Impaired dual tasking in Parkinson's disease is associated with reduced focusing of cortico-striatal activity.

See Bell et al. (doi:10.1093/awx063) for a scientific commentary on this article. Impaired dual tasking, namely the inability to concurrently perform a cognitive and a motor task (e.g. 'stops walking while talking'), is a largely unexplained and frequent symptom of Parkinson's disease. Here we consider two circuit-level accounts of how striatal dopamine depletion might lead to impaired dual tasking in patients with Parkinson's disease. First, the loss of segregation between striatal territories induced by dopamine depletion may lead to dysfunctional overlaps between the motor and cognitive processes usually implemented in parallel cortico-striatal circuits. Second, the known dorso-posterior to ventro-anterior gradient of dopamine depletion in patients with Parkinson's disease may cause a funnelling of motor and cognitive processes into the relatively spared ventro-anterior putamen, causing a neural bottleneck. Using functional magnetic resonance imaging, we measured brain activity in 19 patients with Parkinson's disease and 26 control subjects during performance of a motor task (auditory-cued ankle movements), a cognitive task (implementing a switch-stay rule), and both tasks simultaneously (dual task). The distribution of task-related activity respected the known segregation between motor and cognitive territories of the putamen in both groups, with motor-related responses in the dorso-posterior putamen and task switch-related responses in the ventro-anterior putamen. During dual task performance, patients made more motor and cognitive errors than control subjects. They recruited a striatal territory (ventro-posterior putamen) not engaged during either the cognitive or the motor task, nor used by controls. Relatively higher ventro-posterior putamen activity in controls was associated with worse dual task performance. These observations suggest that dual task impairments in Parkinson's disease are related to reduced spatial focusing of striatal activity. This pattern of striatal activity may be explained by a loss of functional segregation between neighbouring striatal territories that occurs specifically in a dual task context.

Measuring prefrontal cortical activity during dual task walking in patients with Parkinson's disease: feasibility of using a new portable fNIRS device.

BACKGROUND: Many patients with Parkinson's disease (PD) have difficulties in performing a second task during walking (i.e., dual task walking). Functional near-infrared spectroscopy (fNIRS) is a promising approach to study the presumed contribution of dysfunction within the prefrontal cortex (PFC) to such difficulties. In this pilot study, we examined the feasibility of using a new portable and wireless fNIRS device to measure PFC activity during different dual task walking protocols in PD. Specifically, we tested whether PD patients were able to perform the protocol and whether we were able to measure the typical fNIRS signal of neuronal activity. METHODS: We included 14 PD patients (age 71.2 ± 5.4 years, Hoehn and Yahr stage II/III). The protocol consisted of five repetitions of three conditions: walking while (i) counting forwards, (ii) serially subtracting, and (iii) reciting digit spans. Ability to complete this protocol, perceived exertion, burden of the fNIRS devices, and concentrations of oxygenated (O2Hb) and deoxygenated (HHb) hemoglobin from the left and right PFC were measured. RESULTS: Two participants were unable to complete the protocol due to fatigue and mobility safety concerns. The remaining 12 participants experienced no burden from the two fNIRS devices and completed the protocol with ease. Bilateral PFC O2Hb concentrations increased during walking while serially subtracting (left PFC 0.46 µmol/L, 95 % confidence interval (CI) 0.12-0.81, right PFC 0.49 µmol/L, 95 % CI 0.14-0.84) and reciting digit spans (left PFC 0.36 µmol/L, 95 % CI 0.03-0.70, right PFC 0.44 µmol/L, 95 % CI 0.09-0.78) when compared to rest. HHb concentrations did not differ between the walking tasks and rest. CONCLUSIONS: These findings suggest that a new wireless fNIRS device is a feasible measure of PFC activity in PD during dual task walking. Future studies should reduce the level of noise and inter-individual variability to enable measuring differences in PFC activity between different dual walking conditions and across health states.

The Role of the Frontal Lobe in Complex Walking Among Patients With Parkinson's Disease and Healthy Older Adults: An fNIRS Study.

