Sex differences in Parkinson disease-associated episodic memory and processing speed deficits.

OBJECTIVES: This study aims to address a gap in the data on cognitive sex differences in persons living with Parkinson disease (PD). There is some evidence that cognitive dysfunction is more severe in male PD, however data on episodic memory and processing speed is incomplete. METHODS: One hundred and sixty-seven individuals with a diagnosis of PD were included in this study. Fifty-six of those individuals identified as female. The California Verbal Learning Test 1st edition and the Wechsler Memory Scale 3rd edition were used to evaluate verbal and visuospatial episodic memory and the Wechsler Adult Intelligence Scale 3rd edition was used to evaluate processing speed. Multivariate analysis of covariance was used to identify sex-specific differences across groups. RESULTS: Our results show that males with PD performed significantly worse than females in verbal and visuospatial recall as well as a trend for the processing speed task of coding. CONCLUSIONS: Our finding of superior performance among females with PD in verbal episodic memory is consistent with reports in both healthy and PD individuals; however, females outperforming males in measures of visuospatial episodic memory is unique to PD. Cognitive deficits preferentially affecting males appear to be associated with frontal lobe-related function. Therefore, males may represent a disease subgroup more susceptible to disease mechanisms affecting frontal lobe deterioration and cognitive disturbances in PD.

Cortical oscillatory dysfunction in Parkinson disease during movement activation and inhibition.

Response activation and inhibition are functions fundamental to executive control that are disrupted in Parkinson disease (PD). We used magnetoencephalography to examine event related changes in oscillatory power amplitude, peak latency and frequency in cortical networks subserving these functions and identified abnormalities associated with PD. Participants (N = 18 PD, 18 control) performed a cue/target task that required initiation of an un-cued movement (activation) or inhibition of a cued movement. Reaction times were variable but similar across groups. Task related responses in gamma, alpha, and beta power were found across cortical networks including motor cortex, supplementary and pre- supplementary motor cortex, posterior parietal cortex, prefrontal cortex and anterior cingulate. PD-related changes in power and latency were noted most frequently in the beta band, however, abnormal power and delayed peak latency in the alpha band in the pre-supplementary motor area was suggestive of a compensatory mechanism. PD peak power was delayed in pre-supplementary motor area, motor cortex, and medial frontal gyrus only for activation, which is consistent with deficits in un-cued (as opposed to cued) movement initiation characteristic of PD.

A pilot study to evaluate multi-dimensional effects of dance for people with Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease associated with deficits in motor, cognitive, and emotion/quality of life (QOL) domains, yet most pharmacologic and behavioral interventions focus only on motor function. Our goal was to perform a pilot study of Dance for Parkinson's-a community-based program that is growing in popularity-in order to compare effect sizes across multiple outcomes and to inform selection of primary and secondary outcomes for a larger trial. Study participants were people with PD who self-enrolled in either Dance for Parkinson's classes (intervention group, N=8) or PD support groups (control group, N=7). Assessments of motor function (Timed-Up-and-Go, Gait Speed, Standing Balance Test), cognitive function (Test of Everyday Attention, Verbal Fluency, Alternate Uses, Digit Span Forward and Backward), and emotion/QOL (Geriatric Depression Scale, Falls Efficacy Scale-International, Parkinson's Disease Questionnaire-39 (total score and Activities of Daily Living subscale)) were performed in both groups at baseline and follow-up. Standardized effect sizes were calculated within each group and between groups for all 12 measures. Effect sizes were positive (suggesting improvement) for all 12 measures within the intervention group and 7 of 12 measures within the control group. The largest between-group differences were observed for the Test of Everyday Attention (a measure of cognitive switching), gait speed and falls efficacy. Our findings suggest that dance has potential to improve multiple outcomes in people with PD. Future trials should consider co-primary outcomes given potential benefits in motor, cognitive and emotion/QOL domains.

Subjective Cognitive Complaints in Parkinson Disease Without Dementia: A Preliminary Study.

