Is recalibration more important than realignment in prism adaptation training for visuospatial neglect? A randomized controlled trial.

Prism adaptation training (PAT) as a treatment for visuospatial neglect (VSN) involves two components: recalibration and realignment. We conducted a randomized controlled trial with PAT protocols requiring different degrees of recalibration and realignment, by using a single or multi-step protocol and varying visibility of the pointing movement. Twenty-five VSN patients received an alertness treatment without prisms, followed by four PAT protocols, encompassing a multi- or single-step procedure with terminal exposure, a single-step procedure with concurrent exposure, and sham PAT, presented in random order. The primary outcome parameter was the mean response time (RT) to left-sided targets in an endogenous variant of the Posner task, and we also measured the sensorimotor aftereffect. The two protocols without visibility of most of the movement trajectory produced significant aftereffects. The single-step protocol without movement visibility resulted in shorter RTs to left-sided targets. Hence, aftereffects depended on the partial invisibility of the movement. Moreover, only allowing VSN patients to recalibrate several times and direct feedback from the pointing errors had a beneficial effect on non-motor leftward visuospatial attention. We provide preliminary evidence that maximizing the conscious experience of movement errors may be an important component for remediating VSN.Trial registration: German Clinical Trials Register identifier: DRKS00025938.

Monocular eye patching modulates reorienting of covert attention in patients with unilateral middle cerebral artery stroke.

Unilateral brain lesions can lead to impaired contralesional attention and reduced ipsilesional and enhanced contralesional superior colliculus (SC) activity. We aimed to investigate whether modulation of SC activation via monocular eye patching can improve contralesional attention. Twenty left-hemispheric (LH) and 20 right-hemispheric (RH) patients with an acute or subacute middle cerebral artery (MCA) stroke completed an endogenous version of the Posner cueing task twice, while the left or right eye was covered with an eye patch. The LH and RH patients showed significantly slower reactions to contralesional than to ipsilesional stimuli. In addition, the eye patch modulated responses to invalidly but not those to validly cued stimuli. Post hoc analyses could not discriminate whether this effect pertained to a particular target side or eye patch position. However, exploratory analyses indicated that the observed eye patch effect might affect the RH group more than the LH group. As predicted 36 years ago, monocular eye patching modulates visuospatial attention, presumably due to differences in SC activation between the two eye patch conditions. However, this modulation seems too weak and unspecific, and therefore possibly not strong enough to be a treatment option for patients with visuospatial attention impairments.

Heart rate variability and fatigue in MS: two parallel pathways representing disseminated inflammatory processes?

BACKGROUND: Fatigue is a disabling symptom of multiple sclerosis. Its biological causes are still poorly understood. Several years ago, we proposed that fatigue might be the subjective representation of inflammatory processes. An important step for a straight-forward evaluation of our model would be to show that the level of fatigue is associated with vagal activation. The heart rate is under partial control of the vagus nerve. Using power spectrum analysis allows to separate, at least partly, sympathetic and parasympathetic impact on heart rate variability. METHODS: This narrative review summarizes the evidence for heart rate variability changes in MS patients, their relationship with fatigue and disease course. To do this, we conducted a literature search, including 45 articles relevant to the topic treated in this review. RESULTS: We illustrate that (1) inflammation leads to a change in cardiac behavior during acute and chronic phases, both in animals and in humans; (2) MS patients show changes of heart rate variability (HRV) that resemble those during acute and chronic inflammation due to multiple causes; (3) existing evidence favors a set of specific predictions about fatigue and parallel HRV changes; and (4) that MS-related brainstem lesions or neurological impairments do not completely explain HRV changes, leaving enough place for an explanatory relation between HRV and fatigue. DISCUSSION: We discuss the results of this review in relation to our model of fatigue and propose several observational and experimental studies that could be conducted to gain a better insight into whether fatigue and HRV can be interpreted as a common pathway, both reflecting activated autoimmune processes in MS patients.

Comparing two relaxation procedures to ease fatigue in multiple sclerosis: a single-blind randomized controlled trial.

