Biomedical subjects

D S Woodruff-Pak

Publications and source records attributed to D S Woodruff-Pak.

At least 19 recordsLinked to original sources

PubMed2001

Galantamine: effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning.

Classical eyeblink conditioning is a well-characterized model paradigm that engages the septohippocampal cholinergic system. This form of associative learning is impaired in normal aging and severely disrupted in Alzheimer's disease (AD). Some nicotinic cholinergic receptor subtypes are lost in AD, making the use of nicotinic allosterically potentiating ligands a promising therapeutic strategy. The allosterically potentiating ligand galantamine (Gal) modulates nicotinic cholinergic receptors to increase acetylcholine release as well as acting as an acetylcholinesterase (AChE) inhibitor. Gal was tested in two preclinical experiments. In Experiment 1 with 16 young and 16 older rabbits, Gal (3.0 mg/kg) was administered for 15 days during conditioning, and the drug significantly improved learning, reduced AChE levels, and increased nicotinic receptor binding. In Experiment 2, 53 retired breeder rabbits were tested over a 15-wk period in four conditions. Groups of rabbits received 0.0 (vehicle), 1.0, or 3.0 mg/kg Gal for the entire 15-wk period or 3.0 mg/kg Gal for 15 days and vehicle for the remainder of the experiment. Fifteen daily conditioning sessions and subsequent retention and relearning assessments were spaced at 1-month intervals. The dose of 3.0 mg/kg Gal ameliorated learning deficits significantly during acquisition and retention in the group receiving 3.0 mg/kg Gal continuously. Nicotinic receptor binding was significantly increased in rabbits treated for 15 days with 3.0 mg/kg Gal, and all Gal-treated rabbits had lower levels of brain AChE. The efficacy of Gal in a learning paradigm severely impaired in AD is consistent with outcomes in clinical studies.

Acetylcholinesterase↗

PubMed2000

Cerebellar volume in humans related to magnitude of classical conditioning.

Neural circuits in the cerebellum are essential for eyeblink classical conditioning, and hippocampal activation is also present during acquisition. Anatomical (volumetric) brain MRI, delay eyeblink conditioning and neuropsychological tests were administered to eight healthy older subjects. The correlation between cerebellar volume (corrected for total cerebral volume) and conditioned response percentage was 0.81 (p < 0.02), but neither hippocampal nor total cerebral volume correlated with conditioning or any neuropsychological test scores. There was no relationship between age and cerebellar volume, but the correlation between hippocampal volume and age was -0.80 (p < 0.02). These volumetric results add to the increasing evidence in humans demonstrating a relationship between the integrity of the cerebellum and eyeblink classical conditioning.

Aged↗

PubMed2000

Nicotinic modulation in an animal model of a form of associative learning impaired in Alzheimer's disease.

Eyeblink classical conditioning is a widely used associative learning paradigm that has striking behavioral and neurobiological parallels between humans and other mammals. Eyeblink conditioning is impaired in older organisms, and patients with Alzheimer's disease (AD) are impaired beyond the normal aging deficit. The cholinergic system is of demonstrated involvement in eyeblink conditioning. Blockade of nicotinic cholinergic receptors with mecamylamine prolonged acquisition of conditioned responses (CRs) in young adult rabbits, and the nicotinic agonist, GTS-21 ameliorated conditioning deficits in older rabbits. Galantamine induces allosteric modulation of nicotinic cholinergic receptors to increase acetylcholine release as well as acting as an acetylcholinesterase inhibitor. Galantamine doses of 0.0, 1.0, 2.0, 3.0, and 4.0 mg/kg were tested in ten daily sessions in 40 retired breeder rabbits (mean age = 29 months) in the 750 ms delay conditioning paradigm. A dose of 3 mg/kg galantamine was effective in improving conditioning in older rabbits, enabling them to achieve learning criterion rapidly and to produce a very high percentage of CRs. Control tests of rabbits in explicitly unpaired conditions demonstrated that non-associative factors could not account for the results. The efficacy of galantamine in a learning paradigm that shows severe impairment in AD indicates that the drug may be effective as a cognition-enhancer in AD.

Age Factors↗

PubMed2000

Eyeblink classical conditioning: hippocampal formation is for neutral stimulus associations as cerebellum is for association-response.

Extensive evidence has been amassed that the cerebellum, hippocampus, and associated circuitry are activated during classical conditioning of the nictitating membrane/eyeblink response. In this article, the authors argue that the cerebellum is essential to all eyeblink classical conditioning paradigms. In addition, the septohippocampal system plays a critical role when the classical conditioning paradigm requires the formation of associations in addition to the simple association between the conditioned and unconditioned stimuli. When only a simple conditioned stimulus--unconditioned stimulus association is needed, the septohippocampal system has a more limited, modulatory role. The neutral stimulus association versus simple association-response distinction is one of the ways in which declarative or relational memory can be separated from nondeclarative or nonrelational memory in classical conditioning paradigms.