Little is known about the subjective cognitive complaints of individuals with Parkinson disease (PD). Such complaints have become a topic of interest recently as they play a role in the diagnosis of neurocognitive disorders. The aim of this preliminary study was to determine whether a sample of nondemented individuals with PD reported significantly more difficulties with multiple elements of cognition than a control sample and to assess the relation between their ratings and demographics, motor symptom severity, neuropsychological test performance, and measures of depression and anxiety. Forty nondemented individuals with PD and 27 healthy individuals completed a questionnaire assessing everyday cognitive difficulties. Independent t tests indicated that individuals with PD reported significantly more cognitive complaints in general and in specific tasks involving complex attention, executive function, processing speed, and verbal fluency but not memory. Questionnaire ratings significantly correlated with measures assessing anxiety, verbal memory, processing speed, and verbal fluency. Results suggest that it is important to ask individuals with PD about cognitive complaints across several cognitive domains and also inquire about symptoms of anxiety, which may be related to their self-reported cognitive difficulties.

Perceived and performance-based executive dysfunction in Parkinson's disease.

Executive dysfunction is common in early stage Parkinson's disease (PD). We evaluated the relationship between self- and informant-report measurement of real-world executive functions as well as performance-based neuropsychological measures in mildly cognitively impaired individuals with PD and healthy controls. The PD group reported more difficulty with initiation of complex tasks compared to caregiver ratings, and processing speed was a strong predictor of self-reported executive dysfunction for the PD group, followed by depression. Processing speed and semantic verbal fluency predicted informant-reported executive dysfunction in PD. These findings highlight the contribution of speeded processing for performance of everyday executive tasks in PD.

Movement activation and inhibition in Parkinson's disease: a functional imaging study.

BACKGROUND: Parkinson's disease (PD), traditionally considered a movement disorder, has been shown to affect executive function such as the ability to adapt behavior in response to new environmental situations. OBJECTIVE: to identify the impact of PD on neural substrates subserving two specific components of normal movement which we refer to as activation (initiating an un-cued response) and inhibition (suppressing a cued response). METHODS: We used fMRI to measure pre-movement processes associated with activating an un-cued response and inhibiting a cued response plan in 13 PD (ON anti-parkinsonian medications) and 13 control subjects. Subjects were shown a visual arrow cue followed by a matched or mismatched response target that instructed them to respond with a right, left, or bilateral button press. In mismatched trials, an un-cued (new) response was initiated, or the previously cued response was suppressed. RESULTS: We were able to isolate pre-movement responses in dorsolateral prefrontal cortex, specifically in the right hemisphere. During the activation of an un-cued movement, PD subjects showed decreased activity in the putamen and increased cortical activity in bilateral DLPFC, SMA, subcentral gyrus and inferior frontal operculum. During inhibition of a previously cued movement, the PD group showed increased activation in SMA, S1/M1, premotor and superior parietal areas. CONCLUSION: Right DLPFC plays a role in pre-movement processes, and DLPFC activity is abnormal in PD. Decreased specificity of responses was observed in multiple ROI's. The basal ganglia are involved in circuits that coordinate activation and inhibition involved in action selection as well as execution.

The contribution of trail making to the prediction of performance-based instrumental activities of daily living in Parkinson's disease without dementia.

Performance on Part B of the Trail Making Test (TMT) contributes to the prediction of ability to complete instrumental activities of daily living (IADLs) in Parkinson's disease (PD). Although this suggests that cognitive flexibility is important in the everyday functioning of individuals with PD, this may not be the case as the TMT is multifactorial, involving motor speed, visual scanning, sequencing, and cognitive flexibility. The purpose of the current study was to determine which elements of the task contribute to the prediction of IADLs in a sample of 30 nondemented individuals with PD. Correlational analyses indicated strong relationships between a performance-based measure of IADLs and measures involving scanning, sequencing, and cognitive flexibility from the Delis-Kaplan Executive Function System (D-KEFS) TMT. Results from standard regressions indicated that measures of sequencing and level of depression but not scanning, cognitive flexibility, or demographic variables made a significant, independent contribution to the prediction of IADLs. These results suggest that the sequencing element of the TMT is paramount in the prediction of IADLs in PD.

Hemispheric asymmetries and prosodic emotion recognition deficits in Parkinson's disease.