BACKGROUND: Gait is influenced by higher order cognitive and cortical control mechanisms. Functional near infrared spectroscopy (fNIRS) has been used to examine frontal activation during walking in healthy older adults, reporting increased oxygenated hemoglobin (HbO2) levels during dual task walking (DT), compared with usual walking. OBJECTIVE: To investigate the role of the frontal lobe during DT and obstacle negotiation, in healthy older adults and patients with Parkinson's disease (PD). METHODS: Thirty-eight healthy older adults (mean age 70.4 ± 0.9 years) and 68 patients with PD (mean age 71.7 ± 1.1 years,) performed 3 walking tasks: (a) usual walking, (b) DT walking, and (c) obstacles negotiation, with fNIRS and accelerometers. Linear-mix models were used to detect changes between groups and within tasks. RESULTS: Patients with PD had higher activation during usual walking (P < .030). During DT, HbO2 increased only in healthy older adults (P < .001). During obstacle negotiation, HbO2 increased in patients with PD (P = .001) and tended to increase in healthy older adults (P = .053). Higher DT and obstacle cost (P < .003) and worse cognitive performance were observed in patients with PD (P = .001). CONCLUSIONS: A different pattern of frontal activation during walking was observed between groups. The higher activation during usual walking in patients with PD suggests that the prefrontal cortex plays an important role already during simple walking. However, higher activation relative to baseline during obstacle negotiation and not during DT in the patients with PD demonstrates that prefrontal activation depends on the nature of the task. These findings may have important implications for rehabilitation of gait in patients with PD.

Studies with group treatments required special power calculations, allocation methods, and statistical analyses.

OBJECTIVE: In some trials, the intervention is delivered to individuals in groups, for example, groups that exercise together. The group structure of such trials has to be taken into consideration in the analysis and has an impact on the power of the trial. Our aim was to provide optimal methods for the design and analysis of such trials. STUDY DESIGN AND SETTING: We described various treatment allocation methods and presented a new allocation algorithm: optimal batchwise minimization (OBM). We carried out a simulation study to evaluate the performance of unrestricted randomization, stratification, permuted block randomization, deterministic minimization, and OBM. Furthermore, we described appropriate analysis methods and derived a formula to calculate the study size. RESULTS: Stratification, deterministic minimization, and OBM had considerably less risk of imbalance than unrestricted randomization and permuted block randomization. Furthermore, OBM led to unpredictable treatment allocation. The sample size calculation and the analysis of the study must be based on a multilevel model that takes the group structure of the trial into account. CONCLUSION: Trials evaluating interventions that are carried out in subsequent groups require adapted treatment allocation, power calculation, and analysis methods. From the perspective of obtaining overall balance, we conclude that minimization is the method of choice. When the number of prognostic factors is low, stratification is an excellent alternative. OBM leads to better balance within the batches, but it is more complicated. It is probably most worthwhile in trials with many prognostic factors. From the perspective of predictability, a treatment allocation method, such as OBM, that allocates several subjects at the same time, is superior to other methods because it leads to the lowest possible predictability.

Multifactorial fall prevention for pairs of frail community-dwelling older fallers and their informal caregivers: a dead end for complex interventions in the frailest fallers.

OBJECTIVE: To assess whether a multifactorial fall prevention program was more effective than usual geriatric care in preventing falls and reducing fear of falling in frail community-dwelling older fallers, with and without cognitive impairment, and in alleviating subjective caregiver burden in caregivers. DESIGN, SETTING, AND PARTICIPANTS: A randomized, 2 parallel-group, single-blind, multicenter trial conducted in 36 pairs of frail fallers, who were referred to a geriatric outpatient clinic after at least 1 fall in the past 6 months, and their informal caregivers. INTERVENTION: Groups of 5 pairs of patients and caregivers received 10 twice-weekly, 2-hour sessions with physical and psychological components and a booster session. MEASUREMENTS: The primary outcome was the fall rate during a 6-month follow-up. Additionally, we measured fear of falling and subjective caregiver burden. Data on the secondary outcome measures were collected at baseline, directly after, and at 3 and 6 months after the last session of the intervention. RESULTS: Directly after the intervention and at the long-term evaluation, the rate of falls in the intervention group was higher than in the control group, although these differences were not statistically significant (RR = 7.97, P = .07 and RR = 2.12, P = .25, respectively). Fear of falling was higher in the intervention group, and subjective caregiver burden did not differ between groups. CONCLUSION: Although we meticulously developed this pairwise multifactorial fall prevention program, it was not effective in reducing the fall rate or fear of falling and was not feasible for caregivers, as compared with regular geriatric care. Future research initiatives should be aimed at how to implement the evidence-based principles of geriatric fall prevention for all frail fallers rather than developing more complex interventions for the frailest.

