Structural Neuroplasticity Effects of Singing in Chronic Aphasia.

Singing-based treatments of aphasia can improve language outcomes, but the neural benefits of group-based singing in aphasia are unknown. Here, we set out to determine the structural neuroplasticity changes underpinning group-based singing-induced treatment effects in chronic aphasia. Twenty-eight patients with at least mild nonfluent poststroke aphasia were randomized into two groups that received a 4-month multicomponent singing intervention (singing group) or standard care (control group). High-resolution T1 images and multishell diffusion-weighted MRI data were collected in two time points (baseline/5 months). Structural gray matter (GM) and white matter (WM) neuroplasticity changes were assessed using language network region of interest-based voxel-based morphometry (VBM) and quantitative anisotropy-based connectometry, and their associations to improved language outcomes (Western Aphasia Battery Naming and Repetition) were evaluated. Connectometry analyses showed that the singing group enhanced structural WM connectivity in the left arcuate fasciculus (AF) and corpus callosum as well as in the frontal aslant tract (FAT), superior longitudinal fasciculus, and corticostriatal tract bilaterally compared with the control group. Moreover, in VBM, the singing group showed GM volume increase in the left inferior frontal cortex (Brodmann area 44) compared with the control group. The neuroplasticity effects in the left BA44, AF, and FAT correlated with improved naming abilities after the intervention. These findings suggest that in the poststroke aphasia group, singing can bring about structural neuroplasticity changes in left frontal language areas and in bilateral language pathways, which underpin treatment-induced improvement in speech production.

Efficacy of a multicomponent singing intervention on communication and psychosocial functioning in chronic aphasia: a randomized controlled crossover trial.

The ability to produce words through singing can be preserved in severe aphasia, but the benefits of group-based singing rehabilitation in aphasia are largely unknown. Our aim was to determine the efficacy of a multicomponent singing intervention on communication and speech production, emotional-social functioning and caregiver well-being in aphasia. Fifty-four patients with acquired brain injury and chronic aphasia and their family caregivers (n = 43) were recruited. Using a crossover randomized controlled trial design, participants were randomized to two groups who received a 4-month singing intervention either during the first or second half of the study in addition to standard care. The intervention comprised weekly group-based training (including choir singing and group-level melodic intonation therapy) and tablet-assisted singing training at home. At baseline, 5- and 9-month stages, patients were assessed with tests and questionnaires on communication and speech production, mood, social functioning, and quality of life and family caregivers with questionnaires on caregiver burden. All participants who participated in the baseline measurement (n = 50) were included in linear mixed model analyses. Compared with standard care, the singing intervention improved everyday communication and responsive speech production from baseline to 5-month stage, and these changes were sustained also longitudinally (baseline to 9-month stage). Additionally, the intervention enhanced patients' social participation and reduced caregiver burden. This study provides novel evidence that group-based multicomponent singing training can enhance communication and spoken language production in chronic aphasia as well as improve psychosocial wellbeing in patients and caregivers. https://www.clinicaltrials.gov, Unique identifier: NCT03501797.

Neurological Music Therapy Rebuilds Structural Connectome after Traumatic Brain Injury: Secondary Analysis from a Randomized Controlled Trial.

BACKGROUND: Traumatic brain injury (TBI) is a common and devastating neurological condition, associated often with poor functional outcome and deficits in executive function. Due to the neuropathology of TBI, neuroimaging plays a crucial role in its assessment, and while diffusion MRI has been proposed as a sensitive biomarker, longitudinal studies evaluating treatment-related diffusion MRI changes are scarce. Recent evidence suggests that neurological music therapy can improve executive functions in patients with TBI and that these effects are underpinned by neuroplasticity changes in the brain. However, studies evaluating music therapy induced structural connectome changes in patients with TBI are lacking. DESIGN: Single-blind crossover (AB/BA) randomized controlled trial (NCT01956136). OBJECTIVE: Here, we report secondary outcomes of the trial and set out to assess the effect of neurological music therapy on structural white matter connectome changes and their association with improved execute function in patients with TBI. METHODS: Using an AB/BA design, 25 patients with moderate or severe TBI were randomized to receive a 3-month neurological music therapy intervention either during the first (AB, n = 16) or second (BA, n = 9) half of a 6-month follow-up period. Neuropsychological testing and diffusion MRI scans were performed at baseline and at the 3-month and 6-month stage. FINDINGS: Compared to the control group, the music therapy group increased quantitative anisotropy (QA) in the right dorsal pathways (arcuate fasciculus, superior longitudinal fasciculus) and in the corpus callosum and the right frontal aslant tract, thalamic radiation and corticostriatal tracts. The mean increased QA in this network of results correlated with improved executive function. CONCLUSIONS: This study shows that music therapy can induce structural white matter neuroplasticity in the post-TBI brain that underpins improved executive function.

