Enriched music-supported therapy for individuals with chronic stroke: a randomized controlled trial.

OBJECTIVE: Many stroke survivors still present with upper-limb paresis six months post-stroke, impacting their autonomy and quality of life (QoL). We designed an enriched Music-supported Therapy (eMST) program to reduce disability in this population. We evaluated the eMST's effectiveness in improving functional abilities and QoL in chronic stroke individuals compared to the conventional motor program Graded Repetitive Arm Supplementary Program (GRASP). METHODS: We conducted a pragmatic two-arm parallel-group randomized controlled trial with a 3-month follow-up and masked assessment. The eMST involved playing instruments during individual self-administered and group music therapy sessions. The GRASP consisted of self-administered motor exercises using daily objects. Both interventions were completed at home with telemonitoring and involved four one-hour weekly sessions for 10 weeks. The primary outcome was upper-limb motor function measured with the Action Research Arm Test. Secondary outcomes included motor impairment, daily life motor performance, cognitive functions, emotional well-being, QoL, self-regulation, and self-efficacy. Intention-to-treat (ITT) and per-protocol (PP) analyses were conducted including participants who discontinued the intervention and those who completed it entirely, respectively. RESULTS: Fifty-eight chronic stroke patients were randomized to the eMST-group (n = 26; age: 64.2 ± 12.5; 6 [23.1%] females; 2.8 ± 2.9 years post-stroke), and the control group (n = 32; age: 62.2 ± 12; 8 [25%] females; 1.8 ± 6.2 years post-stroke). The eMST-group had more participants achieving a clinically relevant improvement in motor impairment post-intervention than the control group for the ITT (55% vs 21.6%; OR = 4.5 (95% CI 1.4-14); p = .019) and PP analyses (60% vs 20%; OR = 6 (95% CI 1.5-24.7); p = .024), sustained at follow-up. The eMST-group reported greater improvements in emotion (difference = 11.1 (95% CI 0.8-21.5; p = 0.36) and participation (difference = 10.3 (95% CI 0.6-25.9); p = 0.41) subscales of QoL, and higher enjoyment during the sessions (difference = 1 (95% CI 0.3-1.5); p = 0.12). No changes were found in other outcomes. CONCLUSION: eMST demonstrated superiority over conventional motor rehabilitation program in enhancing upper-limb functions and QoL in chronic stroke individuals. TRIAL REGISTRATION: ClinicalTrials.gov (ID: NCT04507542).

Altered brain functional connectivity in patients with resistance to thyroid hormone ß.

To investigate changes in brain network organization and possible neurobehavioral similarities to attention-deficit hyperactivity disorder (ADHD), we measured changes in brain resting-state functional connectivity (rs-fMRI) and cognitive domains in patients with resistance to thyroid hormone ß (RTHß) and compared them with those in healthy control subjects. In this prospective case-control study, twenty-one participants with genetically confirmed RTHß were matched with 21 healthy controls. The Adult ADHD Self-Report Scale (ASRS-v1.1) and ADHD Rating Scale-IV were used to assess self-reported symptoms of ADHD. A voxel-wise and atlas-based approach was used to identify changes in the brain networks. The RTHß group reported behavioral symptoms similar to those of ADHD. We found evidence of weaker network integration of the lingual and fusiform gyri in the RTHß group, which was mainly driven by weaker connectivity to the bilateral insula and supplementary motor cortex. Functional connectivity between regions of the default mode network (angular gyrus/middle temporal gyrus) and regions of the cognitive control network (bilateral middle frontal gyrus) was increased in RTHß patients compared to healthy controls. Increased connectivity between regions of the default mode network and the dorsolateral prefrontal cortex is frequently reported in ADHD and is interpreted to be associated with deficits in attention. Our finding of weaker connectivity of the lingual gyrus to the bilateral insula (salience network) in RTHß patients has also been reported previously in ADHD and may reflect decreased habituation to visual stimuli and increased distractibility. Overall, our observations support the notion of neuropsychological similarities between RTHß and ADHD.

