Stratifying quality of life outcome in subthalamic stimulation for Parkinson's disease.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) for Parkinson's disease (PD) improves quality of life (QoL), motor and non-motor symptoms (NMS). However, in previous studies, 43%-49% of patients did not experience clinically relevant postoperative QoL improvement. To inform individualised prediction of postoperative QoL improvement, we developed a stratification analysis of QoL outcomes based on preoperative non-motor total burden, severity of motor progression and motor response in levodopa challenge tests. METHODS: This was a prospective, open-label, multicentre, international study with a 6-month follow-up. A distribution-based threshold identified 'QoL responders' in the PDQuestionnaire-8 Summary Index (PDQ-8 SI). After baseline stratification based on the NMS Scale, Hoehn and Yahr Scale and levodopa response assessed with the Unified PD Rating Scale-III, we compared postoperative QoL response between these strata. To assess the clinical usefulness and statistical feasibility of stratifications, we compared cumulative distribution function curves, respectively PDQ-8 within-stratum variation. RESULTS: All main outcomes improved postoperatively. Based on the 8.1 points threshold for clinically meaningful PDQ-8 SI improvement, only 80/161 patients were classified as 'QoL responders'. The absolute risk reductions for QoL non-response among respective non-motor, motor progression and levodopa response strata were 23%, 8% and 3%, respectively. Only non-motor stratification reduced PDQ-8 within-stratum variation compared with the overall cohort. CONCLUSIONS: Non-motor stratification, but not motor progression or levodopa response stratification, is clinically useful and statistically feasible for personalised preoperative prediction of postoperative QoL outcome of STN-DBS for PD. Our findings highlight that non-motor assessments are necessary components of a case-based, holistic approach of DBS indication evaluations geared towards optimising postoperative QoL outcomes. TRIAL REGISTRATION NUMBER: GermanClinicalTrialsRegister: #6735.

Results of a Randomized Clinical Trial of Speech After Early Neurostimulation in Parkinson's Disease.

BACKGROUND: The EARLYSTIM trial demonstrated for Parkinson's disease patients with early motor complications that deep brain stimulation of the subthalamic nucleus (STN-DBS) and best medical treatment (BMT) was superior to BMT alone. OBJECTIVE: This prospective, ancillary study on EARLYSTIM compared changes in blinded speech intelligibility assessment between STN-DBS and BMT over 2 years, and secondary outcomes included non-speech oral movements (maximum phonation time [MPT], oral diadochokinesis), physician- and patient-reported assessments. METHODS: STN-DBS (n = 102) and BMT (n = 99) groups underwent assessments on/off medication at baseline and 24 months (in four conditions: on/off medication, ON/OFF stimulation-for STN-DBS). Words and sentences were randomly presented to blinded listeners, and speech intelligibility rate was measured. Statistical analyses compared changes between the STN-DBS and BMT groups from baseline to 24 months. RESULTS: Over the 2-year period, changes in speech intelligibility and MPT, as well as patient-reported outcomes, were not different between groups, either off or on medication or OFF or ON stimulation, but most outcomes showed a nonsignificant trend toward worsening in both groups. Change in oral diadochokinesis was significantly different between STN-DBS and BMT groups, on medication and OFF STN-DBS, with patients in the STN-DBS group performing slightly worse than patients under BMT only. A signal for clinical worsening with STN-DBS was found for the individual speech item of the Unified Parkinson's Disease Rating Scale, Part III. CONCLUSION: At this early stage of the patients' disease, STN-DBS did not result in a consistent deterioration in blinded speech intelligibility assessment and patient-reported communication, as observed in studies of advanced Parkinson's Disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Network Fingerprint of Stimulation-Induced Speech Impairment in Essential Tremor.

