Feasibility of a randomized single-blind crossover trial to assess the effects of the second-generation slow-release dopamine agonists pramipexole and ropinirole on cued recall memory in idiopathic mild or moderate Parkinson's disease without cognitive impairment.

BACKGROUND: The aim was to assess the feasibility of a single-centre, single-blind, randomized, crossover design to explore the effects of two slow-release dopamine agonists, ropinirole and pramipexole, on cued recall in Parkinson's disease. As the design required a switch from the prescribed agonist (pramipexole-to-ropinirole, or ropinirole-to-pramipexole), the primary objectives were to (a) examine the efficacy of processes and procedures used to manage symptoms during the washout period and (b) to use cued recall estimates to inform a power calculation for a definitive trial. Secondary objectives were to assess consent and missing data rates, acceptability of clinical support for the OFF sessions, experience of the OFF sessions and of agonist switching, barriers-to-participation for patients and informal caregivers. METHODS: Patients were randomized in a 1:1 ratio to two treatment arms and stabilized on each agonist for 6 weeks. The arms differed only in the sequence in which the agonists were administered. Cued recall was assessed ON medication and, following a washout period resulting in 93.75% agonist elimination, OFF medication. RESULTS: A total of 220 patients were screened: 145 were excluded and 75 invitations to participate were sent to eligible patients. Fifty-three patients declined, 22 consented and 16 completed the study. There were no serious adverse events, and rates of non-serious adverse events were equivalent between the agonists. Using the largest standard deviation (SD) of the ON-OFF difference cued recall score (inflated by ~25% to give a conservative estimate of the SD in a definitive trial) and assuming an effect of at least 10% of the observed range of OFF medication cued recall scores for either agonist to be clinically important, a main trial requires a sample size of just under 150 patients. The consent and missing data rates were 29 and 27% respectively. The washout period and the preparation for the OFF sessions were acceptable, and the sessions were manageable. The experience of switching was also manageable. Barriers to participation included concerns about disease stability, side effects, research process, carer workload and accessibility of the information sheet. CONCLUSIONS: This study presented challenges to recruitment both in design and execution, and while it was a major aim of the study to assess this, evaluation of these challenges provided the opportunity to explore how they could be overcome for future studies. TRIAL REGISTRATION: EudraCT 2012-000801-64.

Risky decision-making and affective features of impulse control disorders in Parkinson's disease.

Impulse control disorders (ICDs) in Parkinson's disease (PD) are considered dopaminergic treatment side effects. Cognitive and affective factors may increase the risk of ICD in PD. The aim is to investigate risky decision-making and associated cognitive processes in PD patients with ICDs within a four-stage conceptual framework. Relationship between ICDs and affective factors was explored. Thirteen PD patients with ICD (ICD+), 12 PD patients without ICD (ICD-), and 17 healthy controls were recruited. Overall risky decision-making and negative feedback effect were examined with the Balloon Analogue Risk Task (BART). A cognitive battery dissected decision-making processes according to the four-stage conceptual framework. Affective and motivational factors were measured. ANOVA showed no effect of group on overall risky decision-making. However, there was a group × feedback interaction [F (2, 39) = 3.31, p = 0.047]. ICD+, unlike ICD- and healthy controls, failed to reduce risky behaviour following negative feedback. A main effect of group was found for anxiety and depression [F(2, 38) = 8.31, p = 0.001], with higher symptoms in ICD+ vs. healthy controls. Groups did not differ in cognitive outcomes or affective and motivational metrics. ICD+ may show relatively preserved cognitive function, but reduced sensitivity to negative feedback during risky decision-making and higher symptoms of depression and anxiety.

A deficit in familiarity-driven recognition in a right-sided mediodorsal thalamic lesion patient.