BACKGROUND: Various relaxation procedures have been proposed to reduce fatigue in multiple sclerosis (MS). However, it is unknown, which type of relaxation has the largest effect on fatigue reduction and on autonomic nervous system (ANS) activity. OBJECTIVE: We aimed to compare two biofeedback-supported relaxation exercises: a deep breathing (DB) exercise and progressive muscle relaxation (PMR), which may ameliorate MS fatigue and alter ANS activity. METHODS: We performed a single-blind randomized clinical trial, introducing MS patients (n = 34) to the DB or PMR exercise. We first tested cardiovagal integrity, reflected by changes in heart rate variability (HRV) in response to DB. Participants then performed a fatigue-inducing vigilance task, followed by the DB or PMR. State fatigue was recorded consecutively at baseline, after the vigilance task, and after the relaxation exercise, along with HRV reflecting ANS activity. RESULTS: Only patients assigned to the PMR group experienced a significant drop in fatigue, whereas both relaxation exercises changed ANS activity. MS patients showed the expected autonomic response during the cardiovagal reflex test. The vigilance task elevated short-term feelings of fatigue and significantly reduced HRV parameters of parasympathetic activity. Trait fatigue was negatively correlated with HRV during the second half of the vigilance task. CONCLUSION: PMR alleviates short-term feelings of fatigue in persons with MS. The vigilance task in combination with HRV measurements may be helpful for evaluating relaxation procedures as a treatment of fatigue. Hereby, future studies should ensure longer and more frequent relaxation exercises and focus on patients with weak to moderate fatigue. TRIAL REGISTRATION: Trial Registry: DRKS00024358.

Long-term results in three-dimensional, complex bone augmentation procedures with customized titanium meshes.

OBJECTIVES: Complex, three-dimensional bony defects still represent challenging situations in routine implant dentistry. The aim of this study was to evaluate implant survival in customized bone regeneration using a patient-specific titanium mesh. MATERIAL AND METHODS: Patients (n = 21, implants 36) who had obtained an augmentation procedure with patient-specific titanium mesh were examined after 5.7 ± 0.38 years. Survival rate, clinical parameters for periimplantitis (Bleeding on Probing [BOP] and suppuration), and radiographic examination were evaluated. Peri-implant marginal bone loss (MBL) was calculated by using an image assessment program. Additionally, the influence of various factors on treatment outcomes such as periodontitis, smoking, professional maintenance, or diabetes was assessed as well as the impact on quality of life applying the Oral Health Impact Profile (OHIP). RESULTS: The implant survival rate was 97%, with one implant loss in the lower jaw. At the end of the observation period, MBL showed mesial 0.13 ± 1.84 mm and distal -0.13 ± 1.73 mm. The lower jaw showed significant more MBL mesial compared with the upper jaw (p = .034, cluster-adjusted). Periodontitis was significantly associated with MBL mesial and distal (p < .05). Positive BOP (four implants) was significantly associated with MBL mesial (p = .0031) and distal (p = .0018). MBL was significantly associated with suppuration mesial (p < .0001) and distal (p < .0001). CONCLUSIONS: CBR® results in high implant survival rate and stabilized augmented marginal bone after follow-up of minimum 5 years. Periodontitis seems to play the mayor role for long-term stability indicated by BOP and suppuration.

Can biofeedback-based training alleviate fatigue and vigilance performance in fatigued MS patients?

MS related fatigue might be related to autonomous nervous system (ANS) dysfunctions or to inflammation related vagal (hyper-) activation. Consequently, influencing ANS status may lead to relieve of fatigue. We used two opposite biofeedback interventions to either increase sympathetic ("self-alert training", SAT) or parasympathetic activation ("progressive muscle relaxation", PMR). We recorded fatigue status of patients before and after a challenging vigilance task, their behavioural performance on this task, their skin conductance response (SCR), and parameters indicating parasympathetic activity concerning heart rate variability (HRV). We repeated these recordings after the biofeedback training sessions. Patients of the SAT group were able to learn to increase their SCR voluntarily. Patients of the PMR group showed increasing parameters indicating parasympathetic modulation of the HRV. The vigilance task increased their feeling of fatigue. However, there was no effect of biofeedback training on either fatigue status or performance on the vigilance task. Our results show that MS patients can learn to change voluntarily their ANS activity using biofeedback instructions based on SCR and this can be used in future studies to test the postulated link between ANS and fatigue. However, in this experimental intervention we were unable to document a relation between ANS activity and fatigue.Trial registration: ClinicalTrials.gov identifier: NCT03268187.

Repeated application of the covert shift of attention task improves endogenous but not exogenous attention in patients with unilateral visuospatial inattention.

