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Spatial, but not object, delayed response is impaired in early Parkinson's disease
Abstract and Figures
The authors hypothesized that the pathophysiology of early Parkinson's disease (PD) may selectively target structures that support visual working memory for spatial relations but leave structures that support working memory for featural characteristics of objects relatively intact. Fifteen PD and 15 normal control participants took a visual delayed-response test with a spatial condition and a (nonspatial) object condition, equating the perceptual difficulty of the tests for each participant. The stimuli were irregular polygons presented at different locations on a computer screen. Results revealed a selective impairment of spatial delayed response in PD, indicating a disruption of spatial working memory unconfounded by sensory processing difficulties. The selectivity of this deficit may reflect the circumscribed nature of pathophysiological change affecting the caudate nucleus in early PD.
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... Esto avalaría la idea de que los pacientes con EP muestran dificultades en las tareas de respuesta demorada, razonamiento espacial y memoria de imágenes. Así, se encontró una disfunción específica en la EP para el componente espacial en una tarea de respuesta demorada que diferenciaba entre memoria de trabajo espacial y de objetos [78]. Los autores concluyeron que las conexiones anatómicas corticosubcorticales defectuosas eran la causa potencial de su funcionamiento anómalo. ...
... Otra línea de trabajos utiliza tareas de memoria de trabajo visuoespacial y las compara con tareas de memoria de trabajo verbal, y concluye que la primera presenta alteraciones, mientras que la segunda no [79,80]. Otros autores han descrito más específicamente que el déficit se circunscribe al procesamiento espacial, ya que los pacientes no reportan problemas en el reconocimiento de patrones visuales ni en la memoria de objetos [78,81]. ...
... Por otro lado, las tareas típicas que muestran la alteración visuoperceptiva en la EP son: ajuste de la sensibilidad al contraste [36], discriminación en la orientación de enrejados sinusoidales o líneas en el espacio [14,35,38,39], cancelación visual [69], tareas visuoespaciales que requieren una planificación compleja y una secuenciación de acciones [80,86], atención visual alternante [82,84], memoria de trabajo visual [78][79][80]92], orientación, reconocimiento de caras, patrones visuales y dibujos o escenas temáticas [25], en las matrices progresivas de Raven [26] y en la prueba de discriminación visual de formas de Benton [14,27]. ...
... There have been several reports suggesting that there is visuospatial dysfunction in PD (e.g., Boiler et al., 1984;Bondi, Kaszniak, Bayles, & Vance, 1993;Bowen, Hoehn, & Yahr, 1972;Hovestadt, De Jong, & Meerwaldt, 1987;Postle, Jonides, Smith, Corkin, & Growdon, 1997). However, tests of visuospatial skills may often be confounded by the high cognitive demand of these tasks and in particular by the demands these tasks place on frontal executive function (Bondi et al., 1993;Dubois & Pillon, 1997). ...
Patients with Parkinson's disease (PD) have been shown to be impaired on some nondeclarative memory tasks that require cognitive skill learning (perceptual-motor sequence learning, probabilistic classification). To determine what other skill-based tasks are impaired, 13 patients with PD were tested on artificial grammar learning, artificial grammar learning with transfer to novel lettersets, and prototype learning. Patients with PD performed similarly to controls on all 3 tests. The intact learning exhibited by PD patients on these tests suggests that nondeclarative cognitive skill learning is not a single entity supported by the neostriatum. If learning the regularities among visual stimuli is the principal feature of artificial grammar learning and prototype learning, then these forms of skill learning may be examples of perceptual learning, and they may occur in early visual cortical processing areas.
... 2) There is impaired habit learning, as evidenced by a reduced performance of WPT (Wagshal et al. 2014) using probabilistic tasks such as the weather prediction task (Knowlton et al. 1996;Frank et al. 2004;Shohamy et al. 2004). However, this view has been challenged by the previous studies of habitual learning (Frank et al. 2005;Shohamy et al. 2006) and by studies using conditional (motor or nonmotor) learning tasks with error correction, which yielded inconsistencies (Gotham et al. 1988;Vriezen and Moscovitch 1990;Sprengelmeyer et al. 1995;Postle et al. 1997;Marié et al. 1999). In fact, one study using the conflict test has shown intact habit learning with a diseaserelated deficit in goal-directed behavior . ...