OBJECTIVE: This study was undertaken to gain insights into structural networks associated with stimulation-induced dysarthria (SID) and to predict stimulation-induced worsening of intelligibility in essential tremor patients with bilateral thalamic deep brain stimulation (DBS). METHODS: Monopolar reviews were conducted in 14 essential tremor patients. Testing included determination of SID thresholds, intelligibility ratings, and a fast syllable repetition task. Volumes of tissue activated (VTAs) were calculated to identify discriminative fibers for stimulation-induced worsening of intelligibility in a structural connectome. The resulting fiber-based atlas structure was then validated in a leave-one-out design. RESULTS: Fibers determined as discriminative for stimulation-induced worsening of intelligibility were mainly connected to the ipsilateral precentral gyrus as well as to both cerebellar hemispheres and the ipsilateral brain stem. In the thalamic area, they ran laterally to the thalamus and posteromedially to the subthalamic nucleus, in close proximity, mainly anterolaterally, to fibers beneficial for tremor control as published by Al-Fatly et al in 2019. The overlap of the respective clinical stimulation setting's VTAs with these fibers explained 62.4% (p < 0.001) of the variance of stimulation-induced change in intelligibility in a leave-one-out analysis. INTERPRETATION: This study demonstrates that SID in essential tremor patients is associated with both motor cortex and cerebellar connectivity. Furthermore, the identified fiber-based atlas structure might contribute to future postoperative programming strategies to achieve optimal tremor control without speech impairment in essential tremor patients with thalamic DBS. ANN NEUROL 2021;89:315-326.

Impaired context-sensitive adjustment of behaviour in Parkinson's disease patients tested on and off medication: An fMRI study.

The brain's sensitivity to and accentuation of unpredicted over predicted sensory signals plays a fundamental role in learning. According to recent theoretical models of the predictive coding framework, dopamine is responsible for balancing the interplay between bottom-up input and top-down predictions by controlling the precision of surprise signals that guide learning. Using functional MRI, we investigated whether patients with Parkinson's disease (PD) show impaired learning from prediction errors requiring either adaptation or stabilisation of current predictions. Moreover, we were interested in whether deficits in learning over a specific time scale would be accompanied by altered surprise responses in dopamine-related brain structures. To this end, twenty-one PD patients tested on and off dopaminergic medication and twenty-one healthy controls performed a digit prediction paradigm. During the task, violations of sequence-based predictions either signalled the need to update or to stabilise the current prediction and, thus, to react to them or ignore them, respectively. To investigate contextual adaptation to prediction errors, the probability (or its inverse, surprise) of the violations fluctuated across the experiment. When the probability of prediction errors over a specific time scale increased, healthy controls but not PD patients off medication became more flexible, i.e., error rates at violations requiring a motor response decreased in controls but increased in patients. On the neural level, this learning deficit in patients was accompanied by reduced signalling in the substantia nigra and the caudate nucleus. In contrast, differences between the groups regarding the probabilistic modulation of behaviour and neural responses were much less pronounced at prediction errors requiring only stabilisation but no adaptation. Interestingly, dopaminergic medication could neither improve learning from prediction errors nor restore the physiological, neurotypical pattern. Our findings point to a pivotal role of dysfunctions of the substantia nigra and caudate nucleus in deficits in learning from flexibility-demanding prediction errors in PD. Moreover, the data witness poor effects of dopaminergic medication on learning in PD.

Probabilistic sweet spots predict motor outcome for deep brain stimulation in Parkinson disease.

OBJECTIVE: To investigate whether functional sweet spots of deep brain stimulation (DBS) in the subthalamic nucleus (STN) can predict motor improvement in Parkinson disease (PD) patients. METHODS: Stimulation effects of 449 DBS settings in 21 PD patients were clinically and quantitatively assessed through standardized monopolar reviews and mapped into standard space. A sweet spot for best motor outcome was determined using voxelwise and nonparametric permutation statistics. Two independent cohorts were used to investigate whether stimulation overlap with the sweet spot could predict acute motor outcome (10 patients, 163 settings) and long-term overall Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) improvement (63 patients). RESULTS: Significant clusters for suppression of rigidity and akinesia, as well as for overall motor improvement, resided around the dorsolateral border of the STN. Overlap of the volume of tissue activated with the sweet spot for overall motor improvement explained R2 = 37% of the variance in acute motor improvement, more than triple what was explained by overlap with the STN (R2 = 9%) and its sensorimotor subpart (R2 = 10%). In the second independent cohort, sweet spot overlap explained R2 = 20% of the variance in long-term UPDRS-III improvement, which was equivalent to the variance explained by overlap with the STN (R2 = 21%) and sensorimotor STN (R2 = 19%). INTERPRETATION: This study is the first to predict clinical improvement of parkinsonian motor symptoms across cohorts based on local DBS effects only. The new approach revealed a distinct sweet spot for STN DBS in PD. Stimulation overlap with the sweet spot can predict short- and long-term motor outcome and may be used to guide DBS programming. ANN NEUROL 2019;86:527-538.