Neuroanatomical correlates of speech and singing production in chronic post-stroke aphasia.

A classical observation in neurology is that aphasic stroke patients with impairments in speech production can nonetheless sing the same utterances. This preserved ability suggests a distinctive neural architecture for singing that could contribute to speech recovery. However, to date, these structural correlates remain unknown. Here, we combined a multivariate lesion-symptom mapping and voxel-based morphometry approach to analyse the relationship between lesion patterns and grey matter volume and production rate in speech and singing tasks. Lesion patterns for spontaneous speech and cued repetition extended into frontal, temporal and parietal areas typically reported within the speech production network. Impairment in spontaneous singing was associated with damage to the left anterior-posterior superior and middle temporal gyri. Preservation of grey matter volume in the same regions where damage led to poor speech and singing production supported better performance in these tasks. When dividing the patients into fluent and dysfluent singers based on the singing performance from demographically matched controls, we found that the preservation of the left middle temporal gyrus was related to better spontaneous singing. These findings provide insights into the structural correlates of singing in chronic aphasia and may serve as biomarkers to predict treatment response in clinical trials using singing-based interventions for speech rehabilitation.

Effects of neurological music therapy on behavioural and emotional recovery after traumatic brain injury: A randomized controlled cross-over trial.

Traumatic brain injury (TBI) causes deficits in executive function (EF), as well as problems in behavioural and emotional self-regulation. Neurological music therapy may aid these aspects of recovery. We performed a cross-over randomized controlled trial where 40 persons with moderate-severe TBI received a 3-month neurological music therapy intervention (2 times/week, 60 min/session), either during the first (AB, n = 20) or second (BA, n = 20) half of a 6-month follow-up period. The evidence from this RCT previously demonstrated that music therapy enhanced general EF and set shifting. In the current study, outcome was assessed with self-report and caregiver-report questionnaires performed at baseline, 3-month, 6-month, and 18-month stages. The results showed that the self-reported Behavioural Regulation Index of the Behaviour Rating Inventory of Executive Function (BRIEF-A) improved more in the AB than BA group from baseline to 3-month stage and the effect was maintained in the 6-month follow-up. No changes in mood or quality of life questionnaires were observed. However, a qualitative content analysis of the feedback revealed that many participants experienced the intervention as helpful in terms of emotional well-being and activity. Our results suggest that music therapy has a positive effect on everyday behavioural regulation skills after TBI.

Resting-State Network Plasticity Induced by Music Therapy after Traumatic Brain Injury.

Traumatic brain injury (TBI) is characterized by a complex pattern of abnormalities in resting-state functional connectivity (rsFC) and network dysfunction, which can potentially be ameliorated by rehabilitation. In our previous randomized controlled trial, we found that a 3-month neurological music therapy intervention enhanced executive function (EF) and increased grey matter volume in the right inferior frontal gyrus (IFG) in patients with moderate-to-severe TBI (N = 40). Extending this study, we performed longitudinal rsFC analyses of resting-state fMRI data using a ROI-to-ROI approach assessing within-network and between-network rsFC in the frontoparietal (FPN), dorsal attention (DAN), default mode (DMN), and salience (SAL) networks, which all have been associated with cognitive impairment after TBI. We also performed a seed-based connectivity analysis between the right IFG and whole-brain rsFC. The results showed that neurological music therapy increased the coupling between the FPN and DAN as well as between these networks and primary sensory networks. By contrast, the DMN was less connected with sensory networks after the intervention. Similarly, there was a shift towards a less connected state within the FPN and SAL networks, which are typically hyperconnected following TBI. Improvements in EF were correlated with rsFC within the FPN and between the DMN and sensorimotor networks. Finally, in the seed-based connectivity analysis, the right IFG showed increased rsFC with the right inferior parietal and left frontoparietal (Rolandic operculum) regions. Together, these results indicate that the rehabilitative effects of neurological music therapy after TBI are underpinned by a pattern of within- and between-network connectivity changes in cognitive networks as well as increased connectivity between frontal and parietal regions associated with music processing.