Parkinson's disease (PD) is characterized pathologically by alpha-synuclein (α-Syn) aggregates and clinically by the motor as well as cognitive deficits, including impairments in sequence learning and habit learning. Using intracerebral injection of WT and A53T mutant α-Syn fibrils, we investigate the behavioral mechanism of α-Syn for procedure-learning deficit in PD by critically determining the α-Syn-induced effects on model-based goal-directed behavior, model-free (probability-based) habit learning, and hierarchically organized sequence learning. 1) Contrary to the widely held view of habit-learning deficit in early PD, α-Syn aggregates in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS) did not affect acquisition of habit learning, but selectively impaired goal-directed behavior with reduced value sensitivity. 2) α-Syn in the DLS (but not DMS) and SNc selectively impaired the sequence learning by affecting sequence initiation with the reduced first-step accuracy. 3) Adenosine A2A receptor (A2AR) antagonist KW6002 selectively improved sequence learning by preferentially improving sequence initiation and shift of sequence learning as well as behavioral reactivity. These findings established a casual role of α-Syn in the SN-DLS pathway in sequence-learning deficit and DMS α-Syn in goal-directed behavior deficit and suggest a novel therapeutic strategy to improve sequence-learning deficit in PD with enhanced sequence initiation by A2AR antagonists.
... In animal models, administration of D1/D5 receptor antagonist into the hippocampus blocks spatial memory performance [70]. PD patients show greater cognitive impairment in spatial working memory compared to object recognition memory [71,72]. This selective cognitive impairment in our 6-OHDA PD model is consistent with specific impairments in PD patients, reflecting on the utility of using animal models in examining PD neuropsychiatric symptoms. ...
Parkinson’s disease (PD) is a neurological disorder with motor dysfunction and a number of psychiatric symptoms. Symptoms such as anxiety and cognitive deficits emerge prior to motor symptoms and persist over time. There are limited treatments targeting PD psychiatric symptoms. Emerging studies reveal that the gut microbe is altered in PD patients. Here we assessed the effect of a probiotic treatment in a rat model of PD. We used the neurotoxin (6-hydroxydopamine, 6-OHDA) in a preclinical PD model to examine the impact of a probiotic treatment (Lacticaseibacillus rhamnosus HA-114) on anxiety and memory. Rats underwent either sham surgery or received 6-OHDA bilaterally into the striatum. Three weeks post-surgery, rats were divided into three experimental groups: a sham group that received probiotics, a 6-OHDA group that received probiotics, and the third group of 6-OHDA received the placebo formula. All rats had access to either placebo or probiotics formula for 6 weeks. All groups were assessed for anxiety-like behaviour using the elevated plus maze. Cognition was assessed for both non-hippocampal and hippocampal dependent tasks using the novel object recognition and novel place recognition. We report that the 6-OHDA lesion induced anxiety-like behaviour and deficits in hippocampal dependent cognition. Interestingly, the probiotics treatment had no impact on anxiety-like behaviour but selectively improved hippocampal dependent cognition deficits. Together, the results presented here highlight the utility of animal models in examining the neuropsychiatric symptoms of PD and the potential of probiotics as adjunctive treatment for non-motor symptoms of PD.
... Attention, VWM, and SWM are all required in tandem to maintain a visual representation of the world. Nevertheless, a wealth of evidence from neuroimaging and lesion studies suggests they are dissociable behavioural processes subserved by distinct, though partially overlapping, brain networks (Carlesimo, Perri, Turriziani, Tomaiuolo, & Caltagirone, 2001;Della Sala, Gray, Baddeley, Allamano, & Wilson, 1999;Postle, Jonides, Smith, Corkin, & Growdon, 1997;Sala & Courtney, 2007). For example, covert shifts of attention to targets without any mnemonic task demands do not result in automatic memory encoding (Tas, Luck, & Hollingworth, 2016). ...
Visual working memory (VWM) involves the encoding and maintenance of visual information over time, with the requirement that object features be accurately bound to spatial locations. We and others have shown that damage to the right hemisphere leads to impaired spatial working memory. Here, we test the notion that right brain damage (RBD) may have consequences for domain general VWM. We had eight RBD patients and a group of healthy control participants perform a VWM task under different loads (1 to 3 items to recall) and spatial competition (high vs. low). All participants were asked to remember the colour of target items presented on the right side of space. Patients showed impaired encoding of information evident in poor precision of memory representations and increased guessing rates even at a set size of only one item. Our data suggests that VWM capacity is severely limited following RBD. Although five of the eight patients presented with neglect, it is not clear whether this deficit in VWM is unique to the syndrome. We suggest that future work should directly pit attention and VWM demands against one another in the same patients to determine whether the confluence of deficits in these domains is the critical determinant of the neglect syndrome. Regardless of the implications for the neglect syndrome, however, our data show that VWM deficits in RBD patients extend into non-spatial feature space.