A prospective, controlled study of non-motor effects of subthalamic stimulation in Parkinson's disease: results at the 36-month follow-up.

OBJECTIVE: To examine 36-month effects of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on non-motor symptoms (NMS) compared with standard-of-care medical treatment (MED) in Parkinson's disease (PD). METHODS: Here we report the 36-month follow-up of a prospective, observational, controlled, international multicentre study of the NILS cohort. Assessments included NMSScale (NMSS), PDQuestionnaire-8 (PDQ-8), Scales for Outcomes in PD (SCOPA)-motor examination, -activities of daily living, and -complications, and levodopa equivalent daily dose (LEDD). Propensity score matching resulted in a pseudo-randomised sub-cohort balancing baseline demographic and clinical characteristics between the STN-DBS and MED groups. Within-group longitudinal outcome changes were analysed using Wilcoxon signed-rank and between-group differences of change scores with Mann-Whitney U test. Strength of clinical responses was quantified with Cohen's effect size. In addition, bivariate correlations of change scores were explored. RESULTS: Propensity score matching applied on the cohort of 151 patients (STN-DBS n=67, MED n=84) resulted in a well-balanced sub-cohort including 38 patients per group. After 36 months, STN-DBS significantly improved NMSS, PDQ-8, SCOPA-motor examination and -complications and reduced LEDD. Significant between-group differences, all favouring STN-DBS, were found for NMSS, SCOPA-motor complications, LEDD (large effects), motor examination and PDQ-8 (moderate effects). Furthermore, significant differences were found for the sleep/fatigue, urinary (large effects) and miscellaneous NMSS domains (moderate effects). NMSS total and PDQ-8 change scores correlated significantly. CONCLUSIONS: This study provides Class IIb evidence for beneficial effects of STN-DBS on NMS at 36-month follow-up which also correlated with quality of life improvements. This highlights the importance of NMS for DBS outcomes assessments.

Bipolar Directional Deep Brain Stimulation in Essential and Parkinsonian Tremor.

OBJECTIVE: To compare directional monopolar, bipolar, and directional bipolar thalamic deep brain stimulation (DBS) in tremor patients. METHODS: Fourteen tremor patients (7 Essential Tremor and 7 Parkinson's Disease) implanted with directional DBS electrodes in the ventral intermediate nucleus (VIM) were enrolled. Side-effect thresholds of monopolar directional stimulation (DIRECT) were compared to circular DBS as well as, in a randomized design, to those of two different bipolar stimulation settings (BIPOLAR = circular anode; BI-DIRECT = directional anode). Tremor suppression (Tremor Rating Scale, TRS) right below the side-effect threshold was also assessed. RESULTS: Directional DBS in the individually best direction showed higher side-effect thresholds than circular DBS (p = 0.0063). The thresholds were raised further using either one of the bipolar stimulation paradigms (BIPOLAR p = 0.0029, BI-DIRECT p = 0.0022). The side-effect thresholds did not differ between both bipolar settings, but side-effects were less frequent with BI-DIRECT. No difference in TRS scores with stimulation just below the side-effect threshold was found between all stimulation conditions. CONCLUSIONS: Side-effect thresholds of monopolar directional and bipolar stimulation with both circular and directional anodes were higher compared to traditional monopolar circular stimulation in the VIM. Bipolar DBS with directional anodes evoked side-effect less frequently than bipolar and monopolar directional stimulation. All stimulation settings had comparable effects on tremor suppression just below their side-effect thresholds. Thus, directional and different bipolar settings should be explored in patients with bothersome side-effects of thalamic stimulation when monopolar stimulation settings are not satisfying. Further studies are needed to explore the efficiency of the different bipolar stimulation paradigms.