How to perform a preplanned process evaluation for complex interventions in geriatric medicine: exemplified with the process evaluation of a complex falls-prevention program for community-dwelling frail older fallers.

Complex interventions are difficult to develop, document, evaluate, and reproduce. Process evaluations aid the interpretation of outcome results by documenting and evaluating each process step in detail. Despite its importance, process evaluations are not embedded in all evaluations of complex interventions. Based on literature, we structured the process evaluation for trials on complex interventions into 3 main components: (1) the success rate of recruitment and quality of the study population, (2) the quality of execution of the complex intervention, and (3) the process of acquisition of the evaluation data. To clarify these process evaluation components and measures, we exemplified them with the preplanned process evaluation of a complex falls-prevention program for community-dwelling frail older fallers and their informal caregivers. The 3 process evaluation components are operationalized, results are presented, and implications discussed. This process evaluation identified several limitations of the intervention and effect study, and resulted in multiple recommendations for improvement of both the intervention as well as the trial. Thus, a good-quality process evaluation gives a detailed description of the most important components of a complex intervention, resulting in an in-depth insight in the actually performed intervention and effect analysis. This allows us to draw the appropriate conclusions on positive or negative trial results, and results in recommendations for implementation, or adjustment of the intervention or effect evaluation, respectively.

Sex differences in the modulation of vasomotor sympathetic outflow during static handgrip exercise in healthy young humans.

Sex differences in sympathetic neural control during static exercise in humans are few and the findings are inconsistent. We hypothesized women would have an attenuated vasomotor sympathetic response to static exercise, which would be further reduced during the high sex hormone [midluteal (ML)] vs. the low hormone phase [early follicular (EF)]. We measured heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) in 11 women and 10 men during a cold pressor test (CPT) and static handgrip to fatigue with 2 min of postexercise circulatory arrest (PECA). HR increased during handgrip, reached its peak at fatigue, and was comparable between sexes. BP increased during handgrip and PECA where men had larger increases from baseline. Mean ± SD MSNA burst frequency (BF) during handgrip and PECA was lower in women (EF, P < 0.05), as was ΔMSNA-BF smaller (main effect, both P < 0.01). ΔTotal activity was higher in men at fatigue (EF: 632 ± 418 vs. ML: 598 ± 342 vs. men: 1,025 ± 416 a.u./min, P < 0.001 for EF and ML vs. men) and during PECA (EF: 354 ± 321 vs. ML: 341 ± 199 vs. men: 599 ± 327 a.u./min, P < 0.05 for EF and ML vs. men). During CPT, HR and MSNA responses were similar between sexes and hormone phases, confirming that central integration and the sympathetic efferent pathway was comparable between the sexes and across hormone phases. Women demonstrated a blunted metaboreflex, unaffected by sex hormones, which may be due to differences in muscle mass or fiber type and, therefore, metabolic stimulation of group IV afferents.

Assessing executive functioning: on the validity, reliability, and sensitivity of a click/point random number generation task in healthy adults and patients with cognitive decline.

In random number generation (RNG) tasks, used to assess executive functioning, participants are asked to generate a random sequence of digits at a paced rate, either verbally or by writing. Some previous studies used an alternative format in which participants had to randomly press different response keys, assuming that this task version demands the same cognitive processes as those implied in the standard version. The present study examined the validity of this assumption. To this end, the construct validity, reliability, and sensitivity of a conceptually similar task version of the key-press task were examined. Participants had to randomly click on, or point to, the digits 1-9, laid out orderly in a 3 × 3 grid on a computer screen. Psychometric properties of this task were examined, based on the performance of 131 healthy participants and 80 patients with cognitive decline. The results suggest that the click/point RNG task version can be used as a reliable and valid substitute for standard task versions that use the same response set and response pacing rate as those used in the present study. This task might be a useful alternative, demanding no separate recording and recoding of responses, and being suitable for use with patients with speech or writing problems.

Increased intra-individual variability in stride length and reaction time in recurrent older fallers.