OBJECTIVE: According to a still-controversial view of recognition, projections between the perirhinal cortex and the medial subdivision of the mediodorsal thalamic nucleus (mMDT) support the mnemonic processes underlying familiarity, whereas a separate extended hippocampal system is critical for the recollection of episodic details during recognition. METHOD: In this study, we examined item recognition, familiarity, and recollection for faces and words in a patient (OG) with a right-sided lesion centered on the mMDT, which encroached on the central medial midline nucleus and may have resulted in partial disconnection of the mammillothalamic tract. On the basis of OG's neuropathology, the dual-process signal-detection (DPSD) high-threshold theory and the material-specific hypothesis of long-term memory together predicted a material-specific impairment in familiarity for novel facial memoranda, with a lesser decline in recollection of novel faces at short retention intervals. No abnormalities in either familiarity- or recollection-driven recognition of verbal memoranda were expected. RESULTS: Comparing the performance of OG and that of a group of 10 age-, sex-, and IQ-matched healthy controls, the remember-know procedure revealed the dissociations predicted by the material-specific and DPSD hypotheses: With recognition of previously novel faces, OG showed a deficit in familiarity-driven recognition that was significantly greater than the insignificant reduction in his recollection. All components of his word recognition were, however, preserved. CONCLUSION: A memory profile, marked by a dissociation between familiarity and recollection, fits naturally with the DPSD model and is incompatible with the idea that these kinds of memories reflect different degrees of trace strength.

Evidence of an amnesia-like cued-recall memory impairment in nondementing idiopathic Parkinson's disease.

Medicated, non-dementing mild-to-moderate Parkinson's disease (PD) patients usually show recall/recollection impairments but have only occasionally shown familiarity impairments. We aimed to assess two explanations of this pattern of impairment. Recollection typically improves when effortful planning of encoding and retrieval processing is engaged. This depends on prefrontally-dependent executive processes, which are often disrupted in PD. Relative to an unguided encoding and retrieval of words condition (C1), giving suitable guidance at encoding alone (C2) or at encoding and retrieval (C3) should, if executive processes are disrupted, improve PD recollection more than control recollection and perhaps raise it to normal levels. Familiarity, being a relatively automatic kind of memory, whether impaired or intact, should be unaffected by guidance. According to the second explanation, PD deficits are amnesia-like and caused by medial temporal lobe dysfunction and although poorer recollection, which is caused by hippocampal disruption, may be improved by guidance, it should not improve more than control recollection. Familiarity impairment will also occur if the perirhinal cortex is disrupted, but will be unimproved by guidance. Without guidance, recollection/recall was impaired in thirty PD patients relative to twenty-two healthy controls and remained relatively equally impaired when full guidance was provided (C1 vs C3), both groups improving to broadly the same extent. Although impaired, and markedly less so than recollection, familiarity was not improved by guidance in both groups. The patients showed elevated rates of subclinical depressive symptoms, which weakly correlated with recall/recollection in all three conditions. PD executive function was also deficient and correlated with unguided/C1 recollection only. Our results are consistent with a major cause of the patients' recall/recollection impairments being hippocampal disruption, probably exacerbated by subclinical depressive symptoms. However, the results do not exclude a lesser prefrontal cortex contribution because patient executive functions were impaired and correlated solely with unguided overall recollection.

Anarchic hand with abnormal agency following right inferior parietal lobe damage: a case report.

Anarchic hand syndrome (AHS) is characterized by goal-directed movements performed without volitional control (agency). Different AHS subtypes have been identified; however, few studies have examined the posterior subtype. We report a case of AHS following right-hemisphere parietal damage, with left-sided somatosensory and proprioceptive impairment. Agency was examined for nonanarchic (volitional) movements performed using the anarchic hand. The patient experienced abnormal agency for movements whether motor intention and visual feedback were congruent or incongruent, but not when intention was absent (passive movement). Findings suggest a general disturbance of veridical motor awareness and agency in this case of parietal AHS.

Second-generation dopamine agonists and recollection impairments in Parkinson's disease.