Threatening an Illusory Limb: An Event-related Potential Study of the Rubber Hand Illusion.

BACKGROUND: The rubber hand illusion (RHI) is a well-established method for studying body ownership: Given adequate concordance of visual, sensory, and proprioceptive stimuli, the individual experiences a rubber hand as his or her own. OBJECTIVE: To study the effects of a threat to the rubber hand. METHODS: We created a typical RHI paradigm but added threatening pain: Both the real hand of an individual and the rubber hand were stroked with a brush, either synchronously (RHI-inducing condition) or asynchronously (control condition), but only the rubber hand was then pricked with a needle to create a threatening pain condition. Event-related potentials (ERPs) were recorded in a group of 23 typically-developed individuals. ERP effects were source-localized using low-resolution electromagnetic tomography. RESULTS: The individuals consistently reported experience of the RHI during the experiment when the brush strokes were applied synchronously to both the real hand and the rubber hand. ERP analysis revealed that synchronous brush stroking gave rise to higher amplitude of frontal ERPs in the 100-200 ms range than asynchronous brush stroking, which was interpreted as reflecting the RHI. In the threatening pain condition, ERPs showed a greater positivity at frontocentral electrodes, source localized in the supplementary motor area (SMA). CONCLUSION: SMA activation could reflect a control mechanism over reflexive motor activity, facilitating a possible threat-related response. Further studies should address ERP effects and the extent of the RHI to standard and threat stimuli in a correlative fashion to further elucidate the functional significance of the neurophysiological findings.

Event-related brain potentials to typing errors in transparent and intransparent German words.

Error detection in typing is crucial for assessing the adequacy of ongoing actions, leveraging both predictive mechanisms for early detection and sensory feedback for late detection. Neurophysiological studies have supported the anticipation of errors through predictive models. This research extends the understanding of error detection in typing, focusing on the neurocognitive mechanisms underlying errors in transparent and intransparent German words. Thirty-six volunteer students typed out aurally presented words, classified as either orthographically transparent or intransparent, on a computer keyboard without the possibility of correction. Because of poor spelling or excessive artifacts, the final sample comprised 27 participants. Event-related potentials (ERPs) were obtained time-locked to key presses, and behavioral data on typing correctness and speed were collected. A higher error rate and longer latency for intransparent words compared to transparent ones were found, suggesting the complexity of spelling impacts typing correctness. Post-error slowing was observed, aligning with increased cognitive control following errors. ERPs revealed a negative component akin to the error-related negativity (ERN) for typing errors, with a pronounced ERN-like negativity preceding erroneous key-presses, particularly for intransparent words. The study provides evidence of the cognitive and neural mechanisms underlying typing errors, highlighting the impact of orthographic transparency. The detection of an ERN-like negativity before erroneous key-presses, especially in typing intransparent words, underscores the brain's use of predictive mechanisms for error detection.

Slips of the tongue in patients with Gilles de la Tourette syndrome.

BACKGROUND: Motor and vocal tics are the main symptom of Gilles de la Tourette-syndrome (GTS). A particular complex vocal tic comprises the utterance of swear words, termed coprolalia. Since taboo words are socially inappropriate, they are normally suppressed by people, which implies cognitive control processes. METHOD: To investigate the control of the unintentional pronunciation of taboo words and the associated processes of conflict monitoring, we used the "Spoonerisms of Laboratory Induced Predisposition" (SLIP) paradigm. Participants read multiple inductor word pairs with the same phonemes, followed by pronouncing a target pair with inverse phonemes. This led to a conflict between two competing speech plans: the correct word pair and the word pair with inverted phonemes. Latter speech error, a spoonerism, could result in a neutral or taboo word. We investigated 19 patients with GTS and 23 typically developed controls (TDC) and measured participants' electroencephalography (EEG) during the SLIP task. RESULTS: At the behavioral level less taboo than neutral word spoonerisms occurred in both groups without significant differences. Event-related brain potentials (ERP) revealed a difference between taboo and neutral word conditions in the GTS group at the midline electrodes in a time range of 250-400 ms after the speech prompt, which was not found in the TDC group. The extent of this effect depended on the number of inductor word pairs, suggesting an increasing level of cognitive control in the GTS group. CONCLUSION: The differences between taboo and neutral word conditions in patients with GTS compared to TDC suggest an altered recruitment of cognitive control processes in GTS, likely enlisted to suppress taboo words.