Vocal music enhances memory and language recovery after stroke: pooled results from two RCTs.

OBJECTIVE: Previous studies suggest that daily music listening can aid stroke recovery, but little is known about the stimulus-dependent and neural mechanisms driving this effect. Building on neuroimaging evidence that vocal music engages extensive and bilateral networks in the brain, we sought to determine if it would be more effective for enhancing cognitive and language recovery and neuroplasticity than instrumental music or speech after stroke. METHODS: Using data pooled from two single-blind randomized controlled trials in stroke patients (N = 83), we compared the effects of daily listening to self-selected vocal music, instrumental music, and audiobooks during the first 3 poststroke months. Outcome measures comprised neuropsychological tests of verbal memory (primary outcome), language, and attention and a mood questionnaire performed at acute, 3-month, and 6-month stages and structural and functional MRI at acute and 6-month stages. RESULTS: Listening to vocal music enhanced verbal memory recovery more than instrumental music or audiobooks and language recovery more than audiobooks, especially in aphasic patients. Voxel-based morphometry and resting-state and task-based fMRI results showed that vocal music listening selectively increased gray matter volume in left temporal areas and functional connectivity in the default mode network. INTERPRETATION: Vocal music listening is an effective and easily applicable tool to support cognitive recovery after stroke as well as to enhance early language recovery in aphasia. The rehabilitative effects of vocal music are driven by both structural and functional plasticity changes in temporoparietal networks crucial for emotional processing, language, and memory.

Music Therapy Enhances Executive Functions and Prefrontal Structural Neuroplasticity after Traumatic Brain Injury: Evidence from a Randomized Controlled Trial.

Traumatic brain injury (TBI) causes lifelong cognitive deficits, particularly impairments of executive functioning (EF). Musical training and music-based rehabilitation have been shown to enhance cognitive functioning and neuroplasticity, but the potential rehabilitative effects of music in TBI are still largely unknown. The aim of the present crossover randomized controlled trial (RCT) was to determine the clinical efficacy of music therapy on cognitive functioning in TBI and to explore its neural basis. Using an AB/BA design, 40 patients with moderate or severe TBI were randomized to receive a 3-month neurological music therapy intervention either during the first (AB, n = 20) or second (BA, n = 20) half of a 6-month follow-up period. Neuropsychological and motor testing and magnetic resonance imaging (MRI) were performed at baseline and at the 3-month and 6-month stage. Thirty-nine subjects who participated in baseline measurement were included in an intention-to-treat analysis using multiple imputation. Results showed that general EF (as indicated by the Frontal Assessment Battery [FAB]) and set shifting improved more in the AB group than in the BA group over the first 3-month period and the effect on general EF was maintained in the 6-month follow-up. Voxel-based morphometry (VBM) analysis of the structural MRI data indicated that gray matter volume (GMV) in the right inferior frontal gyrus (IFG) increased significantly in both groups during the intervention versus control period, which also correlated with cognitive improvement in set shifting. These findings suggest that neurological music therapy enhances EF and induces fine-grained neuroanatomical changes in prefrontal areas.

Clinical and Demographic Factors Associated with the Cognitive and Emotional Efficacy of Regular Musical Activities in Dementia.

