Transcranial direct current stimulation as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder in Germany (DepressionDC): a triple-blind, randomised, sham-controlled, multicentre trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) has been proposed as a feasible treatment for major depressive disorder (MDD). However, meta-analytic evidence is heterogenous and data from multicentre trials are scarce. We aimed to assess the efficacy of tDCS versus sham stimulation as an additional treatment to a stable dose of selective serotonin reuptake inhibitors (SSRIs) in adults with MDD. METHODS: The DepressionDC trial was triple-blind, randomised, and sham-controlled and conducted at eight hospitals in Germany. Patients being treated at a participating hospital aged 18-65 years were eligible if they had a diagnosis of MDD, a score of at least 15 on the Hamilton Depression Rating Scale (21-item version), no response to at least one antidepressant trial in their current depressive episode, and treatment with an SSRI at a stable dose for at least 4 weeks before inclusion; the SSRI was continued at the same dose during stimulation. Patients were allocated (1:1) by fixed-blocked randomisation to receive either 30 min of 2 mA bifrontal tDCS every weekday for 4 weeks, then two tDCS sessions per week for 2 weeks, or sham stimulation at the same intervals. Randomisation was stratified by site and baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score (ie, <31 or ≥31). Participants, raters, and operators were masked to treatment assignment. The primary outcome was change on the MADRS at week 6, analysed in the intention-to-treat population. Safety was assessed in all patients who received at least one treatment session. The trial was registered with ClinicalTrials.gov (NCT02530164). FINDINGS: Between Jan 19, 2016, and June 15, 2020, 3601 individuals were assessed for eligibility. 160 patients were included and randomly assigned to receive either active tDCS (n=83) or sham tDCS (n=77). Six patients withdrew consent and four patients were found to have been wrongly included, so data from 150 patients were analysed (89 [59%] were female and 61 [41%] were male). No intergroup difference was found in mean improvement on the MADRS at week 6 between the active tDCS group (n=77; -8·2, SD 7·2) and the sham tDCS group (n=73; -8·0, 9·3; difference 0·3 [95% CI -2·4 to 2·9]). Significantly more participants had one or more mild adverse events in the active tDCS group (50 [60%] of 83) than in the sham tDCS group (33 [43%] of 77; p=0·028). INTERPRETATION: Active tDCS was not superior to sham stimulation during a 6-week period. Our trial does not support the efficacy of tDCS as an additional treatment to SSRIs in adults with MDD. FUNDING: German Federal Ministry of Education and Research.

Amantadine for NeuroenhaNcement in acutE patients Study - a protocol for a prospective pilot proof of concept phase IIb study in intensive and intermediate care unit patients (ANNES).

BACKGROUND: Persisting coma is a common complication in (neuro)intensive care in neurological disease such as acute ischemic stroke, intracerebral hemorrhage or subarachnoid hemorrhage. Amantadine acts as a nicotinic receptor antagonist, dopamine receptor agonist and non-competitive N-Methyl-D-aspartate receptor antagonist. Amantadine is a long-known drug, originally approved for treatment of influenza A and Parkinson`s Disease. It has been proven effective in improving vigilance after traumatic brain injury. The underlying mechanisms remain largely unknown, albeit anti-glutamatergic and dopaminergic effects might be most relevant. With limited evidence of amantadine efficacy in non-traumatic pathologies, the aim of our study is to assess the effects of amantadine for neuroenhancement in non-traumatic neurointensive patients with persisting coma. METHODS: An investigator-initiated, monocenter, phase IIb proof of concept open-label pilot study will be carried out. Based on the Simon design, 43 adult (neuro)intensive care patients who meet the clinical criteria of persisting coma not otherwise explained and < 8 points on the Glasgow Coma Scale (GCS) will be recruited. Amantadine will be administered intravenously for five days at a dosage of 100 mg bid. The primary endpoint is an improvement of at least 3 points on the GCS. If participants present as non-responders (increase < 3 points or decrease on the GCS) within the first 48 h, the dosage will be doubled from day three to five. Secondary objectives aim to demonstrate that amantadine improves vigilance via alternative scales. Furthermore, the incidence of adverse events will be investigated and electroencephalography (EEG) will be recorded at baseline and end of treatment. DISCUSSION: The results of our study will help to systematically assess the clinical utility of amantadine for treatment of persisting coma in non-traumatic brain injury. We expect that, in the face of only moderate treatment risk, a relevant number of patients will benefit from amantadine medication by improved vigilance (GCS increase of at least 3 points) finally leading to a better rehabilitation potential and improved functional neurological outcome. Further, the EEG data will allow evaluation of brain network states in relation to vigilance and potentially outcome prediction in this study cohort. TRIAL REGISTRATION: NCT05479032.