BACKGROUND: Most neglect treatment studies focus on automatic re-orientation procedures, assuming a deficit in automatic processes. We compare an automatic- and a controlled procedure, using the endogenous and exogenous variants of Posner's covert shift of attention task. METHOD: In two experiments, neglect patients and patients with a right hemispherical stroke without neglect performed three blocks of Posner's covert shift of attention task (Posner Task) on two days. In Study 1 we used endogenous cues, in Study 2, exogenous cues. RESULTS: In the endogenous task, neglect patients improved significantly with valid left-sided cues between block 1 and 2 on Day 1, subsequently showing a plateauing. They also showed a gradual improvement on invalid trials on both days. In the exogenous condition, all participants responded only increasingly faster on trials with a long stimulus onset asynchrony. Practicing on both tasks led to fewer omissions for left-sided targets, minimally in the exogenous and clearly in the endogenous condition. CONCLUSION: In line with prior neuroanatomical studies, our study shows that practicing an endogenous, but not an exogenous, visuospatial attention task leads to significant improvements in neglect patients, especially for invalid trials, suggesting that neglect treatments based on top-down strategies should be given more attention.

The effect of high vs. low intensity neuropsychological treatment on working memory in patients with acquired brain injury.

AIM: To evaluate the combined effect of compensation therapy and functional training on working memory (WM) in patients with acquired injury and chronic cognitive deficits by investigating the dose-response relationship and specificity of transfer effects. RESEARCH DESIGN: Double-blind randomized controlled trial. METHODS: All patients underwent 4 weeks of compensation therapy in a day-care setting. In addition, they received either 20 sessions of computer-based WM training (n = 11) or attention training (n = 9). Transfer effects on cognition and their functional relevance in daily life were assessed before treatment, after 2 weeks (10 additional training sessions), and after 4 weeks (20 additional training sessions) of therapy. RESULTS: The combined treatment led to significant improvements in WM performance, verbal memory, and self-reported changes in daily life. The amount of training was identified to modulate efficacy: Significant improvements showed only in the later training phase. We observed no differences between the two training schemes (WM vs. attentional training). CONCLUSIONS: Even in the chronic phase after brain lesion WM performance can be enhanced by the combination of compensation therapy and computerized cognitive training when applied intensely; both a more general attention and a specific WM training regimen are effective.

Evaluation of Risk Parameters in Bone Regeneration Using a Customized Titanium Mesh: Results of a Clinical Study.

PURPOSE: The aim of the study was an evaluation of risk factors for an innovative bone regeneration technique using a customized titanium mesh that was tested in a clinical setting. MATERIALS AND METHODS: This retrospective study included 65 patients with 70 grafting procedures of osseous defects of the jaws with a customized titanium mesh together with Advanced- and Injectable-Platelet-Rich Fibrin (A- and I-PRF), resorbable membranes, and bone grafting materials. Exposures of the meshes and grafting outcome were analyzed according to a novel classification as (a) punctual and (b) tooth width or complete exposure of the mesh (c). No exposure was stated as (d). RESULTS: In 37% of cases, exposures of the meshes occurred that were significantly associated with loss of grafted material (P < 0.001). Tobacco abuse (P = 0.032) and grafting procedures together with simultaneous sinus floor elevation techniques (P = 0.001) were found to be risk factors for success of the grafted material. Implant placement was not possible in 2 cases only. CONCLUSION: The results of this study verified the treatment of large defects with a customized titanium mesh as a useful protocol with a predictable outcome, even in cases of dehiscences.

tDCS combined with optokinetic drift reduces egocentric neglect in severely impaired post-acute patients.

Visuospatial neglect is a disabling syndrome resulting in impaired activities of daily living and in longer durations of inpatient rehabilitation. Effective interventions to remediate neglect are still needed. The combination of tDCS and an optokinetic task might qualify as a treatment method. A total of 32 post-acute patients with left (n = 20) or right-sided neglect were allotted to an intervention or a control group (both groups n = 16). The intervention group received eight sessions of 1.5-2.0 mA parietal transcranial direct current stimulation (tDCS) during the performance of an optokinetic task distributed over two weeks. Additionally they received standard therapy for five hours per day. The control group received only the standard therapy. Patients were examined twice before (with 3-4 days between examinations) and twice after treatment (5-6 days between examinations). Compared to the control group and controlling for spontaneous remission, the intervention group improved on spontaneous body orientation and the Clock Drawing Test. Intragroup comparisons showed broad improvements on egocentric but not on allocentric symptoms only for the intervention group. A short additional application of tDCS during an optokinetic task led to improvements of severe neglect compared to a standard neurological early rehabilitation treatment. Improvements seem to concern primarily egocentric rather than allocentric neglect.

Is there a cognitive signature for MS-related fatigue?