Quality of life outcome after subthalamic stimulation in Parkinson's disease depends on age.

OBJECTIVE: The purpose of this study was to investigate how quality of life outcome after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) depends on age. METHODS: In this prospective, open-label, multicenter study including 120 PD patients undergoing bilateral STN-DBS, we investigated the PDQuestionnaire-8 (PDQ-8), Unified PD Rating Scale-III, Scales for Outcomes in PD-motor examination, complications, activities of daily living, and levodopa equivalent daily dose preoperatively and at 5 months follow-up. Significant changes at follow-up were analyzed with Wilcoxon signed-rank test and Bonferroni correction for multiple comparisons. To explore the influence of age post hoc, the patients were classified into 3 age groups (≤59, 60-69, ≥70 years). Intragroup changes were analyzed with Wilcoxon signed-rank and intergroup differences with Kruskal-Wallis tests. The strength of clinical responses was evaluated using effect size. RESULTS: The PDQuestionnaire-8, Scales for Outcomes in PD-motor complications, activities of daily living, and levodopa equivalent daily dose significantly improved in the overall cohort and all age groups with no significant intergroup differences. However, PDQuestionnaire-8 effect sizes for age groups ≤59, 60 to 69, and ≥70 years, respectively, were strong, moderate, and small. Furthermore, PDQuestionnaire-8 domain analyses revealed that all domains except cognition and emotional well-being significantly improved in patients aged ≤59 years, whereas only communication, activities of daily living, and stigma improved in patients aged 60-69 years, and activities of daily living and stigma in patients aged ≥70 years. CONCLUSIONS: Although quality of life, motor complications, and activities of daily living significantly improved in all age groups after bilateral STN-DBS, the beneficial effect on overall quality of life was more pronounced and affected a wider range of quality of life domains in younger patients. © 2017 International Parkinson and Movement Disorder Society.

Unstable impedance of a single electrode contact resulting in loss of DBS therapy-a case report.

Open and short circuits of electrode contacts are important technical dysfunctions of DBS. Here, we report on another type of dysfunction restricted to a single electrode contact: impedance instability within regular absolute values. After 9-year subthalamic DBS, a Parkinson patient developed unilateral motor symptoms and intermittent dysaesthesia due to impedance instability of the active contact. DBS efficacy could be restored without surgical revision by activation of the neighboring contact. During 3-year-follow-up, impedances of the dysfunctional contact varied between 1 and 3 kΩ whereas the other three contacts remained stable. Impedance documentation is crucial to identify such dysfunctions.

Subthalamic Stimulation Improves Quality of Life of Patients Aged 61 Years or Older With Short Duration of Parkinson's Disease.

OBJECTIVE: The optimal timing of subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) is a topic of ongoing debate. In patients with short disease duration an improvement of quality of life (QoL) has been demonstrated for patients aged younger than 61 years. However, this has not been systematically investigated in older patients yet. We hypothesized that patients aged 61 years or older experience a significant QoL improvement after STN-DBS with no difference in effect sizes for groups of patients with short and longer disease duration. MATERIALS AND METHODS: From four centers (Cologne, London, Manchester, Venice) we identified "older patients" aged 61 years or older with short (≤8 years) or longer disease duration and compared QoL, motor impairment, complications, medication requirements, and Mini-Mental State Examination (MMSE) on baseline and five months after surgery. RESULTS: Mean age/disease duration in 21 subjects with shorter disease duration were 65.5/6.3 years compared to 66.8/14.6 in 33 subjects with longer disease duration. The short disease duration group was affected by less baseline motor complications (p = 0.002). QoL in the short/longer disease duration group improved by 35/20% (p = 0.010/p = 0.006), motor complications by 40/44% (p = 0.018/p < 0.001), and medication requirements by 51/49% (both p < 0.001). MMSE remained unchanged in both groups. CONCLUSION: Patients aged 61 years or older benefited from STN-DBS regardless of short (≤8 years) or longer (>8 years) disease duration. Our results contribute to the debate about DBS selection criteria and timing and call for prospective confirmation in a larger cohort.