Tracking the habituation of the event-related EEG potential in automatic change detection using an auditory two-tone oddball paradigm.

The mismatch negativity and the P3a of the event-related EEG potential reflect the electrocortical response to a deviant stimulus in a series of stimuli. Although both components have been investigated in various paradigms, these paradigms usually incorporate many repetitions of the same deviant, thus leaving open whether both components vary as a function of the deviant's position in a series of deviant stimuli-i.e. whether they are subject to qualitative/quantitative habituation from one instantiation of a deviant to the next. This is so because the detection of mismatch negativity/P3a in the event-related EEG potential requires an averaging over dozens or hundreds of stimuli, i.e. over many instantiations of the deviant per participant. The present study addresses this research gap. We used a two-tone oddball paradigm implementing only a small number of (deviant) stimuli per participant, but applying it to a large number of participants (n > 230). Our data show that the mismatch negativity amplitude exhibits no decrease as a function of the deviant's position in a series of (standard and) deviant stimuli. Importantly, only after the very first deviant stimulus, a distinct P3a could be detected, indicative of an orienting reaction and an attention shift, and thus documenting a dissociation of mismatch negativity and P3a.

Inferior parietal cortex represents relational structures for explicit transitive inference.

The human brain is distinguished by its ability to perform explicit logical reasoning like transitive inference. This study investigated the functional role of the inferior parietal cortex in transitive inference with functional MRI. Participants viewed premises describing abstract relations among items. They accurately recalled the relationship between old pairs of items, effectively inferred the relationship between new pairs of items, and discriminated between true and false relationships for new pairs. First, the inferior parietal cortex, but not the hippocampus or lateral prefrontal cortex, was associated with transitive inference. The inferior parietal activity and functional connectivity were modulated by inference (new versus old pairs) and discrimination (true versus false pairs). Moreover, the new/old and true/false pairs were decodable from the inferior parietal representation. Second, the inferior parietal cortex represented an integrated relational structure (ordered and directed series). The inferior parietal activity was modulated by serial position (larger end versus center pairs). The inferior parietal representation was modulated by symbolic distance (adjacent versus distant pairs) and direction (preceding versus following pairs). It suggests that the inferior parietal cortex may flexibly integrate observed relations into a relational structure and use the relational structure to infer unobserved relations and discriminate between true and false relations.

Potential effects of a mobile stroke unit on time to treatment and outcome in patients treated with thrombectomy or thrombolysis: A Danish-German cross-border analysis.

BACKGROUND AND PURPOSE: A mobile stroke unit (MSU) reduces delays in stroke treatment by allowing thrombolysis on board and avoiding secondary transports. Due to the beneficial effect in comparison to conventional emergency medical services, current guidelines recommend regional evaluation of MSU implementation. METHODS: In a descriptive study, current pathways of patients requiring a secondary transport for mechanical thrombectomy were reconstructed from individual patient records within a Danish (n = 122) and an adjacent German region (n = 80). Relevant timestamps included arrival times (on site, primary hospital, thrombectomy centre) as well as the initiation of acute therapy. An optimal MSU location for each region was determined. The resulting time saving was translated into averted disability-adjusted life years (DALYs). RESULTS: For each region, the optimal MSU location required a median driving time of 35 min to a stroke patient. Time savings in the German region (median [Q1; Q3]) were 7 min (-15; 31) for thrombolysis and 35 min (15; 61) for thrombectomy. In the Danish region, the corresponding time savings were 20 min (8; 30) and 43 min (25; 66). Assuming 28 thrombectomy cases and 52 thrombolysis cases this would translate to 9.4 averted DALYs per year justifying an annual net MSU budget of $0.8M purchasing power parity dollars (PPP-$) in the German region. In the Danish region, the MSU would avert 17.7 DALYs, justifying an annual net budget of PPP-$1.7M. CONCLUSION: The effects of an MSU can be calculated from individual patient pathways and reflect differences in the hospital infrastructure between Denmark and Germany.