While Parkinson's disease (PD) has traditionally been described as a movement disorder, there is growing evidence of cognitive and social deficits associated with the disease. However, few studies have looked at multi-modal social cognitive deficits in patients with PD. We studied lateralization of both prosodic and facial emotion recognition (the ability to recognize emotional valence from either tone of voice or from facial expressions) in PD. The Comprehensive Affect Testing System (CATS) is a well-validated test of human emotion processing that has been used to study emotion recognition in several major clinical populations, but never before in PD. We administered an abbreviated version of CATS (CATS-A) to 24 medicated PD participants and 12 age-matched controls. PD participants were divided into two groups, based on side of symptom onset and unilateral motor symptom severity: left-affected (N = 12) or right-affected PD participants (N = 12). CATS-A is a computer-based button press task with eight subtests relevant to prosodic and facial emotion recognition. Left-affected PD participants with inferred predominant right-hemisphere pathology were expected to have difficulty with prosodic emotion recognition since there is evidence that the processing of prosodic information is right-hemisphere dominant. We found that facial emotion recognition was preserved in the PD group, however, left-affected PD participants had specific impairment in prosodic emotion recognition, especially for sadness. Selective deficits in prosodic emotion recognition suggests that (1) hemispheric effects in emotion recognition may contribute to the impairment of emotional communication in a subset of people with PD and (2) the coordination of neural networks needed to decipher temporally complex social cues may be specifically disrupted in PD.

Predictors of HVOT performance in Parkinson's disease.

Evidence suggests that the Hooper Visual Organization Test (HVOT) has naming and executive components that vary in size depending on neurological diagnosis. The current study used a sample of individuals with Parkinson's disease (PD) to demonstrate for the first time that an executive measure can be the best predictor of HVOT performance. Forty-eight nondemented and nondepressed individuals with idiopathic PD completed the HVOT and other measures of visuoperception, executive function, and visual confrontation naming. Despite average performance on all neuropsychological measures, an executive measure, time to complete Trail-Making Test Part B minus time to complete Part A, was clearly the best predictor of HVOT performance in a standard regression. The pattern of neurocognitive predictors is unlike that reported in healthy individuals and other patient samples. This finding suggests that the presence of a neuropathological process can alter neurocognitive correlates even when performance is intact, and supports the contention that executive function is paramount in the cognitive profile associated with PD.

The clinical significance of neuropsychological changes following bilateral subthalamic nucleus deep brain stimulation for Parkinson's disease.

Despite the clinical importance of the question, a number of methodological issues have limited firm conclusions regarding the cognitive safety of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD). Amongst these issues, studies have generally failed to consider the postoperative changes that occur within individual patients. This study utilized reliable change indices (RCIs) derived from a PD sample to determine the frequency of clinically significant postoperative decline on a battery of neuropsychological measures. This approach addresses measurement reliability, potential practice effects, and disease progression. The proportion of patients experiencing clinically significant postoperative decline on measures of list learning and verbal fluency was greater than expected based on disease progression; however, the majority of patients (55%) did not experience a significant decline in performance on any of the cognitive tests administered, and only one experienced decline on more than one test. Therefore, the statistically significant declines on measures of list learning and verbal fluency observed in the sample as a whole were the result of clinically significant declines experienced by a minority of participants.

Cognitive deficits in essential tremor consistent with frontosubcortical dysfunction.

Essential tremor (ET) is increasingly thought to involve a heterogeneous group of patients, with some also exhibiting symptoms of Parkinson's disease (PD), including cognitive deficits. The goal of this study was to utilize a broad battery of neuropsychological measures to compare the cognitive function of 33 ET patients with that of 33 matched PD patients and 21 normal controls. Results indicated that the ET group performed significantly worse than controls across multiple cognitive domains, but performed remarkably similar to PD patients, consistent with frontosubcortical dysfunction.

Dopamine dependency of cognitive switching and response repetition effects in Parkinson's patients.