... Possession of a mnemonic system which uses feature-based and location-based information in fundamentally different ways may be adaptive from an ecological perspective, where such detection of a predator or prey (same features) in a different spatial location may be salient and draw in attention. This view is also consistent with ideas that object-based and spatial WM can function relatively independently (Courtney, Ungerleider, Keil, & Haxby, 1996;Darling, Della Sala, Logie, & Cantagallo, 2006;Owen, Iddon, Hodges, Summers, & Robbins, 1997;Postle, Jonides, Smith, Corkin, & Growdon, 1997). However, based on the present data we cannot fully discount an alternative suggestion that is in keeping with another model of WM (Oberauer, 2002), in which spatial and feature-based information exert different effects on misbinding due to the fact that they had differences in relevancy or due to the attention each dimension was given. ...
Background
Working memory (WM) deficits in neuropsychiatric disorders have often been attributed to altered dopaminergic signalling. Specifically, D 2 receptor stimulation is thought to affect the ease with which items can be gated into and out of WM. In addition, this effect has been hypothesised to vary according to baseline WM ability, a putative index of dopamine synthesis levels. Moreover, whether D 2 stimulation affects WM vicariously through modulating relatively WM-free cognitive control processes has not been explored.
Aims
We examined the effect of administering a dopamine agonist on the ability to ignore or update information in WM.
Method
A single dose of cabergoline (1 mg) was administered to healthy older adult humans in a within-subject, double-blind, placebo-controlled study. In addition, we obtained measures of baseline WM ability and relatively WM-free cognitive control (overcoming response conflict).
Results
Consistent with predictions, baseline WM ability significantly modulated the effect that drug administration had on the proficiency of ignoring and updating. High-WM individuals were relatively better at ignoring compared to updating after drug administration. Whereas the opposite occurred in low-WM individuals. Although the ability to overcome response conflict was not affected by cabergoline, a negative relationship between the effect the drug had on response conflict performance and ignoring was observed. Thus, both response conflict and ignoring are coupled to dopaminergic stimulation levels.
Conclusions
Cumulatively, these results provide evidence that dopamine affects subcomponents of cognitive control in a diverse, antagonistic fashion and that the direction of these effects is dependent upon baseline WM.
... In that investigation the spatial location of the stimuli was irrelevant (did not have to be recalled), but could still influence the results through the obligatory manner in which spatial information consumes mnemonic resources 34,35 and affects the probability of misbinding events occurring. 36 This issue may be particularly important in PD, where it has been argued that spatial WM is prominently affected by the disease 37,38 Here, we seek to examine these hypotheses by testing patients' pure maintenance abilities in a novel paradigm (Fig. 1). Participants had to remember the orientations of two stimuli presented on the left and right of the screen. ...
Cognitive deficits are a recognised component of Parkinson’s disease (PD). However, particularly within the domain of short-term memory, it is unclear whether these impairments are masked, or caused, by patients’ dopaminergic medication. The effect of medication on pure maintenance in PD patients has rarely been explored, with most assessments examining maintenance intercalated between other executive tasks. Moreover, few studies have utilised methods that can measure the quality of mental representations, which can enable the decomposition of recall errors into their underlying neurocognitive components. Here, we fill this gap by examining pure maintenance in PD patients in high and low dopaminergic states. Participants had to encode the orientation of two stimuli and reproduce these orientations after a short (2 s) or long (8 s) delay. In addition, we also examined the performance of healthy, age-matched older adults to contextualise these effects and determine whether PD represents an exacerbation of the normal ageing process. Patients showed improved recall OFF compared to ON their dopaminergic medication, but only for long-duration trials. Moreover, PD patients OFF their medication actually performed at a level superior to age-matched controls, indicative of a paradoxical enhancement of memory in the low dopaminergic state. The application of a probabilistic model of response selection suggested that PD patients made fewer misbinding errors in the low, compared with high, dopaminergic state for longer-delay trials. Thus, unexpectedly, the mechanisms that prevent memoranda from being corrupted by misbinding over time appear to be enhanced in PD patients OFF dopaminergic medication. Possible explanations for this paradoxical effect are discussed.
