal control subjects. The magnitude of the eyeblink reflex, assessed as unconditioned response amplitude, was not different between patients with AT and control subjects. The results indicate that patients with AT are impaired in the acquisition of CRs and provide further evidence for the role of the cerebellum in eyeblink classical conditioning in humans.

Variation of the intertriai interval in human classical conditioning

The effect of using a short intertriai interval (ITI) in eyeblink classical conditioning in humans was examined. The performance of normal young adults in 750-msec delay conditioning was compared at ITIs of 5, 10, and 30 sec. All groups successfully acquired the task. Performance of each ITI group was similar for pseudoconditioning, conditioning, and extinction trials. Use of shorter ITIs during eyeblink conditioning should reduce test time and possible subject boredom or inattention, thus making the eyeblink conditioning task more useful as part of a neuropsychological test battery for evaluating brain damage and drug effectiveness. Shorter ITIs would also allow eyeblink classical conditioning to be used in concert with other technologies, such as PET scanning, to assess functional activity of the brain during learning.

Cerebellar involvement in eyeblink classical conditioning in humans.

Cerebellar involvement in eyeblink classical conditioning in humans.

Cerebellar involvement in eyeblink classical conditioning in humans.

Cerebellar involvement in eyeblink classical conditioning in humans.

Number of trials needed to assess human eyeblink classical conditioning.

Eyeblink classical conditioning (EBCC) is a useful paradigm for studying the neurobiology of learning and memory. EBCC shows large age effects and has been shown to be sensitive to Alzheimer-like neuropathology. The EBCC data of 241 participants, including young, middle-aged, and elderly normal adults, adults with Down's syndrome, and patients with probable Alzheimer's disease, were analyzed to identify a minimum number of trials for reliable assessment. Results indicate that EBCC performance can be as reliably assessed in 63 trials as in 90 trials. Using fewer conditioning trials reduces administration time, making EBCC more practical for both research and potential diagnostic purposes.

Number of trials needed to assess human eyeblink classical conditioning.

Number of trials needed to assess human eyeblink classical conditioning.

Longitudinal Investigation of Eyeblink Classical Conditioning in Elderly Human Subjects

Eyeblink classical conditioning (EBCC) is an important tool in the study of learning, memory, and aging, but few longitudinal data have been collected on EBCC in humans of any age. Our aim was to determine if EBCC would remain stable across time. Fifteen subjects with an initial mean age of 83.2 years ("old-old") were tested three times in just over 2 years, and a subset of 8 of these subjects were tested a fourth time after the third year. Fifteen additional subjects with a mean age of 69.1 years ("young-old") were tested two times in just over one year. Subjects were tested with identical procedures in the 400 msec delay EBCC paradigm. Cognitively normal young-old and old-old adults showed stability in EBCC. In the old-old group, poor EBCC (< 25% conditioned responses; CRs) predicted significantly poorer Blessed Information Memory Concentration scores. Old-old subjects with poor initial EBCC were more likely to become demented or die than were old-old subjects producing over 25% CRs.