A group of people with Parkinson's disease and a group of matched controls were tested on a task involving a switch between perceptual dimensions. Patients were tested both 'on' and 'off' their normal medication cycles. Stimuli appeared in pairs for each trial, with each stimulus consisting of a color and a shape. One dimension of color and one of shape were mapped to each of two response keys. A cue was presented concurrently with each stimulus to indicate whether to respond on the basis of color or shape, following procedures developed by Hayes et al. [Hayes, A.E., Davidson, M.C., Keele, S.W., and Rafal, R.D. (1998). Toward a functional analysis of the basal ganglia. Journal of Cognitive Neuroscience, 10, 178-198]. Replicating previous literature, abnormally large switch costs were observed in patients who were off their normal medication cycles. A novel finding was that patients in the 'on' state demonstrated a slight reversal of switch costs. Also novel, reaction time (RT) costs associated with switching between response keys, and interactions between response switching and task switching were influenced predominantly by on-off dopamine manipulations. It is concluded that abnormal task switching costs and response repetition effects likely reflect impairments of activation and inhibition, and both effects are dopamine-dependent.

Isoflurane disrupts central pattern generator activity and coordination in the lamprey isolated spinal cord.

BACKGROUND: Although volatile anesthetics such as isoflurane can depress sensory and motor neurons in the spinal cord, movement occurring during anesthesia can be coordinated, involving multiple limbs as well as the head and trunk. However, it is unclear whether volatile anesthetics depress locomotor interneurons comprising central pattern generators or disrupt intersegmental central pattern generator coordination. METHODS: Lamprey spinal cords were excised during anesthesia and placed in a bath containing artificial cerebrospinal fluid and D-glutamate to induce fictive swimming. The rostral, middle, and caudal regions were bath-separated using acrylic partitions and petroleum jelly, and in each compartment, the authors recorded ventral root activity. The authors selectively delivered isoflurane (0.5, 1, and 1.5%) only to the middle segments of the spinal cord. Spectral analyses were then used to assess isoflurane effects on central pattern generator activity and coordination. RESULTS: Isoflurane dose-dependently reduced fictive locomotor activity in all three compartments, with 1.5% isoflurane nearly eliminating activity in the middle compartment and reducing spectral amplitudes in the anesthetic-free rostral and caudal compartments to 23% and 31% of baseline, respectively. Isoflurane decreased burst frequency in the caudal compartment only, to 53% of baseline. Coordination of central pattern generator activity between the rostral and caudal compartments was also dose-dependently decreased, to 42% of control at 1.5% isoflurane. CONCLUSION: Isoflurane disrupts motor output by reducing interneuronal central pattern generator activity in the spinal cord. The effects of isoflurane on motor output outside the site of isoflurane application were presumably independent of effects on sensory or motor neurons.

Recognition memory in Parkinson's disease with and without dementia: evidence inconsistent with the retrieval deficit hypothesis.

Parkinson's disease (PD) has been associated with a pattern of performance on memory tests in which free recall is impaired but recognition and cued recall are intact, indicating problems with memory retrieval. Recent findings suggest that PD patients exhibit deficits in recognition as well as free recall, however. The current study set out to provide clear evidence that recognition and cued recall are not intact in PD. Ninety-nine idiopathic PD patients were administered the California Verbal Learning Test and their performance was compared to a well-matched normative sample. A profile analysis revealed that nondemented patients exhibited deficits on measures of cued recall and delayed recognition that were similar in magnitude to that of free recall. This was also the case for the cued recall deficits exhibited by demented patients; however, in this group recognition was worse than free recall. In both groups poor recognition appeared due to an elevated number of false positive errors. These results are inconsistent with the retrieval deficit hypothesis but support the notion that PD memory problems are secondary to prefrontal dysfunction.

Temporal evolution of oscillations and synchrony in GPi/muscle pairs in Parkinson's disease.