... Using this approach, studies investigating WM performance both on and off dopaminergic medication have resulted in conflicting findings. Dopaminergic medication has been reported to both improve (Lange et al. 1992) and impair WM performance (Poewe et al. 1991;Cools et al. 2010;Uitvlugt et al. 2016), sometimes depending on modality of the memory array (Owen et al. 1997;Postle et al. 1997;Gruszka et al. 2016), in tasks employing span or change-detection methodology. To better quantify the effect of dopaminergic medication on WM, a recent study (Fig. 5) examined the effect of dopaminergic medication on a delayed reproduction task examining retention over time (simple maintenance), as well as recall when people either had to ignore distracting information or update the contents of WM (Fallon et al. 2017). ...
Working memory impairments are frequently observed in patients with Alzheimer's disease (AD) and Parkinson's disease (PD). Recent research suggests that the mechanisms underlying these deficits might be dissociable using sensitive tasks, specifically those that rely on the reproduction of the exact quality of features held in memory.In patients with AD, working memory impairments are mainly due to an increase in misbinding errors. They arise when patients misremember which features (e.g., color, orientation, shape, and location) belong to different objects held in memory. Hence, they erroneously report features that belong to items in memory other than the one they are probed on. This misbinding of features that belong to different objects in memory can be considered a form of interference between stored items. Such binding errors are evident even in presymptomatic individuals with familial AD (due to gene mutations) who do not have AD yet. Overall, these findings are in line with the role of the medial temporal lobes, and specifically the hippocampus, in retention of feature bindings, regardless of retention duration, i.e., in both short- or long-term memory.Patients with PD, on the other hand, do not show increased misbinding. Their working memory deficits are associated with making more random errors or guesses. These random responses are not modulated by manipulations of their dopaminergic medication and hence may reflect involvement of non-dopaminergic neurotransmitters in this deficit. In addition, patients with PD demonstrate impairments in gating of information into relevant vs. irrelevant items in memory, a cognitive operation that is modulated by dopaminergic manipulation in line with a frontal executive effect of this neurotransmitter. Thus, although AD and PD are both associated with working memory impairments, these surface manifestations appear to be underpinned by very different mechanisms.
Working memory (WM) impairments are reported to occur in patients with Parkinson's disease (PD). However, the mechanisms are unclear. Here, we investigate several putative factors that might drive poor performance, by examining the precision of recall, the order in which items are recalled and whether memories are corrupted by random guessing (attentional lapses). We used two separate tasks that examined the quality of WM recall under different loads and retention periods, as well as a traditional digit span test. Firstly, on a simple measure of WM recall, where patients were asked to reproduce the orientation of a centrally presented arrow, overall recall was not significantly impaired. However, there was some evidence for increased guessing (attentional lapses). On a new analogue version of the Corsi‐span task, where participants had to reproduce on a touchscreen the exact spatial pattern of presented stimuli in the order and locations in which they appeared, there was a reduction in the precision of spatial WM at higher loads. This deficit was due to misremembering item order. At the highest load, there was reduced recall precision, whereas increased guessing was only observed at intermediate set sizes. Finally, PD patients had impaired backward, but not forward, digit spans. Overall, these results reveal the task‐ and load‐dependent nature of WM deficits in PD. On simple low‐load tasks, attentional lapses predominate, whereas at higher loads, in the spatial domain, the corruption of mnemonic information—both order item and precision—emerge as the main driver of impairment.
Objective:
To provide a select review of our applications of quantitative modeling to highlight the utility of such approaches to better understand the neuropsychological deficits associated with various neurologic and psychiatric diseases.
Method:
We review our work examining category learning in various patient populations, including individuals with basal ganglia disorders (Huntington's Disease and Parkinson's disease), amnesia and Eating Disorders.
Results:
Our review suggests that the use of quantitative models has enabled a better understanding of the learning deficits often observed in these conditions and has allowed us to form novel hypotheses about the neurobiological bases of their deficits.