Directional DBS increases side-effect thresholds-A prospective, double-blind trial.

OBJECTIVE: The objective of this study was to investigate whether directional deep brain stimulation (DBS) of the subthalamic nucleus in Parkinson's disease (PD) offers increased therapeutic windows, side-effect thresholds, and clinical benefit. METHODS: In 10 patients, 20 monopolar reviews were conducted in a prospective, randomized, double-blind design to identify the best stimulation directions and compare them to conventional circular DBS regarding side-effect thresholds, motor improvement, and therapeutic window. In addition, circular and best-directional DBS were directly compared in a short-term crossover. Motor outcome was also assessed after an open-label follow-up of 3 to 6 months. RESULTS: Stimulation in the individual best direction resulted in significantly larger therapeutic windows, higher side-effect thresholds, and more improvement in hand rotation than circular DBS. Rigidity and finger tapping did not respond differentially to the stimulation conditions. There was no difference in motor efficacy or stimulation amplitudes between directional and circular DBS in the short-term crossover. Follow-up evaluations 3 to 6 months after implantation revealed improvements in motor outcome and medication reduction comparable to other DBS studies with a majority of patients remaining with a directional setting. CONCLUSION: Directional DBS can increase side-effect thresholds while achieving clinical benefit comparable to conventional DBS. Whether directional DBS improves long-term clinical outcome needs to be investigated in the future. © 2017 International Parkinson and Movement Disorder Society.

Working Memory Training Responsiveness in Parkinson's Disease Is Not Determined by Cortical Thickness or White Matter Lesions.

Patients with Parkinson's disease are highly vulnerable for cognitive decline. Thus, early intervention by means of working memory training (WMT) may be effective for the preservation of cognition. However, the influence of structural brain properties, i.e., cortical thickness and volume of white matter lesions on training responsiveness have not been studied. Here, behavioral and neuroimaging data of 46 patients with Parkinson's disease, 21 of whom engaged in home-based, computerized adaptive WMT, was analyzed. While cortical thickness and white matter lesions volume were associated with cognitive performance at baseline, these structural brain properties do not seem to determine WMT responsiveness.

Gender differences in referrals for deep brain stimulation for essential tremor.

Deep brain stimulation (DBS) is an established treatment for essential tremor (ET). Gender differences in DBS have been recognized for Parkinson's disease. In this systematic chart review, we also observed a gender differences in DBS for ET. The main reason was an underrepresentation of women in referrals for surgical evaluation.

No Higher Risk-Seeking Tendencies or Altered Self-Estimation in a Social Decision-Making Task in Patients with Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) has been associated with a tendency towards more risky decisions. However, the commonly used paradigms typically neglect the social context. OBJECTIVE: Here, we investigated social decision-making and self-estimation in a competitive experimental task. METHODS: A computerized experimental setting was used in which 86 PD patients (age = 66.5 [50-79], 62.8% male, H&Y = 2 [1.5-3]) and 44 healthy controls (HC; age = 67 [54-79], 54.4% male) in groups of four performed mathematical addition tasks in which they were asked to calculate as many sums as possible in five minutes. Participants had to choose their preferred compensation scheme ("piece rate" versus "tournament") and retrospectively rank their performance in comparison to the suspected performance of the others. A comprehensive neuropsychological test battery was also conducted. RESULTS: No significant difference was found in overall social decision-making and self-estimation between PD patients and HC. However, for those individuals who made inadequate decisions, PD patients engaged in significantly more risk-averse and HC in more risky decisions. Concerning those inadequate decisions, the PD patients made more extreme decisions (severity of social decision-making) in both directions (risk-averse, risk-seeking). CONCLUSION: Our data indicate that social decision-making behavior and self-estimation are largely intact in PD patients with mild to moderate disease stages and intact global cognition, executive functions, and social cognition. Future studies with more heterogeneous PD samples regarding their neuropsychological profile will have to examine at which state social decision-making may be affected and by which factors this behavior might be influenced.