The compensatory approach of fatigue argues that it is a state caused by task load. The neuropsychiatric approach argues that fatigue is a trait (like depression), unrelated to environmental challenges. We propose that fatigue is an internal state that can be measured behaviorally only by applying specific cognitive tasks. PubMed was searched for articles concerning the relation between fatigue and cognitive performance or brain atrophy or functional MRI, distinguishing between the following cognitive domains: learning/memory, cognitive speed/selective attention, language, visuospatial processing, working memory, alerting/vigilance. Only tasks assessing alerting/vigilance are strongly related to fatigue. Areas with brain atrophy in fatigue patients overlap with brain regions activated in healthy controls performing alerting/vigilance tasks. Fatigue is not a compensatory state, nor a psychogenic trait. It is a feeling with behavioral effects that seems to be caused by brain atrophy or a neurochemical dysfunction of the alerting/vigilance system.

Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.

IMPORTANCE: Cerebral amyloid-ß aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. OBJECTIVE: To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. STUDY SELECTION: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. DATA EXTRACTION AND SYNTHESIS: Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS: The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality. CONCLUSIONS AND RELEVANCE: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

[Pursuing the triple aim: evaluation of the integrated care system Gesundes Kinzigtal: population health, patient experience and cost-effectiveness]. / Triple Aim - Evaluation in der Integrierten Versorgung Gesundes Kinzigtal - Gesundheitszustand, Versorgungserleben und Wirtschaftlichkeit.

BACKGROUND: The integrated care system Gesundes Kinzigtal (ICSGK), one of the most comprehensive population-based ICS in Germany, started its work nearly 9 years ago. The ICSGK is pursuing the Triple Aim: improving the health of the population, improving the individual's experience of care, and at the same time reducing the per capita costs of care. OBJECTIVES: To evaluate the impact of the ICSGK on the Triple Aim. MATERIALS AND METHODS: The ICSGK is being evaluated externally and internally via a mix of diverse quantitative and qualitative methods. This paper presents selected results for each Triple Aim dimension. RESULTS AND CONCLUSIONS: Regarding population health, most of the quality indicators examined by the external scientific evaluation show positive development. For example, the prevalence of patients with fractures among all insurants with osteoporosis is presented. In 2011, this prevalence was approximately 26 % in the "Kinzigtal" population (aged ≥ 20 years old) in comparison to 33 % in the control group. As far as patient experience is concerned, to the question "Would you recommend becoming a member of Gesundes Kinzigtal to your friends or relatives?" 92.1 % of those questioned answered "Yes, for sure" or "Yes, probably." Twenty-four percent of those questioned further stated that they would now live "more healthy" than before enrolment in the ICSGK. In the subgroup of questioned insurants who had objective agreements with their doctors 45.4 % answered in this way. On the subject of cost-effectiveness, for both participating socil health insurance schemes, cost savings relative to the costs normally expected for the ICSGK population concerned are observed every year. In the seventh intervention year (2012) the total is 4.56 million Euros for the AOK Baden-Württemberg (BW), which is a contribution margin of 146 Euros per insurant for the 31.156 insurants concerned (LKK BW = 322 Euros per insurant relative to cost savings). The results presented in this paper indicate positive effects in all three Triple Aim dimensions. Further longitudinal studies are recommended to validate those first results together with a detailed analysis to obtain in-depth insights into the specific influence of subcomponents of the total intervention.

Comments on energy conservation treatments for MS-related fatigue and a new proposal.

Psychological treatments of MS-related fatigue mostly depend on energy conservation programs. We argue that the evidence for energy conservation training is weak - in contrast to some reviews on this topic. The reasons for our concerns are the use of informed passive control groups allowing negative placebo effects, the lack of predefined primary outcome parameter, statistically rather than clinically significant effects, and the use of insensitive fatigue questionnaires. We propose to base psychological interventions not on a view of fatigue as a constant loss of mental energy but as a subjective representation ("feeling") of an inflammatory state, which draws away attentional capacity. This conceptualization allows to develop a three-step treatment approach: Getting short-term control on fatigue, extinction to reduce fatigue-related avoidance behavior, and a systematic increase of activities by pacing. Our proposal depends on the techniques, that can interrupt ongoing feelings of fatigue and can serve as a basis for extinction. We propose that Progressive Muscle Relaxation might be such a technique. The advantage of our model is that it shares similarities with well-established treatments for phobias and chronic pain and we discuss the shared set of assumptions. Hopefully, this will help to improve the treatment of fatigue in future.

Xenogeneic matrix for basal cell carcinoma reconstruction: a case report.

This case report introduces an innovative approach for tissue regeneration post-total excision of basal cell carcinoma utilizing a xenogeneic collagen matrix coupled with injectable platelet-rich fibrin. The clinical outcome underscores the efficacy and predictability of this protocol in soft tissue regeneration. While further investigation on a larger patient cohort is warranted to fully elucidate its effects and advantages, this technique holds promise in streamlining surgical procedures following excision of extraoral neoplasms. Notably, its simple handling, minimal resource requirements, and potential to mitigate donor site morbidity and patient comorbidities post-surgery signify its value in clinical practice.