Blinking↗

PubMed1999

Relationships among age, conditioned stimulus-unconditioned stimulus interval, and neuropsychological test performance.

To evaluate the effect of age at various conditioned stimulus (CS)-unconditioned stimulus (US) intervals, 144 young, middle-aged, and older adults were tested on eyeblink classical conditioning at CS-US intervals of 500, 1,000, or 1,500 ms. Reaction time, response timing, motor learning, declarative memory, and attention were assessed to identify correlates of conditioning at various CS-US intervals. Previously reported middle-aged and older adults were impaired at a 400-ms CS-US interval, but the addition of 100 ms to the CS-US interval in this study enabled equal conditioning in middle-aged and young adults. At a 1,000-ms CS-US interval, older adults remained significantly impaired. It was only at the 1,500-ms CS-US interval that conditioning was equal for the 3 age groups. Measures of reaction time, timing, and motor learning were not correlated systematically with conditioning. Whereas the results of age differences at various CS-US intervals were clear and striking, patterns of relationships among neuropsychological and conditioning variables were not consistent in indicating sources of age differences.

Adolescent↗

PubMed1998

Predictors of eyeblink classical conditioning over the adult age span.

The major aim was to identify predictors of the large age differences that exist in eyeblink classical conditioning. Eyeblink conditioning was assessed in 190 participants over the age range of 20-89 years, with 150 trained in the paired condition and 40 trained in the explicitly unpaired control condition. Timed-interval tapping was used to assess cerebellar function. Blink reaction time and explicit learning and memory were also assessed. Stepwise multiple regression indicated that the effect of age accounted for the largest proportion of the variance, but the cerebellar measure also predicted eyeblink conditioning at a significant level. Reaction time and explicit memory measures did not account for a significant amount of the variance in eyeblink conditioning. Age-related effects in the cerebellum apparently affect timing and learning in normal adults.

Adult↗

PubMed1997

Hippocampus in delay eyeblink classical conditioning: essential for nefiracetam amelioration of learning in older rabbits.

Rabbits acquire conditioned responses (CRs) normally with bilateral removal of the hippocampus, but alterations of the intact hippocampus can affect the rate of acquisition. The cognition-enhancing drug, nefiracetam ameliorated the acquisition of CRs in older rabbits, protected membrane dysfunction in hippocampal CA1 neurons following oxygen and glucose deprivation, and promoted the release of diverse neurotransmitters, including acetylcholine. Because the septo-hippocampal cholinergic system is demonstrated to be involved in eyeblink conditioning, this experiment was undertaken to explore whether nefiracetam ameliorates conditioning via the hippocampus. Data from 53 rabbits of a mean age of 28 months were tested under two drug conditions (10 or 0 mg/kg nefiracetam) and 4 lesion conditions (bilateral hippocampectomy, bilateral neocortical removal, sham surgery, no surgery). The three groups of nefiracetam-treated rabbits with intact hippocampus acquired CRs more rapidly than the vehicle-treated groups, but rabbits with bilateral hippocampectomy treated with nefiracetam learned like vehicle-treated rabbits. Results suggest that nefiracetam ameliorates learning via the hippocampus. Because of the parallels between conditioning in rabbits with disrupted hippocampal cholinergic systems and conditioning in Alzheimer's disease (AD), these results suggest that nefiracetam may ameliorate conditioning in AD as it ameliorates conditioning in older rabbits.

Aging↗

PubMed1997

Mecamylamine- or scopolamine-induced learning impairment: ameliorated by nefiracetam.

Nefiracetam is undergoing preclinical and clinical tests as a cognition-enhancing drug in Alzheimer's disease (AD). Nicotinic cholinergic receptors are lost in AD, and nicotinic as well as muscarinic cholinergic receptors are involved in the modulation of eyeblink conditioning. Experiments were carried out using young rabbits to examine the effect of nefiracetam on cholinergic antagonists to nicotinic (mecamylamine) and muscarinic (scopolamine) receptors. Rabbits were tested for 15 days in the 750 ms delay eyeblink classical conditioning paradigm in paired and explicitly unpaired conditions. Nefiracetam at a dose of 15 mg/kg significantly ameliorated the effects of 0.5 mg/kg mecamylamine, and nefiracetam at a dose of 10 mg/kg significantly ameliorated the effect of 1.5 mg/kg scopolamine. The vehicle alone and nefiracetam alone groups performed similarly to the groups treated with mecamylamine or scopolamine and nefiracetam. Reversal by nefiracetam of a nicotinic as well as a muscarinic cholinergic antagonist indicates that the drug may affect deficits specific to AD.