Recent evidence suggests that music-based interventions can be beneficial in maintaining cognitive, emotional, and social functioning in persons with dementia (PWDs). Our aim was to determine how clinical, demographic, and musical background factors influence the cognitive and emotional efficacy of caregiver-implemented musical activities in PWDs. In a randomized controlled trial, 89 PWD-caregiver dyads received a 10-week music coaching intervention involving either singing or music listening or standard care. Extensive neuropsychological testing and mood and quality of life (QoL) measures were performed before and after the intervention (n = 84) and six months later (n = 74). The potential effects of six key background variables (dementia etiology and severity, age, care situation, singing/instrument playing background) on the outcome of the intervention were assessed. Singing was beneficial especially in improving working memory in PWDs with mild dementia and in maintaining executive function and orientation in younger PWDs. Music listening was beneficial in supporting general cognition, working memory, and QoL especially in PWDs with moderate dementia not caused by Alzheimer's disease (AD) who were in institutional care. Both music interventions alleviated depression especially in PWDs with mild dementia and AD. The musical background of the PWD did not influence the efficacy of the music interventions. Our findings suggest that clinical and demographic factors can influence the cognitive and emotional efficacy of caregiver-implemented musical activities and are, therefore, recommended to take into account when applying and developing the intervention to achieve the greatest benefit.

Structural changes induced by daily music listening in the recovering brain after middle cerebral artery stroke: a voxel-based morphometry study.

Music is a highly complex and versatile stimulus for the brain that engages many temporal, frontal, parietal, cerebellar, and subcortical areas involved in auditory, cognitive, emotional, and motor processing. Regular musical activities have been shown to effectively enhance the structure and function of many brain areas, making music a potential tool also in neurological rehabilitation. In our previous randomized controlled study, we found that listening to music on a daily basis can improve cognitive recovery and improve mood after an acute middle cerebral artery stroke. Extending this study, a voxel-based morphometry (VBM) analysis utilizing cost function masking was performed on the acute and 6-month post-stroke stage structural magnetic resonance imaging data of the patients (n = 49) who either listened to their favorite music [music group (MG), n = 16] or verbal material [audio book group (ABG), n = 18] or did not receive any listening material [control group (CG), n = 15] during the 6-month recovery period. Although all groups showed significant gray matter volume (GMV) increases from the acute to the 6-month stage, there was a specific network of frontal areas [left and right superior frontal gyrus (SFG), right medial SFG] and limbic areas [left ventral/subgenual anterior cingulate cortex (SACC) and right ventral striatum (VS)] in patients with left hemisphere damage in which the GMV increases were larger in the MG than in the ABG and in the CG. Moreover, the GM reorganization in the frontal areas correlated with enhanced recovery of verbal memory, focused attention, and language skills, whereas the GM reorganization in the SACC correlated with reduced negative mood. This study adds on previous results, showing that music listening after stroke not only enhances behavioral recovery, but also induces fine-grained neuroanatomical changes in the recovering brain.

Cognitive, emotional, and social benefits of regular musical activities in early dementia: randomized controlled study.

PURPOSE OF THE STUDY: During aging, musical activities can help maintain physical and mental health and cognitive abilities, but their rehabilitative use has not been systematically explored in persons with dementia (PWDs). Our aim was to determine the efficacy of a novel music intervention based on coaching the caregivers of PWDs to use either singing or music listening regularly as a part of everyday care. DESIGN AND METHODS: Eighty-nine PWD-caregiver dyads were randomized to a 10-week singing coaching group (n = 30), a 10-week music listening coaching group (n = 29), or a usual care control group (n = 30). The coaching sessions consisted primarily of singing/listening familiar songs coupled occasionally with vocal exercises and rhythmic movements (singing group) and reminiscence and discussions (music listening group). In addition, the intervention included regular musical exercises at home. All PWDs underwent an extensive neuropsychological assessment, which included cognitive tests, as well as mood and quality of life (QOL) scales, before and after the intervention period and 6 months later. In addition, the psychological well-being of family members was repeatedly assessed with questionnaires. RESULTS: Compared with usual care, both singing and music listening improved mood, orientation, and remote episodic memory and to a lesser extent, also attention and executive function and general cognition. Singing also enhanced short-term and working memory and caregiver well-being, whereas music listening had a positive effect on QOL. IMPLICATIONS: Regular musical leisure activities can have long-term cognitive, emotional, and social benefits in mild/moderate dementia and could therefore be utilized in dementia care and rehabilitation.

Music and speech listening enhance the recovery of early sensory processing after stroke.