Delirium REduction after administration of melatonin in acute ischemic stroke (DREAMS): A propensity score-matched analysis.

BACKGROUND AND PURPOSE: Poststroke delirium (PSD) comprises a common and severe complication after stroke. However, treatment options for PSD remain insufficient. We investigated whether prophylactic melatonin supplementation may be associated with reduced risk for PSD. METHODS: Consecutive patients admitted to the Tübingen University Stroke Unit, Tübingen, Germany, with acute ischemic stroke (AIS), who underwent standard care between August 2017 and December 2017, and patients who additionally received prophylactic melatonin (2 mg per day at night) within 24 h of symptom onset between August 2018 and December 2018 were included. Primary outcomes were (i) PSD prevalence in AIS patients and (ii) PSD risk and PSD-free survival in patients with cerebral infarction who underwent melatonin supplementation compared to propensity score-matched (PSM) controls. Secondary outcomes included time of PSD onset and PSD duration. RESULTS: Out of 465 (81.2%) patients with cerebral infarction and 108 (18.8%) transient ischemic attack (TIA) patients, 152 (26.5%) developed PSD (median time to onset [IQR]: 16 [8-32] h; duration 24 [8-40] h). Higher age, cerebral infarction rather than TIA, and higher National Institutes of Health Stroke Scale score and aphasia on admission were significant predictors of PSD. After PSM (164 melatonin-treated patients with cerebral infarction versus 164 matched controls), 42 (25.6%) melatonin-treated patients developed PSD versus 60 (36.6%) controls (odds ratio, 0.597; 95% confidence interval, 0.372-0.958; p = 0.032). PSD-free survival differed significantly between groups (p = 0.027), favoring melatonin-treated patients. In patients with PSD, no between-group differences in the time of PSD onset and PSD duration were noted. CONCLUSIONS: Patients prophylactically treated with melatonin within 24 h of AIS onset had lower risk for PSD than patients undergoing standard care. Prospective randomized trials are warranted to corroborate these findings.

Treatment of major depressive disorder with bilateral theta burst stimulation: study protocol for a randomized, double-blind, placebo-controlled multicenter trial (TBS-D).

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (dlPFC) is currently evolving as an effective and safe therapeutic tool in the treatment of major depressive disorder (MDD). However, already established rTMS treatment paradigms are rather time-consuming. With theta burst stimulation (TBS), a patterned form of rTMS, treatment time can be substantially reduced. Pilot studies and a randomized controlled trial (RCT) demonstrate non-inferiority of TBS to 10 Hz rTMS and support a wider use in MDD. Still, data from placebo-controlled multicenter RCTs are lacking. In this placebo-controlled multicenter study, 236 patients with MDD will be randomized to either intermittent TBS (iTBS) to the left and continuous TBS (cTBS) to the right dlPFC or bilateral sham stimulation (1:1 ratio). The treatment will be performed with 80% resting motor threshold intensity over six consecutive weeks (30 sessions). The primary outcome is the treatment response rate (Montgomery-Asberg Depression Rating Scale reduction ≥ 50%). The aim of the study is to confirm the superiority of active bilateral TBS compared to placebo treatment. In two satellite studies, we intend to identify possible MRI-based and (epi-)genetic predictors of responsiveness to TBS therapy. Positive results will support the clinical use of bilateral TBS as an advantageous, efficient, and well-tolerated treatment and pave the way for further individualization of MDD therapy.Trial registration: ClinicalTrials.gov (NCT04392947).