White adipose tissue distribution and amount are associated with increased white matter connectivity.

Obesity represents a significant public health concern and is linked to various comorbidities and cognitive impairments. Previous research indicates that elevated body mass index (BMI) is associated with structural changes in white matter (WM). However, a deeper characterization of body composition is required, especially considering the links between abdominal obesity and metabolic dysfunction. This study aims to enhance our understanding of the relationship between obesity and WM connectivity by directly assessing the amount and distribution of fat tissue. Whole-body magnetic resonance imaging (MRI) was employed to evaluate total adipose tissue (TAT), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT), while MR liver spectroscopy measured liver fat content in 63 normal-weight, overweight, and obese males. WM connectivity was quantified using microstructure-informed tractography. Connectome-based predictive modeling was used to predict body composition metrics based on WM connectomes. Our analysis revealed a positive dependency between BMI, TAT, SAT, and WM connectivity in brain regions involved in reward processing and appetite regulation, such as the insula, nucleus accumbens, and orbitofrontal cortex. Increased connectivity was also observed in cognitive control and inhibition networks, including the middle frontal gyrus and anterior cingulate cortex. No significant associations were found between WM connectivity and VAT or liver fat. Our findings suggest that altered neural communication between these brain regions may affect cognitive processes, emotional regulation, and reward perception in individuals with obesity, potentially contributing to weight gain. While our study did not identify a link between WM connectivity and VAT or liver fat, further investigation of the role of various fat depots and metabolic factors in brain networks is required to advance obesity prevention and treatment approaches.

Creative thinking and cognitive estimation in Parkinson's disease.

BACKGROUND: Patients with Parkinson's disease (PD) have been reported to exhibit unusual bouts of creativity (e.g., painting, writing), in particular in the context of treatment with dopaminergic agents. Here we investigated divergent and convergent thinking thought to underlie creativity. In addition we assessed cognitive estimation. METHOD: Twenty PD patients and 20 matched healthy control participants were subjected to the Guilford Alternate Uses task (divergent thinking), the remote associates task (convergent thinking) and two tests of cognitive estimation. RESULTS: No group differences were found for the convergent thinking task, while the Guilford Alternate Uses task revealed a decreased number of correct responses and a reduced originality for PD patients. Originality in PD was correlated to total daily dose of dopaminergic medication. Moreover, both tasks of cognitive estimation showed an impairment in PD. CONCLUSION: Only minor effects were found for psychometric indices of subprocesses of creative thinking, while estimation, relying on executive functioning, is impaired in PD. We suggest to take a product oriented view of creativity in further research on altered creative processes in PD.

Cross-frequency and inter-regional phase synchronization in explicit transitive inference.

Explicit logical reasoning, like transitive inference, is a hallmark of human intelligence. This study investigated cortical oscillations and their interactions in transitive inference with EEG. Participants viewed premises describing abstract relations among items. They accurately recalled the relationship between old pairs of items, effectively inferred the relationship between new pairs of items, and discriminated between true and false relationships for new pairs. First, theta (4-7 Hz) and alpha oscillations (8-15 Hz) had distinct functional roles. Frontal theta oscillations distinguished between new and old pairs, reflecting the inference of new information. Parietal alpha oscillations changed with serial position and symbolic distance of the pairs, representing the underlying relational structure. Frontal alpha oscillations distinguished between true and false pairs, linking the new information with the underlying relational structure. Second, theta and alpha oscillations interacted through cross-frequency and inter-regional phase synchronization. Frontal theta-alpha 1:2 phase locking appeared to coordinate spectrally diverse neural activity, enhanced for new versus old pairs and true versus false pairs. Alpha-band frontal-parietal phase coherence appeared to coordinate anatomically distributed neural activity, enhanced for new versus old pairs and false versus true pairs. It suggests that cross-frequency and inter-regional phase synchronization among theta and alpha oscillations supports human transitive inference.