Cognitive Performance and Learning Parameters Predict Response to Working Memory Training in Parkinson's Disease.

BACKGROUND: Working memory (WM) training (WMT) is a popular intervention approach against cognitive decline in patients with Parkinson's disease (PD). However, heterogeneity in WM responsiveness suggests that WMT may not be equally efficient for all patients. OBJECTIVE: The present study aims to evaluate a multivariate model to predict post-intervention verbal WM in patients with PD using a supervised machine learning approach. We test the predictive potential of novel learning parameters derived from the WMT and compare their predictiveness to other more commonly used domains including demographic, clinical, and cognitive data. METHODS: 37 patients with PD (age: 64.09±8.56, 48.6% female, 94.7% Hoehn & Yahr stage 2) participated in a 5-week WMT. Four random forest regression models including 1) cognitive variables only, 2) learning parameters only, 3) both cognitive and learning variables, and 4) the entire set of variables (with additional demographic and clinical data, 'all' model), were built to predict immediate and 3-month-follow-up WM. RESULT: The 'all' model predicted verbal WM with the lowest root mean square error (RMSE) compared to the other models, at both immediate (RMSE = 0.184; 95% -CI=[0.184;0.185]) and 3-month follow-up (RMSE = 0.216; 95% -CI=[0.215;0.217]). Cognitive baseline parameters were among the most important predictors in the 'all' model. The model combining cognitive and learning parameters significantly outperformed the model solely based on cognitive variables. CONCLUSION: Commonly assessed demographic, clinical, and cognitive variables provide robust prediction of response to WMT. Nonetheless, inclusion of training-inherent learning parameters further boosts precision of prediction models which in turn may augment training benefits following cognitive interventions in patients with PD.

A Randomized, Double-Blinded Crossover Trial of Short Versus Conventional Pulse Width Subthalamic Deep Brain Stimulation in Parkinson's Disease.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) is a well-established treatment for patients with Parkinson's disease. Previous acute challenge studies suggested that short pulse widths might increase the therapeutic window while maintaining motor symptom control with a decrease in energy consumption. However, only little is known about the effect of short pulse width stimulation beyond the setting of an acute challenge. OBJECTIVE: To compare 4 weeks of STN-DBS with conventional pulse width stimulation (60 µs) to 4 weeks of STN-DBS with short pulse width stimulation (30 µs) regarding motor symptom control. METHODS: This study was a monocentric, double-blinded, randomized crossover non-inferiority trial investigating whether short pulse width stimulation with 30 µs maintains equal motor control as conventional 60 µs stimulation over a period of 4 weeks (German Clinical Trials Register No. DRKS00017528). Primary outcome was the difference in motor symptom control as assessed by a motor diary. Secondary outcomes included energy consumption measures, non-motor effects, side-effects, and quality of life. RESULTS: Due to a high dropout rate, the calculated sample size of 27 patients was not met and 24 patients with Parkinson's disease and STN-DBS were included in the final analysis. However, there were no differences in any investigated outcome parameter between the two treatment conditions. CONCLUSION: This study demonstrates that short pulse width settings (30 µs) provide non-inferior motor symptom control as conventional (60 µs) stimulation without significant differences in energy consumption. Future studies are warranted to evaluate a potential benefit of short pulse width settings in patients with pronounced dyskinesia.

Predicting Working Memory Training Responsiveness in Parkinson's Disease: Both "System Hardware" and Room for Improvement Are Needed.