Our surrounding auditory environment has a dramatic influence on the development of basic auditory and cognitive skills, but little is known about how it influences the recovery of these skills after neural damage. Here, we studied the long-term effects of daily music and speech listening on auditory sensory memory after middle cerebral artery (MCA) stroke. In the acute recovery phase, 60 patients who had middle cerebral artery stroke were randomly assigned to a music listening group, an audio book listening group, or a control group. Auditory sensory memory, as indexed by the magnetic MMN (MMNm) response to changes in sound frequency and duration, was measured 1 week (baseline), 3 months, and 6 months after the stroke with whole-head magnetoencephalography recordings. Fifty-four patients completed the study. Results showed that the amplitude of the frequency MMNm increased significantly more in both music and audio book groups than in the control group during the 6-month poststroke period. In contrast, the duration MMNm amplitude increased more in the audio book group than in the other groups. Moreover, changes in the frequency MMNm amplitude correlated significantly with the behavioral improvement of verbal memory and focused attention induced by music listening. These findings demonstrate that merely listening to music and speech after neural damage can induce long-term plastic changes in early sensory processing, which, in turn, may facilitate the recovery of higher cognitive functions. The neural mechanisms potentially underlying this effect are discussed.

Therapeutic role of music listening in stroke rehabilitation.

We performed two parallel interview studies of stroke patients (n= 20) and professional nurses (n= 5) to gain more insight into the therapeutic role of music listening in stroke rehabilitation. Results suggest that music listening can be used to relax, improve mood, and provide both physical and mental activation during the early stages of recovery from stroke. Thus, music listening could provide a useful clinical tool in stroke rehabilitation.

Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer.

Many studies have shown that primary prostate cancers are multifocal and are composed of multiple genetically distinct cancer cell clones. Whether or not multiclonal primary prostate cancers typically give rise to multiclonal or monoclonal prostate cancer metastases is largely unknown, although studies at single chromosomal loci are consistent with the latter case. Here we show through a high-resolution genome-wide single nucleotide polymorphism and copy number survey that most, if not all, metastatic prostate cancers have monoclonal origins and maintain a unique signature copy number pattern of the parent cancer cell while also accumulating a variable number of separate subclonally sustained changes. We find no relationship between anatomic site of metastasis and genomic copy number change pattern. Taken together with past animal and cytogenetic studies of metastasis and recent single-locus genetic data in prostate and other metastatic cancers, these data indicate that despite common genomic heterogeneity in primary cancers, most metastatic cancers arise from a single precursor cancer cell. This study establishes that genomic archeology of multiple anatomically separate metastatic cancers in individuals can be used to define the salient genomic features of a parent cancer clone of proven lethal metastatic phenotype.

Music listening enhances cognitive recovery and mood after middle cerebral artery stroke.

We know from animal studies that a stimulating and enriched environment can enhance recovery after stroke, but little is known about the effects of an enriched sound environment on recovery from neural damage in humans. In humans, music listening activates a wide-spread bilateral network of brain regions related to attention, semantic processing, memory, motor functions, and emotional processing. Music exposure also enhances emotional and cognitive functioning in healthy subjects and in various clinical patient groups. The potential role of music in neurological rehabilitation, however, has not been systematically investigated. This single-blind, randomized, and controlled trial was designed to determine whether everyday music listening can facilitate the recovery of cognitive functions and mood after stroke. In the acute recovery phase, 60 patients with a left or right hemisphere middle cerebral artery (MCA) stroke were randomly assigned to a music group, a language group, or a control group. During the following two months, the music and language groups listened daily to self-selected music or audio books, respectively, while the control group received no listening material. In addition, all patients received standard medical care and rehabilitation. All patients underwent an extensive neuropsychological assessment, which included a wide range of cognitive tests as well as mood and quality of life questionnaires, one week (baseline), 3 months, and 6 months after the stroke. Fifty-four patients completed the study. Results showed that recovery in the domains of verbal memory and focused attention improved significantly more in the music group than in the language and control groups. The music group also experienced less depressed and confused mood than the control group. These findings demonstrate for the first time that music listening during the early post-stroke stage can enhance cognitive recovery and prevent negative mood. The neural mechanisms potentially underlying these effects are discussed.

EZH2, Ki-67 and MCM7 are prognostic markers in prostatectomy treated patients.