Both standard spectral analysis and time-dependent phase correlation techniques were applied to 27 pairs of tremor-related single units in the globus pallidus internus (GPi) and EMG of patients with Parkinson's disease (PD) undergoing stereotactic neurosurgery. Over long time-scales (approximately 60 s), GPi tremor-related units were statistically coherent with restricted regions of the peripheral musculature displaying tremor. The distribution of pooled coherence across all pairs supports a classification of GPi cell/EMG oscillatory pairs into coherent or noncoherent. Analysis using approximately 2-s sliding windows shows that oscillatory activity in both GPi tremor units and muscles occurs intermittently over time. For brain/muscle pairs that are coherent, there is partial overlap in the times of oscillatory activity but, in most cases, no significant correlation between the times of oscillatory subepisodes in the two signals. Phase locking between coherent pairs occurs transiently; however, the phase delay is similar for different phase-locking subepisodes. Noncoherent pairs also show episodes of transient phase locking, but they occurred less frequently, and no preferred phase delay was seen across subepisodes. Tremor oscillations in pallidum and EMGs are punctuated by phase slips, which were classified as synchronizing or desynchronizing depending on their effect on phase locking. In coherent pairs, the incidence of synchronizing slips is higher than desynchronizing slips, whereas no significant difference was seen for noncoherent pairs. The results of this quantitative characterization of parkinsonian tremor provide a foundation for hypotheses about the structure and dynamical functioning of basal ganglia motor control networks involved in tremor generation.

Statistical method for detection of phase-locking episodes in neural oscillations.

In many networks of oscillatory neurons, synaptic interactions can promote the entrainment of units into phase-coupled groups. The detection of synchrony in experimental data, especially if the data consist of single-trial runs, can be problematic when, for example, phase entrainment is of short duration, buried in noise, or masked by amplitude fluctuations that are uncorrelated among the oscillating units. In the present study, we tackle the problem of detecting neural interactions from pairs of oscillatory signals in a narrow frequency band. To avoid the interference of amplitude fluctuations in the detection of synchrony, we extract a phase variable from the data and utilize statistical indices to measure phase locking. We use three different phase-locking indices based on coherence, entropy, and mutual information between the phase variables. Phase-locking indices are calculated over time using sliding analysis windows. By varying the duration of the analysis windows, we were able to inspect the data at different levels of temporal resolution and statistical reliability. The statistical significance of high index values was evaluated using four different surrogate data methods. We determined phase-locking indices using alternative methods for generating surrogate data and found that results are sensitive to the particular method selected. Surrogate methods that preserve the temporal structure of the individual phase time series decrease substantially the number of false positives when tested on a pair of independent signals.

Modeling facilitation and inhibition of competing motor programs in basal ganglia subthalamic nucleus-pallidal circuits.

The motor symptoms of Parkinson's disease (PD) implicate the basal ganglia (BG) in some aspect of motor control, although the role the BG play in regulation of motor behavior is not completely understood. The modeling study presented here takes advantage of available cellular, systems, and clinical data on BG and PD to begin to build a biophysically based network model of pallidosubthalamic circuits of BG, to integrate this information and better understand the physiology of the normal BG and PD pathophysiology. The model reflects the experimentally supported hypothesis that the BG are involved in facilitation of the desired motor program and inhibition of competing motor programs that interfere with the desired movement. Our model network consists of subthalamic and pallidal (both external and internal segments) neural assemblies, with inputs from cortex and striatum. Functional subsets within each of the BG nuclei correspond to the desired motor program and the unwanted motor programs. A single compartment conductance-based model represents each subset. This network can discriminate between competing signals for motor program initiation, thus facilitating a single motor program. This ability depends on metabotropic gamma-aminobutyric acid B projections from the external pallidum to subthalamic nucleus and rebound properties of subthalamic cells, as well as on the structure of projections between pallidum and subthalamus. The loss of this ability leads to hypokinesia, known PD motor deficits characterized by a slowness or inability to switch between motor programs.

The relationship between executive function and verbal memory in Parkinson's disease.

A growing body of evidence suggests that the various cognitive symptoms found in Parkinson's disease (PD) are secondary to executive dysfunction. Studies addressing this possibility for memory impairment specifically have not included measures of working memory nor have they ruled-out potential mediating variables such as overall level of cognitive impairment or depression. The purpose of this study was to include measures of these variables in determining the relationship between multiple aspects of executive function and delayed verbal recall in 32 idiopathic PD patients. Results were consistent with the original hypothesis and further suggest that working memory is a key factor in recall memory and may mediate the relationship between other executive measures and recall in PD.