Preserved Corticospinal Tract Revealed by Acute Perfusion Imaging Relates to Better Outcome After Thrombectomy in Stroke.

BACKGROUND: The indication for mechanical thrombectomy (MT) in stroke patients with large vessel occlusion has been constantly expanded over the past years. Despite remarkable treatment effects at the group level in clinical trials, many patients remain severely disabled even after successful recanalization. A better understanding of this outcome variability will help to improve clinical decision-making on MT in the acute stage. Here, we test whether current outcome models can be refined by integrating information on the preservation of the corticospinal tract as a functionally crucial white matter tract derived from acute perfusion imaging. METHODS: We retrospectively analyzed 162 patients with stroke and large vessel occlusion of the anterior circulation who were admitted to the University Medical Center Lübeck between 2014 and 2020 and underwent MT. The ischemic core was defined as fully automatized based on the acute computed tomography perfusion with cerebral blood volume data using outlier detection and clustering algorithms. Normative whole-brain structural connectivity data were used to infer whether the corticospinal tract was affected by the ischemic core or preserved. Ordinal logistic regression models were used to correlate this information with the modified Rankin Scale after 90 days. RESULTS: The preservation of the corticospinal tract was associated with a reduced risk of a worse functional outcome in large vessel occlusion-stroke patients undergoing MT, with an odds ratio of 0.28 (95% CI, 0.15-0.53). This association was still significant after adjusting for multiple confounding covariables, such as age, lesion load, initial symptom severity, sex, stroke side, and recanalization status. CONCLUSIONS: A preinterventional computed tomography perfusion-based surrogate of corticospinal tract preservation or disconnectivity is strongly associated with functional outcomes after MT. If validated in independent samples this concept could serve as a novel tool to improve current outcome models to better understand intersubject variability after MT in large vessel occlusion stroke.

Mechanisms and consequences of weight gain after deep brain stimulation of the subthalamic nucleus in patients with Parkinson's disease.

Body weight gain in combination with metabolic alterations has been observed after deep brain stimulation (DBS) of subthalamic nucleus (STN) in patients with Parkinson's disease (PD), which potentially counteracts the positive effects of motor improvement. We aimed to identify stimulation-dependent effects on motor activities, body weight, body composition, energy metabolism, and metabolic blood parameters and to determine if these alterations are associated with the local impact of DBS on different STN parcellations. We assessed 14 PD patients who underwent STN DBS (PD-DBS) before as well as 6- and 12-months post-surgery. For control purposes, 18 PD patients under best medical treatment (PD-CON) and 25 healthy controls (H-CON) were also enrolled. Wrist actigraphy, body composition, hormones, and energy expenditure measurements were applied. Electrode placement in the STN was localized, and the local impact of STN DBS was estimated. We found that STN DBS improved motor function by ~ 40% (DBS ON, Med ON). Weight and fat mass increased by ~ 3 kg and ~ 3% in PD-DBS (all P ≤ 0.005). fT3 (P = 0.001) and insulin levels (P = 0.048) increased solely in PD-DBS, whereas growth hormone levels (P = 0.001), daily physical activity, and VO2 during walking were decreased in PD-DBS (all P ≤ 0.002). DBS of the limbic part of the STN was associated with changes in weight and body composition, sedentary activity, insulin levels (all P ≤ 0.040; all r ≥ 0.56), and inversely related to HOMA-IR (P = 0.033; r = - 0.62). Daily physical activity is decreased after STN DBS, which can contribute to weight gain and an unfavorable metabolic profile. We recommend actigraphy devices to provide feedback on daily activities to achieve pre-defined activity goals.