Self-reported sleep problems, but not fatigue, lead to decline in sustained attention in MS patients.

OBJECTIVE: According to the compensation theory, fatigue in MS results from efforts to compensate for a reduction in capacity due to demyelination or neurodegeneration. Recently, it has been argued that fatigue may result from poor sleep. Both explanations predict a worsening of fatigue and a cognitive decline during sustained attention tasks (higher fatigability). METHOD: We compared MS patients with and without self-reported cognitive fatigue, in three sessions with a two-back working memory task, registering hits and response latencies as well as changes in fatigue. In the two breaks between the sessions, either a video instruction to relax or a stimulating video was presented. Subsequently, patients were divided into those with and those without self-reported sleep problems and the analyses were repeated. RESULTS: Patients with fatigue performed worse than healthy controls, irrespective of task duration and type of video during the break. The task-related increase of fatigue also did not differ between the groups and no differential effect of the videos was observed in the MS patients with fatigue. In contrast, patients with sleep problems did show a performance decline as predicted by the compensation theory. CONCLUSION: MS patients with fatigue were impaired in working memory, but did not show greater fatigability, whereas MS participants with self-reported sleep problems showed fatigability, which could be improved with a restorative rest period. Our data therefore do not support the compensation theory of fatigue, and we argue that sleep problems and fatigue in MS patients differ with respect to their functional consequences.

Neural correlates of stimulus response and stimulus outcome shifting in healthy participants and MS patients.

INTRODUCTION: Adaptation to changing situations can be mediated by two strategies: (1) Evaluation of a response and (2) Evaluation of outcome values in relation to objects. Previous studies indicate that response shifting is associated with a network comprising the left frontal cortex and parietal cortex connected by the superior longitudinal fascicle, whereas outcome evaluation is associated with a network consisting of the orbitofrontal cortex, amygdala and uncinate fascicle. However, these studies rarely compared both kinds of adaptation directly and existing fMRI studies with healthy subjects are not informative about the role of the two fiber systems. METHODS: We analyzed stimulus response shifting and stimulus outcome shifting in two studies, one fMRI-study on healthy participants and one study on patients with MS involving structural MRI (Diffusion Tensor Imaging, Voxel Based Morphometry, Ventricular volumetry). Two tasks were used, identical in presentation but different in instruction, controlling for effects of lower level processing. In the SRS task, participants had to perform a "Go" or "NoGo" response depending on a stimulus change: if the stimulus remained the same, they had to continue with the former type of response, if it changed they had to adapt their response pattern. In the SOS task they had to perform a "Go" response only if the presented stimulus corresponded to that of an internal alternating series. RESULTS: fMRI findings showed that SRS is related to a bilateral parietal-premotor network. In the left hemisphere the prefrontal cortex was also involved. SOS was lateralized to the right hemisphere, particularly to the anterior temporal pole and amygdala, and the inferior parietal cortex. MS patients impaired on this task suffered from lesions in the right uncinate fascicle and showed an enlarged right frontal lateral ventricle. CONCLUSION: With physically identical tasks, a functional neuronal segregation can be demonstrated for stimulus response shifting (bilateral activations with a focus in the left prefrontal cortex) and stimulus outcome shifting (right anterior temporal lobe and right supramarginal gyrus).

Is recovery from left-sided neglect based on changes in automatic attention? An auditory event related potentials study.

An automatic spatial attention deficit is the primary deficit in neglect. However, the cognitive processes enabling recovery from neglect have rarely been studied. We used event-related potentials (ERP) to analyze if recovery is based on changes in automatic attention components. Twelve sub-acute patients with left visuospatial neglect were included. They received 3 weeks of intensive treatment. ERPs were recorded using two auditory paradigms: either a tone was presented randomly to the right or left ear (ATP) or as a Posner paradigm (PP) with left to right and vice versa moving cue tones and validly and invalidly cued target tones. Patients improved significantly on neuropsychological tests and neurological scales. For the ATP, no differences were observed related to the side of stimulation, but the auditory PP showed characteristic results, that is, smaller amplitudes for left-sided targets and higher amplitudes for invalid trials. Both paradigms revealed a treatment effect, but no changes were found in the amplitudes for the two target sides, which would be expected if the treatment would affect the automatic attention bias. Recovery from neglect seems not to be associated with changes in the automatic spatial attention bias, arguing that recovery might be due to higher cognitive compensatory processes.