A selective deficit in the recollection of episodic details is frequently reported in Parkinson's disease (PD). Previous explanations implicate dopamine dysregulation in prefrontal structures on which strategic memory processes rely. However, neuroimaging advancements suggest dopaminergic dysregulation of hippocampally dependent memory processes. Accordingly, dopamine agonists, which target D3 receptors in the hippocampus, may impair hippocampal functioning, causing a more pronounced recollection decline. Recognition memory (RM), familiarity, and recollection were examined in 21 patients with mild-to-moderate PD (Hoehn and Yahr mean: 2.67). Patients were subdivided into two subgroups according to dopamine agonist (pramipexole [PPX] or ropinirole [RPR]), and completed matched versions of an RM test in a medicated and unmedicated condition (termed ON and OFF, respectively). Ten demographically matched healthy volunteers (HVs) also completed both RM tasks in two separate sessions. The PD group (PPX and RPR subgroups combined) showed impairments in RM and recollection, but spared familiarity. When subdivided by dopamine agonist, the PPX subgroup's ON-medication recollection performance was significantly lower than that of both the HVs and RPR subgroup. There was no evidence of decline in OFF-medication recollection or familiarity in either the PPX or RPR subgroups. Recollection in both PD subgroups correlated positively with a composite measure of recall, but not prefrontally dependent measures of cognitive control. These findings suggest that mild-to-moderate PD patients may show relatively preserved recollection and familiarity, but that recollection is selectively disrupted by PPX, but not RPR and that this effect may depend on disrupted hippocampal function rather than impaired pre-frontally dependent executive functions.

Impairment in material-specific long-term memory following unilateral mediodorsal thalamic damage and presumed partial disconnection of the mammillo-thalamic tract.

Neuropsychological findings suggest material-specific lateralization of the medial temporal lobe's role in long-term memory, with greater left-sided involvement in verbal memory, and greater right-sided involvement in visual memory. Whether material-specific lateralization of long-term memory also extends to the anteromedial thalamus remains uncertain. We report two patients with unilateral right (OG) and left (SM) mediodorsal thalamic pathology plus probable correspondingly lateralized damage of the mammillo-thalamic tract. The lesions were mapped using high-resolution structural magnetic resonance imaging and schematically reconstructed. Mean absolute volume estimates for the mammillary bodies, hippocampus, perirhinal cortex, and ventricles are also presented. Estimates of visual and verbal recall and item recognition memory were obtained using the Doors and People, the Rey Complex Figure Test, and the Logical Memory subtests of the Wechsler Memory Scales. Each patient's performance was compared to a group of healthy volunteers matched for demographic characteristics, premorbid IQ, and current levels of functioning. A striking double dissociation was evident in material-specific long-term memory, with OG showing significant impairments in visual memory but not verbal memory, and SM showing the opposite profile of preserved visual memory and significantly impaired verbal memory. These impairments affected both recall and item recognition. The reported double dissociation provides the strongest evidence yet that material-specific lateralization of long-term memory also extends to the anteromedial thalamus. The findings are also discussed in relation to proposals that distinct anatomical regions within the medial temporal lobe, anteromedial thalamus, and associated tracts make qualitatively different contributions to recall and item recognition.

Unawareness after stroke: a review and practical guide to understanding, assessing, and managing anosognosia for hemiplegia.

How should stroke patients with poor motor awareness be managed? This question is important because unawareness (or anosognosia) is related to poor rehabilitation and prognosis. This narrative review provides a guide for clinicians and (applied) academics to understanding, assessing and managing anosognosia. Questions addressed are: What is anosognosia? What causes anosognosia? How can anosognosia be assessed? And how can anosognosia be managed? We suggest that anosognosia is a multifaceted disorder, with diverse neuroanatomical and psychopathological origins. Assessment should measure various aspects of awareness, and management should be multidimensional to address problems with motor function, awareness, and emotional/motivational disturbance.

Effect of disease severity and dopaminergic medication on recollection and familiarity in patients with idiopathic nondementing Parkinson's.