Animals↗

PubMed1997

Classical conditioning.

Evidence has amassed from research in humans indicating that the cerebellar circuitry serving as the substrate for eyeblink classical conditioning is similar to that in nonhuman primates. In patients with bilateral cerebellar lesions or neurodegenerative cerebellar disease, few conditioned eyeblink responses are produced with either the ipsilesional or the contralesional eye. Cerebellar patients with lateralized lesions, like rabbits with experimentally produced unilateral cerebellar lesions, produce relatively normal conditioned responses (CRs) with the contralesional eye and few or no CRs with the ipsilesional eye. Age-related deficits in eyeblink classical conditioning appear in humans and rabbits in middle age. In normal aging in many species, including humans, there is Purkinje cell loss in cerebellar cortex. In rabbits, the Purkinje cell number correlates highly with the rate of learning, regardless of age. Positron emission tomography imaging of normal young adults during eyeblink conditioning reveals changes in activity in the cerebellum. Timed interval tapping, a task that assesses cerebellar function, also predicts performance on eyeblink conditioning. In dual-task conditions involving simultaneous performance of eyeblink conditioning and timed interval tapping, eyeblink conditioning is impaired. Investigations of patients with lesions or neurodegenerative disease not involving the cerebellum demonstrate that acquisition of CRs is possible, although prolonged in the case of hippocampal cholinergic disruption. Evidence to date suggests that the human analogue of the rabbit interpositus nucleus, the globose nucleus, is essential for the production of the conditioned eyeblink response and that cerebellar cortical Purkinje cells play a role in normal acquisition.

Aging↗

PubMed1997

Nefiracetam ameliorates learning deficits in older rabbits and may act via the hippocampus.

Behavioral and neurobiological parallels between rabbits and humans in eyeblink classical conditioning (EBCC) make this paradigm potentially useful for preclinical and clinical trials. The known involvement of hippocampal pyramidal cells in EBCC in rabbits led us to evaluate the nootropic compound, nefiracetam. In Expt. 1, 56 rabbits of a mean age of 27.9 months received daily doses of vehicle, 1, 3, 10, or 15 mg/kg nefiracetam 15 min before testing in the 750 ms delay EBCC paradigm. Trials to learning criterion (T/C) was significantly better with 10 mg/kg. To investigate whether nefiracetam ameliorated EBCC via the hippocampus, 20 older rabbits received bilateral hippocampal aspirations in Expt. 2. Eleven rabbits of a mean age of 26.8 months had histologically confirmed bilateral hippocampectomy and were dosed with vehicle or 10 mg/kg nefiracetam and tested with EBCC. Hippocampectomized rabbits treated with vehicle and 10 mg/kg nefiracetam had 718 and 996 T/C, respectively, that were not different from 845 T/C of 8 intact older rabbits and vehicle mg/kg nefiracetam, but significantly worse than 473 T/C for 8 intact older rabbits and 10 mg/kg nefiracetam. Nefiracetam ameliorated EBCC in older rabbits only when the hippocampus was intact.

Aging↗

PubMed1997

Concurrent eyeblink classical conditioning and rotary pursuit performance: implications for independent nondeclarative memory systems.

The authors examined whether 2 nondeclarative tasks, simple eyeblink classical conditioning (EBCC) and rotary pursuit (RP), would interfere with each other when performed simultaneously. In Experiment 1,100 participants were assigned to 1 of 5 groups: paired EBCC/RP, unpaired EBCC/RP, paired EBCC as a single task, unpaired EBCC as a single task, and RP as a single task. Participants in the paired EBCC/RP group showed significantly greater acquisition of conditioned responses than did participants in the unpaired EBCC/RP group, and the unconditioned eyeblink response was similar in both groups. Comparisons of the paired EBCC/RP and paired EBCC-as-a-single-task groups indicated no differences in trials to criterion, but on some measures the single-task group conditioned better. Controls introduced in Experiment 2 did not change this pattern. Results provide some evidence for the lack of interference between EBCC and RP.

Adult↗

PubMed1996

Huntington's disease and eyeblink classical conditioning: normal learning but abnormal timing.