AIMS: To study and compare both mean performance measures as well as intra-individual variability measures of stride length and reaction time in vulnerable recurrent and non-recurrent older fallers. METHODS: Stride length during walking and walking while dual-tasking (GAITRite®) and choice reaction time (CANTAB®) were assessed in geriatric outpatients and their informal caregivers (n=60, ≥ 60 yrs). Logistic regression and Receiver Operating Characteristic (ROC) analysis were used to generate models with mean performance measures and intra-individual variability measures (coefficients of variation; CV=[sd/mean]x100)), as risk factors for recurrent falls. RESULTS: Reaction-time CV was higher in recurrent fallers than in non-recurrent fallers: 21.3% [9.3-47.7] vs 15.8% [8.3-34.9] (p=0.04). Also, stride-length CV was higher in recurrent fallers during performance of the verbal fluency dual-task: 4.5% [1.2-31.4] vs 3.5% [0.9-9.7] (p=0.017). The model with CVs provided an explained variance of 23.7%, and an area under the curve (AUC) of 0.73, which was higher than that of the model including mean performance measures (8.6% and 0.65 respectively). CONCLUSIONS: Older recurrent fallers are characterized by increased within-task variability in reaction time and stride length while dual-tasking. In addition, variability in performance is a more sensitive measure in discrimination of recurrent falls than mean performance itself, suggesting deterioration in neurocognitive regulation mechanisms as part of the causal pathway for recurrent falls.

Developing and evaluating complex healthcare interventions in geriatrics: the use of the medical research council framework exemplified on a complex fall prevention intervention.

Geriatrics focuses on a variety of multiorgan problems in a heterogeneous older population. Therefore, most geriatric healthcare interventions are complex interventions. The UK Medical Research Council (MRC) has developed a framework to systematically design, evaluate, and implement complex interventions. This article provides an overview of this framework and illustrates its use in geriatrics by showing how it was used to develop and evaluate a fall prevention intervention. The consecutive phases of the framework are described: Phase I: Development. This phase began with a literature review, which provided the existing evidence and the theoretical understanding of the process of change. This understanding was further developed through focus groups with experts and interviews with patients and caregivers. The intervention was modeled using qualitative testing of the preliminary intervention through focus groups and through the completion of Delphi surveys by independent specialists. Phase II: Feasibility and piloting. In this phase, a pilot study was conducted in a group of patients and caregivers. The feasibility of the intervention and evaluation was also discussed in focus groups of participants and instructors. Phase III: Evaluation. The information from phases I and II shaped the design of a randomized controlled trial to test the effectiveness of the intervention. Phase IV: Dissemination. The purpose of the final phase is to examine the implementation of the intervention into practice. The MRC framework provides an innovative and useful methodology for the development and evaluation of complex geriatric interventions that deserves greater dissemination and implementation.

Qualitative study on the impact of falling in frail older persons and family caregivers: foundations for an intervention to prevent falls.

OBJECTIVES: The primary aim of this study was to explore the impact of falling for frail community-dwelling older persons with and without cognitive impairments who have experienced a recent fall and their primary family caregivers. The secondary aim was to define components for a future fall prevention programme. METHODS: Grounded theory interview study, with 10 patients (three cognitively unimpaired, four with mild cognitive impairment and three with dementia) and 10 caregivers. RESULTS: All patients described a fear of falling and social withdrawal. Caregivers reported a fear of their care recipient (CR) falling. Most patients were unable to name a cause for the falls. Patients rejected the ideas that falling is preventable and that the fear of falling can be reduced. Some caregivers rated the consequences of their CRs' cognitive problems as more burdensome than their falls and believed that a prevention programme would not be useful because of the CRs' cognitive impairment, physical problems, age and personalities. CONCLUSION: Falling has major physical and emotional consequences for patients and caregivers. A fall prevention programme should focus on reducing the consequences of falling and on promoting self-efficacy and activity. The causes of falls should be discussed. The programme should include dyads of patients and caregivers because caregivers are highly involved and also suffer from anxiety. Before beginning such a programme, providers should transform negative expectations about the programme into positive ones. Finally, caregivers must learn how to deal with the consequences of their CRs' falling as well as their cognitive impairment.

Studywise minimization: a treatment allocation method that improves balance among treatment groups and makes allocation unpredictable.