Pattern of Cerebellar Atrophy in Friedreich's Ataxia-Using the SUIT Template.

Whole-brain voxel-based morphometry (VBM) studies revealed patterns of patchy atrophy within the cerebellum of Friedreich's ataxia patients, missing clear clinico-anatomic correlations. Studies so far are lacking an appropriate registration to the infratentorial space. To circumvent these limitations, we applied a high-resolution atlas template of the human cerebellum and brainstem (SUIT template) to characterize regional cerebellar atrophy in Friedreich's ataxia (FRDA) on 3-T MRI data. We used a spatially unbiased voxel-based morphometry approach together with T2-based manual segmentation, T2 histogram analysis, and atlas generation of the dentate nuclei in a representative cohort of 18 FRDA patients and matched healthy controls. We demonstrate that the cerebellar volume in FRDA is generally not significantly different from healthy controls but mild lobular atrophy develops beyond normal aging. The medial parts of lobule VI, housing the somatotopic representation of tongue and lips, are the major site of this lobular atrophy, which possibly reflects speech impairment. Extended white matter affection correlates with disease severity across and beyond the cerebellar inflow and outflow tracts. The dentate nucleus, as a major site of cerebellar degeneration, shows a mean volume loss of about 30%. Remarkably, not the atrophy but the T2 signal decrease of the dentate nuclei highly correlates with disease duration and severity.

Higher-Faster-Farther: Maximum Performance Tests in the Assessment of Neurogenic Speech Impairment.

BACKGROUND: Maximum performance tests are widely used in dysarthria assessment. From a theoretical perspective, the motor demands of such tasks differ from those of speaking. Therefore, their validity as measures of dysarthric impairment needs to be established empirically. PATIENTS AND METHODS: Maximum phonation time (MPT) and maximum syllable repetition rate (MRR) were compared with sentence reading/repetition tasks. In study 1, 130 patients with neurologic movement disorders and 130 healthy control participants were examined. Presence/severity of dysarthria was measured using psychometrically standardized auditory scales. In study 2, 16 healthy volunteers participated in an experiment designed to examine the intraspeaker variability of MPT, MRR, and sentence repetition across eight trials. RESULTS: Study 1: MPT made no reasonable contribution to the diagnosis of dysarthria or of any specific dimension of perceived speech impairment. MRR correlated with overall speech impairment but turned out to be an insensitive and highly unspecific statistical marker, afflicted with aetiology-specific errors. Study 2: compared with sentence repetition, both MPT and MRR demonstrated highly increased within-subject inconsistencies. CONCLUSION: The validity of MPT and MRR tasks as measures of dysarthria is still unsettled.

Treatment of auditory hallucinations with bilateral theta burst stimulation (cTBS): protocol of a randomized, double-blind, placebo-controlled, multicenter trial.

Auditory verbal hallucinations (AH) are core symptoms of schizophrenia. They are often severely distressing and refractory to therapy. Their perception is associated with increased activity in temporoparietal areas of the brain. Repetitive transcranial magnetic stimulation (rTMS) can reduce focal brain hyperactivity and has been shown to ameliorate AH. However, controlled multicenter clinical trials are still missing, effect sizes are moderate, and the treatment with rTMS is time consuming. Continuous theta burst stimulation (cTBS) is a quicker and potentially more effective technique to reduce cortical hyperactivity. First case and pilot studies indicate effectiveness in the treatment of AH. In this randomized, sham-controlled, double-blind multicenter clinical trial, 86 patients with schizophrenia spectrum disorder will be randomized to either cTBS or sham to the left and right temporoparietal cortex during three consecutive weeks (15 sessions totally). In each session, both hemispheres will be stimulated sequentially. The order in the first session (left-right or right-left, respectively) will be determined by randomization and alternated in all following sessions. Primary outcome is the reduction of mean PSYRATS-AH score after cTBS as compared to sham treatment. Follow-up measurements will be performed 1, 3 and 6 months after the end of the treatment. Statistical analysis will be based on the intention-to-treat population including all randomized patients using an analysis of covariance. This multicenter-controlled clinical trial will be able to provide decisive evidence for the efficacy of cTBS in the treatment of AH. The results will be suitable to clarify the role of this innovative, pathophysiology-based therapeutic approach in treatment guidelines for AH. TRIAL REGISTRY: ClinicalTrials.gov identifier: NCT02670291.