Changes in brain structure in subjects with resistance to thyroid hormone due to THRB mutations.

BACKGROUND: Being critical for brain development and neurocognitive function thyroid hormones may have an effect on behaviour and brain structure. Our exploratory study aimed to delineate the influence of mutations in the thyroid hormone receptor (TR) ß gene on brain structure. METHODS: High-resolution 3D T1-weighted images were acquired in 21 patients with a resistance to thyroid hormone ß (RTHß) in comparison to 21 healthy matched-controls. Changes in grey and white matter, as well as cortical thickness were evaluated using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). RESULTS: RTHß patients showed elevated circulating fT4 & fT3 with normal TSH concentrations, whereas controls showed normal thyroid hormone levels. RTHß patients revealed significantly higher scores in a self-rating questionnaire for attention deficit hyperactivity disorder (ADHD). Imaging revealed alterations of the corticospinal tract, increased cortical thickness in bilateral superior parietal cortex and decreased grey matter volume in bilateral inferior temporal cortex and thalamus. CONCLUSION: RTHb patients exhibited structural changes in multiple brain areas. Whether these structural changes are causally linked to the abnormal behavioral profile of RTHß which is similar to ADHD, remains to be determined.

Neural, physiological and behavioural correlates of empathy for pain in Tourette syndrome.

Persons with Tourette syndrome show altered social behaviours, such as echophenomena and increased personal distress in emotional situations. These symptoms may reflect an overactive mirror neuron system, causing both increased automatic imitation and a stronger tendency to share others' emotions. To test this, we measured the individual level of echophenomena with a video protocol and experimentally induced empathy for pain in 21 participants with Tourette syndrome and 25 matched controls. In the empathy for pain paradigm, pictures of hands and feet in painful or neutral situations were presented, while we measured participants' EEG and skin conductance response. Changes in somatosensory mu suppression during the observation of the pictures and pain ratings were compared between groups, and correlations were calculated with the occurrence of echophenomena, self-reported empathy and clinical measures. Our Tourette syndrome sample showed significantly more echophenomena than controls, but the groups showed no behavioural differences in empathic abilities. However, controls, but not patients with Tourette syndrome, showed the predicted increased mu suppression when watching painful compared to neutral actions. While echophenomena were present in all persons with Tourette syndrome, the hypothesis of an overactive mirror neuron system in Tourette syndrome could not be substantiated. On the contrary, the Tourette syndrome group showed a noticeable lack of mu attenuation in response to pain stimuli. In conclusion, we found a first hint of altered processing of others' emotional states in a brain region associated with the mirror neuron system.

Differences in Implicit Attitudes in West and East Germans as Measured by the Go/NoGo Association Task and Event-related EEG Potentials.

BACKGROUND AND OBJECTIVE: Implicit social cognition refers to attitudes and stereotypes that may reside outside conscious awareness and control but that still affect human behavior. In particular, the implicit favoritism of an ingroup, to which an individual belongs, as opposed to an outgroup, to which the individual does not belong, characterized as ingroup bias, is of interest and is investigated here. METHOD: We used a Go/NoGo association task (GNAT) and behavioral and electroencephalographic (event-related EEG potential [ERP] analysis) measures to investigate the implicit bias toward cities in East Germany, West Germany, and Europe, in 16 individuals each from West and East Germany (mixed gender, M age = 24). The GNAT assesses an individual's Go and NoGo responses for a given association between a target category and either pole (positive or negative) of an evaluative dimension. RESULTS: Behavioral measures revealed slightly faster reaction times to the combination of European city names and negative, as compared with positive, evaluative words in both groups. ERP analysis showed an increased negativity at 400-800 ms poststimulus in the incongruent conditions of East German city/positive word pairings (in West Germans) and West German city/positive word pairings (in East Germans). CONCLUSION: An implicitly moderately negative evaluation of Europe by both groups was exhibited based on the behavioral data, and an increased level of conflict arising from the "incongruent" pairings (ie, as manifestation of an implicitly negative attitude toward East Germany in West Germans, and toward West Germany in East Germans) was exhibited based on the electrophysiological data.