OBJECTIVES: In randomized controlled trials with many potential prognostic factors, serious imbalance among treatment groups regarding these factors can occur. Minimization methods can improve balance but increase the possibility of selection bias. We described and evaluated the performance of a new method of treatment allocation, called studywise minimization, that can avoid imbalance by chance and reduce selection bias. STUDY DESIGN AND SETTING: The studywise minimization algorithm consists of three steps: (1) calculate the imbalance for all possible allocations, (2) list all allocations with minimum imbalance, and (3) randomly select one of the allocations with minimum imbalance. We carried out a simulation study to compare the performance of studywise minimization with three other allocation methods: randomization, biased-coin minimization, and deterministic minimization. Performance was measured, calculating maximal and average imbalance as a percentage of the group size. RESULTS: Independent of trial size and number of prognostic factors, the risk of serious imbalance was the highest in randomization and absent in studywise minimization. The largest differences among the allocation methods regarding the risk of imbalance were found in small trials. CONCLUSION: Studywise minimization is particularly useful in small trials, where it eliminates the risk of serious imbalances without generating the occurrence of selection bias.

The influence of fear of falling on gait and balance in older people.

BACKGROUND: fear of falling (FoF) has great impact on functioning and quality of life of older people, but its effects on gait and balance are largely unknown. METHODS: we examined FoF in 100 participants aged >or=75 years, using the Activities-specific Balance Confidence scale. Participants with a mean score <67% were assigned to the FoF group. We quantified gait and balance during walking at the preferred velocity with and without a cognitive dual task (arithmetic task and verbal fluency), using an electronic walkway (Gaitrite) and a trunk accelerometer (SwayStar). Primary outcome measures were gait velocity, stride-length and stride-time variability, as well as mediolateral angular displacement and velocity. RESULTS: gait velocity was significantly lower (P < 0.05) and stride-length and stride-time variability were significantly higher (P < 0.05) in the FoF group. However, after standardisation for gait velocity, differences became non-significant. Mediolateral angular displacement and velocity were not associated with FoF. We found no difference between the FoF and no-FoF group with respect to the dual-task effect on gait and balance variables. CONCLUSIONS: the lower gait velocity in the FoF group may be a useful adaptation to optimise balance, rather than a sign of decreased balance control. The ability to attend to a secondary task during walking is not influenced by FoF.

Menstrual cycle effects on sympathetic neural responses to upright tilt.

Young women are more susceptible to orthostatic intolerance than men, though the sex-specific pathophysiology remains unknown. As blood pressure (BP) is regulated through the baroreflex mechanism, we tested the hypothesis that baroreflex control of muscle sympathetic nerve activity (MSNA) during orthostasis is impaired in women and can be affected by the menstrual cycle. MSNA and haemodynamics were measured supine and during a graded upright tilt (30 deg for 6 min, 60 deg for 45 min or till presyncope) in 11 young men and 11 women during the early follicular (EFP) and mid-luteal phase (MLP) of the menstrual cycle. Sympathetic baroreflex sensitivity was quantified using the slope of the linear correlation between total activity and diastolic BP during spontaneous breathing. Baroreflex function was further assessed during a Valsalva manoeuvre (VM). Although MSNA burst frequency responses during tilting were similar between sexes and menstrual phases, increases in total activity were lower in women during EFP than MLP (P = 0.030), while total peripheral resistance and plasma noradrenaline were not similarly lower; upright total activity tended to be lower in women during EFP than men (P = 0.102). Sympathetic baroreflex sensitivity did not differ between sexes (P = 0.676) supine (-281 +/- 46 (S.E.M.) units beat(-1) mmHg(-1) in men vs -252 +/- 52 in EFP and -272 +/- 40 in MLP in women), at 30 deg tilt (-648 +/- 129 vs -611 +/- 79 and -487 +/- 94), and at 60 deg tilt (-792 +/- 135 vs -831 +/- 92 and -814 +/- 142); this sensitivity was not affected by the menstrual cycle (P = 0.747). Similar sympathetic baroreflex sensitivity between sexes and phases was also observed during the VM. Cardiovagal baroreflex sensitivity assessed during decreasing BP (i.e. early phase II of the VM) was comparable between sexes, but it was greater in men than women during increasing BP (i.e. phase IV); the menstrual cycle had no influences on cardiovagal baroreflex sensitivity. We conclude that the menstrual cycle affects sympathetic neural responses but not sympathetic baroreflex sensitivity during orthostasis, though upright vasomotor sympathetic activity is not clearly different between men and women. Not only sympathetic but also cardiovagal baroreflex sensitivity is similar between sexes and menstrual phases during a hypotensive stimulus. However, cardiovagal baroreflex-mediated bradycardia during a hypertensive stimulus is different between sexes but not affected by the menstrual cycle. Thus, other factors rather than sympathetic baroreflex control mechanisms contribute to sex differences in orthostatic tolerance in young humans.