The aim of the study was to evaluate the prognostic value of Ki-67, EZH2, MCM7 and EIF3S3 in prostatectomy treated patients. A retrospective population-based material of 249 radical prostatectomy specimens on tissue microarrays was utilized. The median follow-up of the patients was approximately 5.5 years and the main end-point was biochemical progression. The expression of Ki-67, EZH2 and MCM7 was determined by immunohistochemistry and the gene copy number of EIF3S3 was analyzed by fluorescence in situ hybridization (FISH). In the whole material, increased immunostainings of EZH2, MCM7 and Ki-67 were significantly associated with a high Gleason score and a short progression-free survival. In multivariate analysis, MCM7 and Ki-67 showed independent prognostic value with relative risks (RR) of 2.65 (95%-confidence interval of 1.22-5.70), and 1.85 (1.14-3.01), respectively. In subgroup analysis of patients, whose treatment was evaluated to be truly radical (n = 226), EZH2 (3.14, 1.38-7.16), MCM7 (2.70, 1.16-6.30) and PSA (1.5, 1.03-2.20) showed independent prognostic value. In subgroup analysis of cases with a Gleason score <7, low Ki-67 staining was associated with favorable prognosis with RR of 0.09 (0.01-0.69). In conclusion, Ki-67, EZH2 and MCM7 are potential prognostic biomarkers in prostatectomy treated patients.

Cellular changes in prostate cancer cells induced by intermittent androgen suppression.

OBJECTIVES: This study used tumour specimens from a clinical trial on intermittent androgen suppression (IAS) to study the effects of castration on tissue morphology, cell proliferation, apoptosis, and the expression of androgen receptor (AR). METHODS: A total of 113 representative needle biopsy specimens were available from 29 patients for evaluation of the Gleason score as well as Ki-67, cleaved caspase-3, and AR immunostaining. RESULTS: At 6 mo from the beginning of the first androgen withdrawal, cell proliferation activity was significantly (p = 0.002) reduced, whereas no effect on apoptosis was found. A nonsignificant trend to an increase in Gleason score after castration was found. Subsequent cycles of withdrawals had no significant effect on any of the measured parameters. The Gleason score, proliferation activity, and apoptosis rate showed only heterogeneous, nonsignificant changes after the first progression. Strong nuclear AR staining was evident in all cancer specimens. CONCLUSIONS: The findings suggest that the long-term (months) effect of androgen withdrawal on tumour growth is due to the inhibition of proliferation. Because the tumours seem to become resistant to castration at the first cycle of treatment withheld, it is possible that IAS does not postpone the emergence of ablation-resistant tumours. There was no consistent sign of increased proliferation or Gleason score during the treatment, suggesting that the biologic aggressiveness of a particular tumour is defined already at an early stage of disease. The constant nuclear expression of AR in cancer cells indicates that the AR signalling remains active despite of the androgen withdrawal.

Chromosomal aberrations in prostate cancer xenografts detected by comparative genomic hybridization.

A major problem in studying prostate cancer has been the lack of model systems because of the difficulties in growing prostate cancer cells in vitro. Recently, however, several human prostate cancer xenografts, grown in immune-deficient mice, have been established. Here, we characterized 13 such xenografts (LuCaP 23.8, 23.12, 35, 41, 49, 58, 69, 70, 73, LAPC-4AD, LAPC-4AI, LAPC-9AD, and LAPC-9AI) as well as one prostate cancer cell line (22Rv1) derived from a xenograft for chromosomal alterations by comparative genomic hybridization and a modification of multicolor fluorescence in situ hybridization. On average, the xenografts contained 13 (range 5-28) aberrations, 5 (1-13) gains, and 8 (1-15) losses, per case. The chromosome arms that most often contained losses were 2q, 5q, 6q, 8p, 13q, and 18q, and gains were 7q, 8q, and Xq. The same regions were previously shown to be often altered in advanced prostate carcinomas in patients. The androgen-dependent and corresponding androgen-independent sublines of LAPC-4 and LAPC-9 shared all genetic alterations, suggesting that the transition of the growth from androgen dependency to independence does not involve major chromosomal aberrations in these two models. In conclusion, the identified genetic aberrations lay the groundwork for further detailed genetic analyses of these xenografts.