Procedural learning is impaired in Huntington's disease: evidence from the serial reaction time task.

The purpose of the study was to test the hypothesis that Huntington's disease (HD) is associated with impairment of procedural learning. We identified 13 patients with mild to moderate HD whose manual performance was still sufficiently intact to assess learning on the serial reaction time (SRT) task. Twelve age-matched neurologically normal control subjects were studied as well. The SRT task was a four-choice reaction time task in which the stimuli followed a sequence (10 items in length) which repeated itself 10 times during each of the first four blocks of trials. During the fifth block of trials, the stimuli were random. Learning was manifested by a reduction in response latency over the first four blocks and an increase in response latency in the fifth (random) block. Learning in this task has been demonstrated in other amnesics of other etiologies. The HD patients were significantly impaired on sequence-specific learning, using the log-transformed reaction time data (P less than 0.004). In addition, in an individual-by-individual analysis, five of the HD patients and none of the control subjects failed to show sequence-specific learning, a difference in proportions that was significant (P less than 0.04). No feature of the standard cognitive or motor assessment of the HD patients was associated with efficacy of procedural learning. HD, including patients with mild disease, was associated with a deficit in procedural learning, consistent with the hypothesis that the striatum plays a critical role in supporting procedural learning.     

Memory and learning are not impaired in presymptomatic individuals with an increased risk of Huntington's disease

Retrieval from long-term memory in patients with brain injuries was investigated with a memory scanning paradigm (Conway & Engle, 1994), that allows dissociation of scanning processes within short-term memory and memory retrieval processes from long-term memory. The study focused on the influence of brain injury on memory retrieval processes that are assumed to be automatic. Thirteen patients with memory impairment and 13 healthy matched control subjects were tested. In general, patients showed increased reaction times, but they showed set size independent retrieval from long-term memory indicating preserved automatic retrieval processes. In a subgroup of patients with more severe memory deficits, however, automatic retrieval processes appeared not to be intact. Learning profiles of the patients were characterized by smaller item chunks, indicating differences in the process of information acquisition.     

Odor detection, learning, and memory in Huntington's disease.

We compared 7 mildly affected Huntington's disease (HD) patients to 7 age- and education-matched healthy controls (NC) on an odor detection test, the California Odor Learning Test, and the California Verbal Learning Test. Results demonstrated that odor detection sensitivity, but not group membership, accounted for significant variance in total olfactory learning. Both groups learned fewer items in the olfactory modality compared to the verbal modality, but retained a similar amount following a delay. No group differences were demonstrated for verbal recognition discriminability, but the HD group demonstrated significantly impaired odor recognition discriminability. Finally, odor detection provided excellent classification sensitivity and specificity between the patients and controls, suggesting that olfactory testing may provide a sensitive measure of the early disease process in HD.     

Perceptual categorization is impaired in Huntington's disease: an electrophysiological study

Recent evidence raised the possibility that the neostriatum and the corticostriatal circuits could play an important role in semantic categorization. In this study, we examined the electrophysiological correlates of natural scene categorization in Huntington's disease (HD) patients and their asymptomatic relatives who were Huntington's disease mutation carriers (HDC). Event-related potentials were recorded in HD patients, HDC subjects, and age-matched control subjects using a natural scene categorization task. The subjects had to decide whether a briefly presented image contained animals or no animals. Concerning the N1 component (150-250 ms), the mean amplitudes were more negative for nonanimal scenes as compared with stimuli containing animals at all electrode sites in the control group and at all but the lateral temporal electrode sites (T3, T4) in the HD group. Between-group comparison demonstrated that the N1 amplitudes were significantly smaller for both kinds of stimuli in the HD group in spite of a normal primary occipital component (P100). The HDC subjects were not significantly different from the controls concerning the N1 amplitudes. These results suggest that perceptual (N1) processes related to the categorization of natural scenes are specifically impaired in HD. The findings are in agreement with the hypothesis emphasizing the importance of neostriatal mechanisms in human categorization functions.     

