Michelle Papka

Cerebellar involvement in eyeblink classical conditioning in humans.

The role of the ipsilateral cerebellum in human eyeblink conditioning was investigated using the 400-ms delay paradigm and testing 14 cerebellar patients (7 with unilateral lesions and 7 with bilateral lesions) and 20 control participants. Patients performed significantly worse with the ipsilesional eye than control participants but showed no difference when tested with (he contralesional eye. Conditioned responses (CRs) totaled 14% for all patients in comparison with 60% for control participants. Data on timed-interval tapping for 6 patients and 14 control participants showed that clock variability was greater with Ihe ipsilesional hand in patients. Only clock variability correlated significantly with percentage of CRs in control participants. Comparisons of paired associate learning and memory for 8 patients and 14 control participants revealed no significant differences. Results confirm that the ipsilateral cerebellum plays a role in eyeblink classical conditioning.

Parkinson's disease and dementia with Lewy bodies: One disease or two?

Parkinsons disease (PD) and dementia with Lewy bodies (DLB) have clinical features in common and are both characterized neuropathologically by the presence of Lewy bodies (LBs). We conducted a clinicopathological correlation pilot study to better understand whether PD and DLB represent two distinct nosological entities or rather exist along the spectrum of a single LB disease. A neuropathologist blinded to clinical diagnoses evaluated brains with largely pure LB pathology to determine LB distribution and frequency. Research clinicians blinded to LB distribution and frequency determined consensus clinical diagnoses. Clinical features separated cases into two groups, one having features most compatible with PD and the other with DLB. The groups were distinguishable mainly by the time course of clinical symptoms. Although the presence of neocortical LBs was more common in the group of patients with clinical features of DLB, neocortical LBs were also present in 1 member of the PD group and even in the clinically normal control subject. Thus, there appear to be two clinical syndromes, distinguished mainly by the time course of symptoms. The mechanisms responsible for the different clinical presentations are not known, and the issue of whether PD and DLB represent two distinct diseases remains unsettled.

Movement disorders in Alzheimer's disease: More rigidity of definitions is needed

Rigidity, slowness, gait impairment, and other disorders of movement accompany Alzheimers disease (AD) at various stages of the illness. The presence of these so‐called extrapyramidal features have been reported to predict disease prognosis and pathologic localization. Unfortunately, failure to accurately characterize the movement disorder, particularly to distinguish parkinsonism from cortically based motor disturbances (that is, paratonia, apraxia), makes the results of many published studies difficult to interpret. There is an important need to precisely characterize movement disorders in studies of AD to clarify the clinical phenomenology and neurobiology of the condition and to accurately distinguish AD from other degenerative dementias, such as dementia with Lewy bodies.

Alzheimer's disease and eyeblink conditioning : 750 ms trace vs. 400 ms delay paradigm

Patients with probable Alzheimers disease (AD) and hippocampal disruption are severely impaired in eyeblink classical conditioning (EBCC) in the 400 ms delay paradigm. Hippocampectomized rabbits are not impaired in the delay paradigm but perform poorly in the trace paradigm. It was anticipated that probable AD patients would be severely impaired in the 750 ms trace paradigm. In Study 1, probable AD patients were significantly impaired in the trace EBCC paradigm, but the sensitivity of the test was poorer than for the delay paradigm. In Study 2, probable AD patients tested in trace were tested in the delay paradigm 4 months later. Sensitivity for AD was also better for the delay paradigm. Rabbits and humans show behavioral parallels in the 400 ms delay paradigm but not in the 750 ms trace paradigm. The 400 ms delay EBCC paradigm was superior to the 750 ms trace paradigm for the detection of AD.

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 Huntingtons 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 Alzheimers 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.

Eyeblink classical conditioning in Alzheimer's disease and cerebrovascular dementia

Eyeblink classical conditioning (EBCC) is severely and consistently impaired in probable Alzheimers disease (AD), presumably due to normal age related changes in the cerebellum and AD-related hippocampal cholinergic disruption. Less consistent impairment and more variable EBCC performance was predicted in patients with cerebrovascular dementia (CVD) because some CVD patients should have impairment in EBCC when their lesions affect the EBCC circuitry, whereas others with lesions in noncritical regions should have normal EBCC. As predicted, variability in EBCC performance was greater in patients with CVD than in probable AD patients. Acquisition of conditioned responses in the group of CVD patients was better than in the probable AD group. These data show in another sample of normal control subjects and probable AD patients that EBCC has a high sensitivity for probable AD.

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 Alzheimers disease (AD) and older adults with Downs 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.

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.

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 Downs syndrome, and patients with probable Alzheimers 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.