Basal Ganglia Atrophy as a Marker for Prodromal X-Linked Dystonia-Parkinsonism.

In neurodegenerative diseases, the characterization of the prodromal phase is essential for the future application of disease-modifying therapies. X-linked dystonia-parkinsonism is a hereditary neurodegenerative movement disorder characterized by severe adult-onset dystonia accompanied by parkinsonism. Distinct striatal and pallidal atrophy is present already in early disease stages indicating a long-lasting presymptomatic degenerative process. To gain insight into the prodromal phase of X-linked dystonia-parkinsonism, structural and iron-sensitive magnetic resonance imaging (MRI) was performed in 10 non-manifesting carriers and 24 healthy controls in a double-blind fashion. Seventeen patients with X-linked dystonia-parkinsonism were recruited to replicate previous findings of basal ganglia pathology and iron accumulation. Age at onset was estimated in non-manifesting carriers and patients using the repeat length of the hexanucleotide expansion and 3 single-nucleotide polymorphisms associated with age at onset. Voxel-based morphometry and subcortical volumetry showed striatal and pallidal atrophy in non-manifesting carriers (~10%) and patients (~40%). Substantia nigra volume was similarly reduced in patients (~40%). Caudate volume correlated with time to estimated onset in non-manifesting carriers. Susceptibility-weighted imaging confirmed iron deposition in the anteromedial putamen in patients. Non-manifesting carriers also showed small clusters of iron accumulation in the same area after lowering the statistical threshold. In conclusion, basal ganglia atrophy and iron accumulation precede the clinical onset of X-linked dystonia-parkinsonism and can be detected years before the estimated disease manifestation. It thereby highlights the potential of multimodal imaging to identify clinically unaffected mutation carriers with incipient neurodegeneration and to monitor disease progression independent of clinical measures. Longitudinal studies are needed to further elucidate the onset and progression rate of neurodegeneration in prodromal X-linked dystonia-parkinsonism. ANN NEUROL 2023;93:999-1011.

Combined optokinetic stimulation and cueing-assisted reading therapy to treat hemispatial neglect: A randomized controlled crossover trial.

BACKGROUND: Hemispatial neglect is a disabling cognitive disorder following stroke and effective therapies are required. OBJECTIVES: To evaluate the effects of combined optokinetic stimulation (OKS) and cueing-assisted reading therapy (READ) on the remission of hemispatial neglect following stroke. METHODS: Randomized, controlled, two-period, crossover trial conducted at a German neurorehabilitation center. Twenty participants with left neglect following right hemispheric stroke (mean age 66 years (SD 11), mean time since stroke 50 days (SD 33)) finished the trial (12 received OKSREAD first, 8 CONTROL first). The intervention consisted of 15 daily sessions of OKS (20 min) and text reading assisted by a therapist providing cues (20 min). The control treatment was a same-number, same-length neuropsychological treatment not targeting visuospatial attention. Primary outcomes were the change in performance of a customized neuropsychological test battery for neglect (0% worst - 100% best) and a test of neglect-related functional disability (Catherine Bergego Scale, 0 no impairment - 30 severest impairment), assessed before and after each treatment period. Secondary outcomes were performance in the 6 single tests composing the battery (e.g., omissions in text reading, center of cancellation in the Bells test, spatial bias of fixations when freely viewing photographs) and a clinical test of anosognosia. RESULTS: Overall performance in the neglect test battery improved slightly more after OKSREAD than after CONTROL (d=6%; p=0.002). The remission of neglect-related functional disability did not differ between treatments (d=-2; p=0.291). Ipsilesional fixation bias during free viewing was the only secondary outcome that was improved by OKSREAD as compared to CONTROL (d= -2.8°; p=0.005). CONCLUSION: At the applied intensity, the combined OKSREAD intervention slightly attenuated the ipsilesional attention bias in persons with neglect, but it did not improve neglect-related functional disability, anosognosia, or other neglect symptoms to a clinically meaningful degree. CLINICAL TRIAL REGISTRATION: URL: http://www. CLINICALTRIALS: gov. Unique identifier: NCT04273620.