Increased GABAergic function in mouse models of Huntington's disease: reversal by BDNF

Huntington's disease (HD) is characterized by loss of striatal gamma-aminobutyric acid (GABA)ergic medium-sized spiny projection neurons (MSSNs), whereas some classes of striatal interneurons are relatively spared. Striatal interneurons provide most of the inhibitory synaptic input to MSSNs and use GABA as their neurotransmitter. We reported previously alterations in glutamatergic synaptic activity in the R6/2 and R6/1 mouse models of HD. In the present study, we used whole-cell voltage clamp recordings to examine GABAergic synaptic currents in MSSNs from striatal slices in these two mouse models compared to those in age-matched control littermates. The frequency of spontaneous GABAergic synaptic currents was increased significantly in MSSNs from R6/2 transgenics starting around 5-7 weeks (when the overt behavioral phenotype begins) and continuing in 9-14-week-old mice. A similar increase was observed in 12-15-month-old R6/1 transgenics. Bath application of brain-derived neurotrophic factor, which is downregulated in HD, significantly reduced the frequency of spontaneous GABAergic synaptic currents in MSSNs from R6/2 but not control mice at 9-14 weeks. Increased GABA current densities also occurred in acutely isolated MSSNs from R6/2 animals. Immunofluorescence demonstrated increased expression of the ubiquitous alpha1 subunit of GABA(A) receptors in MSSNs from R6/2 animals. These results indicate that increases in spontaneous GABAergic synaptic currents and postsynaptic receptor function occur in parallel to progressive decreases in glutamatergic inputs to MSSNs. In conjunction, both changes will severely alter striatal outputs to target areas involved in the control of movement.     

Preclinical Huntington's disease: compensatory brain responses during learning

Motor sequence learning is abnormal in presymptomatic Huntington's disease (p-HD). The neural substrates underlying this early manifestation of HD are poorly understood. To study the mechanism of this cognitive abnormality in p-HD, we used positron emission tomography to record brain activity during motor sequence learning in these subjects. Eleven p-HD subjects (age, 45.8 +/- 11.0 years; CAG repeat length, 41.6 +/- 1.8) and 11 age-matched control subjects (age, 45.3 +/- 13.4 years) underwent H(2) (15)O positron emission tomography while performing a set of kinematically controlled motor sequence learning and execution tasks. Differences in regional brain activation responses between groups and conditions were assessed. In addition, we identified discrete regions in which learning-related activity correlated with performance. We found that sequence learning was impaired in p-HD subjects despite normal motor performance. In p-HD, activation responses during learning were abnormally increased in the left mediodorsal thalamus and orbitofrontal cortex (OFC; BA 11/47). Impaired learning performance in these subjects was associated with increased activation responses in the precuneus (BA 18/31). These data suggest that enhanced activation of thalamocortical pathways during motor learning can compensate for caudate degeneration in p-HD. Nonetheless, this mechanism may not be sufficient to sustain a normal level of task performance, even during the presymptomatic stage of the disease.     

Patients with Huntington's disease have impaired awareness of cognitive, emotional, and functional abilities

The clinical literature in Huntington's disease (HD) suggests that unawareness of deficits is prevalent among HD patients. However, few studies have characterized unawareness of different types of impairment within this neuropsychiatric disorder. The purpose of the current study was to examine self-awareness of functioning across symptom domains in HD patients and to explore the association between impaired awareness and cognitive dysfunction. A total of 66 pairs of HD patients and collaterals of the patients completed symptom-rating measures regarding both the patients' and the collaterals' behavior. A subset of 19 patients also underwent neurological and neuropsychological assessments. The results indicated that patients lacked awareness across symptom domains (i.e., behavioral control, emotional control, activities of daily living), which was significantly greater for their perception of their own behavior than for their perception of their collateral's behavior. Exploratory analyses revealed associations between impaired self-awareness, global cognition, and deficits in executive functioning and memory. The current findings underscore the importance of examining different types of impaired awareness including both over- and underreporting of abilities. Future studies will benefit also from examining the association between awareness and cognition in larger samples.     