Background. Patients with Parkinson's disease (PD) are highly vulnerable to develop cognitive dysfunctions, and the mitigating potential of early cognitive training (CT) is increasingly recognized. Predictors of CT responsiveness, which could help to tailor interventions individually, have rarely been studied in PD. This study aimed to examine individual characteristics of patients with PD associated with responsiveness to targeted working memory training (WMT). Methods. Data of 75 patients with PD (age: 63.99 ± 9.74 years, 93% Hoehn & Yahr stage 2) without cognitive dysfunctions from a randomized controlled trial were analyzed using structural equation modeling. Latent change score models with and without covariates were estimated and compared between the WMT group (n = 37), who participated in a 5-week adaptive WMT, and a waiting list control group (n = 38). Results. Latent change score models yielded adequate model fit (χ2-test p > .05, SRMR ≤ .08, CFI ≥ .95). For the near-transfer working memory composite, lower baseline performance, younger age, higher education, and higher fluid intelligence were found to significantly predict higher latent change scores in the WMT group, but not in the control group. For the far-transfer executive function composite, higher self-efficacy expectancy tended to significantly predict larger latent change scores. Conclusions. The identified associations between individual characteristics and WMT responsiveness indicate that there has to be room for improvement (e.g., lower baseline performance) and also sufficient "hardware" (e.g., younger age, higher intelligence) to benefit in training-related cognitive plasticity. Our findings are discussed within the compensation versus magnification account. They need to be replicated by methodological high-quality research applying advanced statistical methods with larger samples.

Working memory training increases neural efficiency in Parkinson's disease: a randomized controlled trial.

Impairment of working memory and executive functions is already frequently observed in early stages of Parkinson's disease. Improvements in working memory performance in this cohort could potentially be achieved via working memory training. However, the specific neural mechanisms underlying different working memory processes such as maintenance as opposed to manipulation are largely under-investigated in Parkinson's disease. Moreover, the plasticity of these correlates as a function of working memory training is currently unknown in this population. Thus, the working memory subprocesses of maintenance and manipulation were assessed in 41 cognitively healthy patients with Parkinson's disease using a newly developed working memory paradigm and functional MRI. Nineteen patients were randomized to a 5-week home-based digital working memory training intervention while the remaining patients entered a control, wait list condition. Working memory task-related activation patterns and context-dependent functional connectivity, as well as the change of these neural correlates as a function of training, were assessed. While both working memory processes activated an extended frontoparietal-cerebellar network, only the manipulation of items within working memory also recruited the anterior striatum. The intervention effect on the neural correlates was small, but decreased activation in areas relevant for working memory could be observed, with activation changes correlating with behavioural change. Moreover, training seemed to result in decreased functional connectivity when pure maintenance was required, and in a reorganization of functional connectivity when items had to be manipulated. In accordance with the neural efficacy hypothesis, training resulted in overall reduced activation and reorganized functional connectivity, with a differential effect on the different working memory processes under investigation. Now, larger trials including follow-up examinations are needed to further explore the long-term effects of such interventions on a neural level and to estimate the clinical relevance to potentially delay cognitive decline in cognitively healthy patients with Parkinson's disease.

Effects of working memory training in patients with Parkinson's disease without cognitive impairment: A randomized controlled trial.

OBJECTIVE: To determine the feasibility and evaluate effects of a computerized working memory (WM) training (WMT) in patients with Parkinson's Disease (PD) on cognitive and clinical outcomes. METHODS: 76 patients with PD without cognitive impairment were randomized to either the WMT group (n = 37), who participated in a 5-week adaptive WMT, or a passive waiting-list control group (CG, n = 39). Patients underwent clinical and neuropsychological examination at baseline, after training, and at 3-months follow-up, with verbal WM and non-verbal WM as primary outcomes. Outcome assessors were blinded for group allocation. RESULTS: All WMT participants completed the training successfully and reported high levels of motivation for and satisfaction with the training. Repeated-measures, linear mixed-effects models revealed positive training effects for the WMT group compared to the CG in verbal working memory with a small relative effect size 0.39 [95%CI 0.05; 0.76] for the 3-months follow-up only. No other reliable training effects in cognitive and clinical variables were found for either point of time. CONCLUSIONS: In this randomized controlled trial, WMT was feasible and yielded some evidence for 3-months follow-up training gains in patients with PD. WMT might be an effective intervention to prevent cognitive decline in this patient group, however, more longitudinal studies with longer follow-up periods and more sensitive assessment tools will have to proof this concept. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00009379).