The effect of disease severity and dopaminergic medication on the assessment of familiarity and the recollection of episodic details during recognition in nondementing idiopathic Parkinson's is uncertain. Some studies have reported familiarity as deficient in mild Parkinson's yet others have found it intact even in moderate Parkinson's. Recollection has been found to be both preserved and deficient in mild and moderate Parkinson's. The extent to which these conflicting findings are explained by disease severity or dopaminergic medication or a combination of the two is uncertain, as all studies assessed patients in a medicated state, and disease severity has not always been consistently reported. Twelve patients with mild Parkinson's and 11 with moderate Parkinson's (medicated Hoehn and Yahr mean: 2.1 and 3.2, respectively), completed matched versions of a yes/no recognition memory test in a medicated and unmedicated condition (termed ON and OFF, respectively). Twenty-one matched healthy volunteers also completed both memory tasks in 2 separate sessions (termed Blue and Green, respectively). In the ON/Green condition, the moderate Parkinson's recollection performance was significantly poorer than the healthy volunteers and mild Parkinson's. By contrast, recognition memory and familiarity measures in both Parkinson's group were relatively spared. In the OFF/Blue condition, the moderate Parkinson's recollection was impaired, but only in relation to the healthy volunteer set. There were no significant differences in recollection performance between the mild and moderate Parkinson's groups. Again, recognition memory and familiarity measures in both Parkinson's group were relatively spared. Further analyses showed the moderate patients' recollection rates to be significantly poorer ON-medication compared to OFF. These findings are discussed in relation to the staging of disease progression on medial temporal areas which separately support recollection and familiarity, and the putative effects the different classes of dopaminergic drugs may have on these areas.

Why are some Parkinson disease patients unaware of their dyskinesias?

OBJECTIVE: To test the hypothesis that anosognosia for dyskinesias in Parkinson disease (PD) results from a failure to detect discrepancies between intended and actual movement. BACKGROUND: PD patients often complain of drug-induced dyskinesias (involuntary movements) less than their carers. This remarkable unawareness is an example of anosognosia (ie, unawareness of deficits associated with an illness). A better understanding of anosognosia for dyskinesias in PD is important to understand the impact of the illness and side effects of treatment. METHODS: The ability to detect a discrepancy between intended movement and visual feedback about actual movement was investigated in 6 PD patients with anosognosia for dyskinesias, 11 nonanosognosic PD controls with dyskinesias, and 22 healthy volunteers, using a mirror to reverse the expected visual consequences of an executed movement. RESULTS: Nonanosognosic PD patients and healthy volunteers rated mirror-reversed movement as significantly stranger than normal movement (P=0.024 and <0.001, respectively), whereas PD patients with anosognosia for dyskinesias did not (P=0.375). CONCLUSIONS: The findings support our proposal, in that PD patients with anosognosia for dyskinesias do not report mirror-reversed movement (in which intentions and visual feedback conflict) as feeling distinct from normal movement.

Reality monitoring in anosognosia for hemiplegia.

Anosognosia for hemiplegia (AHP) is a lack of awareness about paralysis following stroke. Recent explanations use a 'forward model' of movement to suggest that AHP patients fail to register discrepancies between internally- and externally-generated sensory information. We predicted that this failure would impair the ability to recall from memory whether information is internally- or externally-generated (i.e., reality monitor). Two experiments examined this prediction. Experiment 1 demonstrated that AHP patients exhibit a reality monitoring deficit for non-motor information (i.e., perceived vs. imagined drawings), whilst hemiplegic controls without anosognosia (nonAHP) perform like age-matched healthy volunteers (HVs). Experiment 2 explored if this deficit occurs when AHP patients discriminate performed, imagined, or observed movement. Results showed impaired reality monitoring for movements in AHP and nonAHP patients relative to HVs. Findings suggest that reality monitoring processes not directly related to movement, together with a failure to reality monitor movements, contribute to the pathogenesis of AHP.

Imagining the impossible: motor representations in anosognosia for hemiplegia.