Abnormal platelet aggregation response in Huntington's disease

Platelet aggregation response to epinephrine, dopamine, serotonin, adenosine diphosphate, arachidonic acid, and collagen was examined in seven patients with Huntington's disease and nine of their relatives. All patients, except for two cases that were in terminal states, showed enhanced response to all the stimulants, especially to dopamine and epinephrine. The platelet aggregation response in many relatives also deviated from the normal limit. The relationship between platelet aggregation abnormality in Huntington's disease and the pathophysiology of the disease was discussed from the view of a generalized membrane defect hypothesis in Huntington's disease, and of disturbed cathecholamine metabolism, both in the CNS and periphery. A possibility that platelet aggregation response examination will be a useful screening test of offspring at risk was proposed.     

Abnormal platelet aggregation response in Huntington's disease

Summary Platelet aggregation response to epinephrine, dopamine, serotonin, adenosine diphosphate, arachidonic acid, and collagen was examined in seven patients with Huntington's disease and nine of their relatives. All patients, except for two cases that were in terminal states, showed enhanced response to all the stimulants, especially to dopamine and epinephrine. The platelet aggregation response in many relatives also deviated from the normal limit.The relationship between platelet aggregation abnormality in Huntington's disease and the pathophysiology of the disease was discussed from the view of a generalized membrane defect hypothesis in Huntington's disease, and of disturbed cathecholamine metabolism, both in the CNS and periphery.A possibility that platelet aggregation response examination will be a useful screening test of offspring at risk was proposed.This paper was read at the 9th International Workshop of the World Federation of Neurology Research Group on Huntington's Chorea, Fuji, Shizuoka, Japan, in September 1981.     

Implicit and explicit aspects of sequence learning in pre-symptomatic Huntington's disease

Learning deficits may be part of the early symptoms of Huntington's disease (HD). Here we characterized implicit and explicit aspects of sequence learning in 11 pre-symptomatic HD gene carriers (pHD) and 11 normal controls. Subjects moved a cursor on a digitizing tablet and performed the following tasks: SEQ: learning to anticipate the appearance of a target sequence in two blocks; VSEQ: learning a sequence by attending to the display without moving for one block, and by moving to the sequence in a successive block (VSEQ test). Explicit learning was measured with declarative scores and number of anticipatory movements. Implicit learning was measured as a strategy change reflected in movement time. By the end of SEQ, pHD had a significantly lower number of correct anticipatory movements and lower declarative scores than controls, while in VSEQ and VSEQ test these indices improved. During all three tasks, movement time changed in controls, but not in pHD. These results suggest that both explicit and implicit aspects of sequence learning may be impaired before the onset of motor symptoms. However, when attentional demands decrease, explicit, but not implicit, learning may improve.     

Discrimination learning and reversal of the conditioned eyeblink reflex in a rodent model of autism

Offspring of rats exposed to valproic acid (VPA) on gestational day (GD) 12 have been advocated as a rodent model of autism because they show neuron loss in brainstem nuclei and the cerebellum resembling that seen in human autistic cases . Studies of autistic children have reported alterations in acquisition of classical eyeblink conditioning and in reversal of instrumental discrimination learning . Acquisition of discriminative eyeblink conditioning depends on known brainstem-cerebellar circuitry whereas reversal depends on interactions of this circuitry with the hippocampus and prefrontal cortex. In order to explore behavioral parallels of the VPA rodent model with human autism, the present study exposed pregnant Long-Evans rats to 600 mg/kg VPA on GD12 and tested their offspring from Postnatal Day (PND26-31) on discriminative eyeblink conditioning and reversal. VPA rats showed faster eyeblink conditioning, consistent with studies in autistic children . This suggests that previously reported parallels between human autism and the VPA rodent model with respect to injury to brainstem-cerebellar circuitry are accompanied by behavioral parallels when a conditioning task engaging this circuitry is used. VPA rats also showed impaired reversal learning, but this likely reflected "carry-over" of enhanced conditioning during acquisition rather than a reversal learning deficit like that seen in human autism. Further studies of eyeblink conditioning in human autism and in various animal models may help to identify the etiology of this developmental disorder.     