Conclusions:
We feel that the use of neurobiologically inspired quantitative modeling holds great promise in neuropsychological assessment and that future clinical measures should incorporate the use of such models as part of their standard scoring. Appropriate studies need to be completed, however, to determine whether such modeling techniques adhere to the rigorous psychometric properties necessary for a valid and reliable application in a clinical setting. (PsycINFO Database Record
We used positron emission tomography (PET) to answer the following question: Is working memory a unitary storage system, or does it instead include different storage buffers for different kinds of information? In Experiment 1, PET measures were taken while subjects engaged in either a spatial-memory task (retain the position of three dots for 3 sec) or an object-memory task (retain the identity of two objects for 3 sec). The results manifested a striking double dissociation, as the spatial task activated only right-hemisphere regions, whereas the object task activated primarily left-hemisphere regions. The spatial (right-hemisphere) regions included occipital, parietal, and prefrontal areas, while the object (left-hemisphere) regions included inferotemporal and parietal areas. Experiment 2 was similar to Experiment 1 except that the stimuli and trial events were identical for the spatial and object tasks; whether spatial or object memory was required was manipulated by instructions. The PET results once more showed a double dissociation, as the spatial task activated primarily right-hemisphere regions (again including occipital, parietal and prefrontal areas), whereas the object task activated only left-hemisphere regions (again including inferotemporal and parietal areas). Experiment 3 was a strictly behavioral study, which produced another double dissociation. It used the same tasks as Experiment 2, and showed that a variation in spatial similarity affected performance in the spatial but not the object task, whereas a variation in shape similarity affected performance in the object but not the spatial task. Taken together, the results of the three experiments clearly imply that different working-memory buffers are used for storing spatial and object information.
Tested (1) the hypothesis that Parkinson's disease (PD), thought to result in disturbed neuronal outflow from the striatum, leads to circumscribed deficits in cognitive functions presumed to be dependent on the functional integrity of the frontal lobes and (2) whether such deficits could account for previously reported memory and visuoperceptual difficulties in PD. 19 nondemented PD patients were demographically matched to 19 normal elderly control Ss. Three categories of tests were given: (1) tests sensitive to frontal system dysfunction, (2) tests of learning and memory, and (3) tests of visuoperceptual and visuoconstructive skills. Nondemented PD patients demonstrated selective deficits on frontal system tasks; tests of learning and memory and of visuoperceptual and visuoconstructive skill were not significantly impaired once performance on the frontal related tasks was statistically covaried. Results are consistent with the striatofrontal outflow model of neuropsychological impairment in nondemented PD patients. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Concepts of basal ganglia organization have changed markedly over the past decade, due to significant advances in our understanding of the anatomy, physiology and pharmacology of these structures. Independent evidence from each of these fields has reinforced a growing perception that the functional architecture of the basal ganglia is essentially parallel in nature, regardless of the perspective from which these structures are viewed. This represents a significant departure from earlier concepts of basal ganglia organization, which generally emphasized the serial aspects of their connectivity. Current evidence suggests that the basal ganglia are organized into several structurally and functionally distinct 'circuits' that link cortex, basal ganglia and thalamus, with each circuit focused on a different portion of the frontal lobe. In this review, Garrett Alexander and Michael Crutcher, using the basal ganglia 'motor' circuit as the principal example, discuss recent evidence indicating that a parallel functional architecture may also be characteristic of the organization within each individual circuit.
This study investigates the hypothesis that, as a consequence of Parkinson's disease, disturbed caudate outflow will lead to deficits in cognitive functions dependent upon the integrity of the prefrontal cortex, the cortical focus of caudatofugal signals. Since Parkinson's disease also involves lesions in extrastriatal midbrain cells which reduce the intrinsic supply of dopamine to this cortical region, such functions are at double risk. Forty nondemented parkinsonian patients were drawn from a pool of 100 consecutive patients and matched with 40 normal control subjects according to age, education, IQ, and sex. All patients were quantitatively rated on neurological indices of disease. Neuropsychological assessment of the patient and normal groups included tests of general intelligence, psychomotor skills, memory, visuospatial and executive functions. No global cognitive decline was observed in the parkinsonian group. Moreover, memory and visuospatial abilities were generally intact. A small cluster of deficits emerged, interpreted as reflecting impairment in the ability to spontaneously generate efficient strategies when relying on self-directed task-specific planning. In addition, several tests thought to be sensitive to frontal lobe function distinguished patients with symptoms strongly lateralized to the right versus left side of the body. Deficits in strategic planning were later investigated in relation to severity of disease and to patient attributes including IQ and age, both of which were relevant to performance on specific tasks. Results were compared with previous investigations in parkinsonian patients and discussed from the perspective of both animal and human studies involving damage to the cerebral cortex and basal ganglia. As the prefrontal cortex is thought to play a crucial role in self-directed behavioural planning, the validity of an outflow model in predicting the consequences of caudate nucleus dysfunction was supported.