Pramipexole modulates fronto-subthalamic pathway in sequential working memory.

Brain dopamine may regulate the ability to maintain and manipulate sequential information online. However, the precise role of dopamine remains unclear. This pharmacological fMRI study examined whether and how the dopamine D2/3 receptor agonist pramipexole modulates fronto-subthalamic or fronto-striatal pathways during sequential working memory. This study used a double-blind, randomized crossover design. Twenty-two healthy male volunteers completed a digit ordering task during fMRI scanning after receiving a single oral dose of 0.5-mg pramipexole or placebo. The pramipexole effects on task performance, regional activity, activity pattern similarity, and functional connectivity were analyzed. Pramipexole impaired task performance, leading to less accurate and slower responses in the digit ordering task. Also, it downregulated the maintenance-related subthalamic and dorsolateral prefrontal activity, increasing reaction times for maintaining sequences. In contrast, pramipexole upregulated the manipulation-related subthalamic and dorsolateral prefrontal activity, increasing reaction time costs for manipulating sequences. In addition, it altered the dorsolateral prefrontal activity pattern similarity and fronto-subthalamic functional connectivity. Finally, pramipexole reduced maintenance-related striatal activity, which did not affect the behavior. This study confirms the role of the fronto-subthalamic pathway in sequential working memory. Furthermore, it shows that D2 transmission can regulate sequential working memory by modulating the fronto-subthalamic pathway.

Gaze-contingent display technology can help to reduce the ipsilesional attention bias in hemispatial neglect following stroke.

BACKGROUND: Hemispatial neglect results from unilateral brain damage and represents a disabling unawareness for objects in the hemispace opposite the brain lesion (contralesional). The patients' attentional bias for ipsilesional hemispace represents a hallmark of neglect, which results from an imbalanced attentional priority map in the brain. The aim of this study was to investigate whether gaze-contingent display (GCD) technology, reducing the visual salience of objects in ipsilesional hemispace, is able to rebalance this map and increase awareness and exploration of objects in the neglected contralesional hemispace. METHODS: Using remote eye-tracking, we recorded gaze positions in 19 patients with left hemispatial neglect following right-hemisphere stroke and 22 healthy control subjects, while they were watching static naturalistic scenes. There were two task conditions, free viewing (FV) or goal-directed visual search (VS), and four modification conditions including the unmodified original picture, a purely static modification and two differently strong modifications with an additional gaze-contingent mask (GC-LOW, GC-HIGH), that continuously reduced color saturation and contrast of objects in the right hemispace. RESULTS: The patients' median gaze position (Center of Fixation) in the original pictures was markedly deviated to the right in both tasks (FV: 6.8° ± 0.8; VS: 5.5° ± 0.7), reflecting the neglect-typical ipsilesional attention bias. GC modification significantly reduced this bias in FV (GC-HIGH: d = - 3.2 ± 0.4°; p < 0.001). Furthermore, in FV and VS, GC modification increased the likelihood to start visual exploration in the (neglected) left hemifield by about 20%. This alleviation of the ipsilesional fixation bias was not associated with an improvement in detecting left-side targets, in contrast, the GC mask even decreased and slowed the detection of right-side targets. Subjectively, patients found the intervention pleasant and most of the patients did not notice any modification. CONCLUSIONS: GCD technology can be used to positively influence visual exploration patterns in patients with hemispatial neglect. Despite an alleviation of the neglect-related ipsilesional fixation bias, a concomitant functional benefit (improved detection of contralesional targets) was not achieved. Future studies may investigate individualized GCD-based modifications as augmented reality applications during the activities of daily living.