The effect of Parkinson's disease and Huntington's disease on human visuomotor learning

Visuomotor adaptation is often driven by error‐based (EB) learning in which signed errors update motor commands. There are, however, visuomotor tasks where signed errors are unavailable or cannot be mapped onto appropriate motor command changes, rendering EB learning ineffective; and yet, healthy subjects can learn in these EB learning‐free conditions. While EB learning depends on cerebellar integrity, the neural bases of EB‐independent learning are poorly understood. As basal ganglia are involved in learning mechanisms that are independent of signed error feedback, here we tested whether patients with basal ganglia lesions, including those with Huntington's disease and Parkinson's disease, would show impairments in a visuomotor learning task that prevents the use of EB learning. We employed two visuomotor throwing tasks that were similar, but were profoundly different in the resulting visual feedback. This difference was implemented through the introduction of either a lateral displacement of the visual field via a wedge prism (EB learning) or a horizontal reversal of the visual field via a dove prism (non‐EB learning). Our results show that patients with basal ganglia degeneration had normal EB learning in the wedge prism task, but were profoundly impaired in the reversing prism task that does not depend on the signed error signal feedback. These results represent the first evidence that human visuomotor learning in the absence of EB feedback depends on the integrity of the basal ganglia.     

Huntington's disease patients show impaired perception of disgust in the gustatory and olfactory modalities

Patients with Huntington's disease show deficits in recognizing disgust in the facial expressions and vocal intonations of others. In this study, the authors demonstrate that these disgust-related deficits extend to foul-smelling olfactory stimuli and inappropriate combinations of taste stimuli.     

DARPP-32 knockout mice exhibit impaired reversal learning in a discriminated operant task

The current study was conducted to examine the performance of mice with a targeted deletion of the gene for DARPP-32 in a discriminated operant task using food reinforcement. DARPP-32 plays a central role in regulating the efficacy of dopaminergic neurotransmission. Initially, wild-type and DARPP-32 knockout mice were trained to nose-poke for food on a continuous reinforcement schedule. The minimum response requirement was increased every 5 days until the animals were responding on an FR-15 schedule of reinforcement. At the completion of extensive operant training, reversal learning was assessed. Wild-type and DARPP-32 knockout mice exhibited equivalent performance during acquisition of this task, with both groups increasing operant responding as the schedule of reinforcement was raised. However, significant differences in discrimination learning were observed during the reversal phase, with DARPP-32 knockout mice requiring significantly more trials to reach criterion than wild-type controls. These results provide evidence for a functional role of DARPP-32 in the mediation of processes underlying learning and memory.     

亨廷顿病的发病机制和治疗进展

亨廷顿病(HD)为遗传性进行性神经变性疾病,以异常的自主运动、认知功能障碍和精神疾病为临床特征,中老年发病,发病后10～15年死亡。已知致病基因为IT15基因,其1号外显子含有一段多态性三核苷酸[胞嘧啶-腺嘌呤-鸟嘌呤(CAG)]重复序列,当CAG重复拷贝数大于36次即引起发病。I715基因编码氨基末端(N末端)含有多聚谷氨酰胺(PolyQ)的大分子蛋白质亨廷顿蛋白(Htt),目前对     

Procedural learning in Parkinson's disease: intact and impaired cognitive components.

Two experiments were carried out to study procedural learning in Parkinson's disease (PD) patients. In Experiment 1, ten patients and their normal controls participated in a classical mirror reading task and in an inverted reading task where word-stimuli made of non inverted letters had to be processed from right to left (e.g., ygoloruen). In both tasks, reading times for new stimuli were compared to reading times for stimuli that repeated over blocks. Although PD patients and their controls exhibited learning for repeated words in both tasks, PD patients did not respond faster with practice for new words in the inverted reading task. In Experiment 2, PD patients and their controls were presented with an original dot counting task in which participants were asked to process a horizontal series of black and white dots from right to left and to indicate whether a dot that had been designated by a number at the beginning of each trial was black or white. Results showed that PD patients, in contrast to controls, did not exhibit learning in this task. Results are discussed in terms of the cognitive components involved in these tasks. It is suggested that PD patients are impaired in the acquisition of a right-to-left visual scanning skill that could be studied directly in Experiment 2.