Anosognosia for hemiplegia (AHP) is characterised by poor insight or underestimation of hemiplegia after brain injury. Recent explanations of AHP have used an established 'forward model', which proposes that normal motor awareness involves comparing the predicted and actual sensory consequences of movements. These accounts propose that AHP patients may be able to form representations of their intended movements (i.e., motor representations), but fail to register discrepancy between intended and actual movements. A prediction arising from this proposal is that AHP patients are able to generate motor representations involving their hemiplegic limb(s). Our study provides the first direct examination of this prediction in patients with AHP. We used an existing 'grip selection task', which investigates motor representations by comparing how patients would grasp an object and how they actually grasp the same object. Eight right hemisphere stroke patients with AHP, 10 control patients (non-AHP), and 22 age-matched healthy volunteers (HVs) completed the task. Results showed that HVs outperformed both AHP and non-AHP patients in their motor representations for the hemiplegic limb; however, the performance of AHP and non-AHP patients did not differ significantly. Motor representations for the intact limb were lower than normal in AHP patients, whereas performance in non-AHP patients was midway between the AHP and HV groups. Findings suggested that the ability to form motor representations lie on a continuum, but that impaired motor representations for the paralysed limb cannot account for AHP. Distorted motor representations, in combination with other deficits, might contribute to the pathogenesis of AHP.

Recognition, recollection, familiarity and executive function in medicated patients with moderate Parkinson's disease.

There is conflicting evidence about whether Parkinson's disease (PD) is associated with deficiencies in recognition memory (RM) and the processes which underlie it, namely recollection (a form of recall) and familiarity (a feeling of memory in the absence of recall). The aims of the current study were to examine forced-choice verbal RM (assessed with the Warrington Recognition memory Test), yes-no RM, recollection, familiarity and executive functioning in 17 patients with moderate PD and 17 healthy volunteers matched for age and premorbid intelligence. We predicted that patients with moderate PD would display a significant recollection deficit on the yes-no RM test, because their strategic memory processing that depends on executive functioning and is necessary for efficient encoding and/or retrieval, was disrupted. In contrast, familiarity memory, which is not dependent on these processes, and forced-choice RM (which is largely dependent on familiarity) should show higher levels of preservation. We also predicted that recollection should be correlated with severity of executive dysfunction. Our findings revealed that the PD patients were as likely to accurately discriminate between targets and distractors as the healthy volunteers on both RM tests. However, the PD patients were significantly less reliant on recollection-driven recognition decisions on the yes-no RM test when compared with the healthy control group. The patients also displayed executive function deficits, but these were not correlated with recollection. The extent to which the PD patients' reliance on familiarity at the expense of recollection is explained by impairments in strategic memory processes/executive function and/or medial temporal lobe retrieval processes needs further exploration.

Bilateral dorsolateral thalamic lesions disrupts conscious recollection.

In an earlier study we disputed the claim that the mediodorsal thalamic nucleus is critical for familiarity. We reported patient (QX) who showed a severe deficit in conscious recollection, and behavioural problems (disinhibition, emotional lability) with relative sparing of familiarity-aware memory following a left mediodorsal thalamic lesion. More recent MR imaging has revealed that QX's lesions are more extensive than previously reported and involve both dorsolateral thalamic nuclei, and whilst there is evidence of left mediodorsal thalamic damage, it is not the main focus of damage. This paper reports a full analysis of QX's thalamic pathology alongside a more detailed investigation of his recognition memory, using yes/no and forced-choice procedures, and executive function. The results revealed impairments in yes/no recognition and conscious recollection rates of famous, artist and unknown names. In addition to the previously noted behavioural disinhibition and emotional lability, a deficit in spontaneous planning ability was evident on the Zoo Map Test (subtest of the Bahavioural Assessment of the Dysexecutive Syndrome). Forced-choice recognition, familiarity estimates and remote memory showed higher levels of preservation. The findings indicate that the dorsolateral thalamus is part of the extended hippocampal circuit which is causally critical only for recall and conscious recollection of complex associations rather than for the more automatic processes linked with novelty detection.