On the basis of what is known about the neural circuitry essential or normally involved in eyeblink classical conditioning (EBCC), the pattern of neurodegeneration in Huntington's disease (HD) would not appear to interfere with this type of learning. HD causes severe atrophy of the basal ganglia and thinning and shrinkage of the cerebral cortex. However, the hippocampus and hippocampal cholinergic system remain relatively intact, as does the cerebellum. Because the brain circuitry engaged in EBCC is neither lesioned nor disrupted in HD, it was predicted that HD patients would perform like normal control subjects in the 400-ms delay EBCC paradigm. Performance of seven patients with HD was compared to age-matched normals, with two control subjects matched to each HD patient. There were no differences in production of conditioned responses (CRs) between HD patients and normal control subjects, but the timing of the CR was abnormal in HD. Comparisons of HD patients to patients with other neurodegenerative diseases (probable Alzheimer's disease (pAD) and Down syndrome (DS) over the age of 35 with presumed Alzheimer-like neuropathology) and to patients with cerebellar lesions demonstrated significantly better EBCC performance in HD. Results suggest that the ability to acquire CRs is normal in HD, but the striatum may have some role in optimizing the timing of the CR.

Adult↗

PubMed1996

Training to criterion in eyeblink classical conditioning in Alzheimer's disease, Down's syndrome with Alzheimer's disease, and healthy elderly.

The cholinergic antagonist scopolamine delays acquisition of eyeblink classical conditioning (EBCC) in rabbits and humans, but scopolamine-treated organisms eventually acquire conditioned responses (CRs). Patients with probable Alzheimer's disease (AD) and older adults with Down's syndrome (DS/AD) have disrupted cholinergic systems and perform EBCC very poorly. It was hypothesized that patients with probable AD and DS/AD, like scopolamine-injected organisms, would acquire CRs if given sufficient training. Twelve probable AD patients, 12 DS/AD patients, and 6 healthy elderly control individuals participated in 5 daily 90-trial sessions of EBCC. Fifty-eight percent of the probable AD, 92% of the DS/AD, and 100% of the control participants achieved learning criterion. Probable AD, DS/AD, and control participants had statistically significant increases in the percentage of CRs produced over 5 EBCC sessions. The neural substrate for EBCC was not eliminated in probable AD or DS/AD patients, although the learning mechanism was disrupted.

Adult↗

PubMed1996

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.

Adult↗

PubMed1995

Selective disruption of eyeblink classical conditioning by concurrent tapping.

A total of 140 normal adults participated in one of seven conditions designed to test the hypothesis that memory systems may be distinguished on the basis of their neurobiological substrates. The results revealed a selective disruption of eyeblink classical conditioning (EBCC) when it was performed concurrently with tapping, another cerebellar task. Subjects simultaneously engaged in EBCC and a recognition task or control tasks were relatively unimpaired in EBCC. Results provide evidence for the existence of neurobiologically distinct memory systems, and suggest that the selective disruption of EBCC, when concurrently performed with tapping, may be attributed to cerebellar involvement in both tasks.

Adolescent↗

PubMed1995

Larger nondeclarative than declarative deficits in learning and memory in human aging.

This study used classical conditioning as a measure of nondeclarative learning and compared it with verbal learning as a declarative measure. Eighty participants were tested using 1 of 2 paradigms (400-ms and 750-ms delay) for eyeblink classical conditioning (EBCC) and the California Verbal Learning Test (CVLT). Large age differences were observed in the nondeclarative EBCC task, even in the 750-ms paradigm, which is more optimal for older adults. Age differences in the nondeclarative EBCC task were larger in the 400-ms paradigm and equal in the 750-ms paradigm to the magnitude of age differences in the declarative CVLT task. Partial correlations (removing the variance that was due to age) showed no relation between performance on the nondeclarative and declarative tasks. The results contradict the common assumption that, in the same participants, nondeclarative learning and memory are more resistant to the effects of aging than are declarative learning and memory and suggest that nondeclarative learning and memory are not unitary.

Adolescent↗

PubMed1995

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.

Aged↗

PubMed1995

Fragile-X and Down's syndrome: are there syndrome-specific cognitive profiles at low IQ levels?

Individuals with either fragile-X syndrome or Down's syndrome with IQ scores less than 40 were assessed on the Down Syndrome Mental Status Exam. The results of the testing were examined for syndrome-specific cognitive profiles. No evidence for syndrome-specific cognitive profiles were found. These same individuals were then classified as high or low IQ, and each group was examined for IQ-level-specific profiles. Unique IQ level cognitive profiles were found. Classifying the individuals with regard to aetiology obscured IQ-level-specific strengths and weaknesses. Researchers and developers of curricula are cautioned against generalizing cognitive profiles to all IQ levels of a specific genetic syndrome.

Activities of Daily Living↗