Friedreich ataxia: dysarthria profile and clinical data.

Friedreich ataxia (FRDA) is the most frequent recessive ataxia in the Western world. Dysarthria is a cardinal feature of FRDA, often leading to severe impairments in daily functioning, but its exact characteristics are only poorly understood so far. We performed a comprehensive evaluation of dysarthria severity and the profile of speech motor deficits in 20 patients with a genetic diagnosis of FRDA based on a carefully selected battery of speaking tasks and two widely used paraspeech tasks, i.e., oral diadochokinesis and sustained vowel productions. Perceptual ratings of the speech samples identified respiration, voice quality, voice instability, articulation, and tempo as the most affected speech dimensions. Whereas vocal instability predicted ataxia severity, tempo turned out as a significant correlate of disease duration. Furthermore, articulation predicted the overall intelligibility score as determined by a systematic speech pathology assessment tool. In contrast, neurologists' ratings of intelligibility--a component of the "Scale for the Assessment and Rating of Ataxia"--were found to be related to perceived speech tempo. Obviously, clinicians are more sensitive to slowness of speech than to any other feature of spoken language during dysarthria evaluation. Our results suggest that different components of speech production and trunk/limb motor functions are differentially susceptible to FRDA pathology. Furthermore, evidence emerged that paraspeech tasks do not allow for an adequate scaling of speech deficits in FRDA.

Speech and Nonspeech Parameters in the Clinical Assessment of Dysarthria: A Dimensional Analysis.

Nonspeech (or paraspeech) parameters are widely used in clinical assessment of speech impairment in persons with dysarthria (PWD). Virtually every standard clinical instrument used in dysarthria diagnostics includes nonspeech parameters, often in considerable numbers. While theoretical considerations have challenged the validity of these measures as markers of speech impairment, only a few studies have directly examined their relationship to speech parameters on a broader scale. This study was designed to investigate how nonspeech parameters commonly used in clinical dysarthria assessment relate to speech characteristics of dysarthria in individuals with movement disorders. Maximum syllable repetition rates, accuracies, and rates of isolated and repetitive nonspeech oral-facial movements and maximum phonation times were compared with auditory-perceptual and acoustic speech parameters. Overall, 23 diagnostic parameters were assessed in a sample of 130 patients with movement disorders of six etiologies. Each variable was standardized for its distribution and for age and sex effects in 130 neurotypical speakers. Exploratory Graph Analysis (EGA) and Confirmatory Factor Analysis (CFA) were used to examine the factor structure underlying the diagnostic parameters. In the first analysis, we tested the hypothesis that nonspeech parameters combine with speech parameters within diagnostic dimensions representing domain-general motor control principles. In a second analysis, we tested the more specific hypotheses that diagnostic parameters split along effector (lip vs. tongue) or functional (speed vs. accuracy) rather than task boundaries. Our findings contradict the view that nonspeech parameters currently used in dysarthria diagnostics are congruent with diagnostic measures of speech characteristics in PWD.

Complete and Incomplete Resection for Progressive Glioblastoma Prolongs Post-Progression Survival.

OBJECTIVE: The role of resection in progressive glioblastoma (GBM) to prolong survival is still controversial. The aim of this study was to determine 1) the predictors of post-progression survival (PPS) in progressive GBM and 2) which subgroups of patients would benefit from recurrent resection. METHODS: We have conducted a retrospective bicentric cohort study on isocitrate dehydrogenase (IDH) wild-type GBM treated in our hospitals between 2006 and 2015. Kaplan-Maier analyses and univariable and multivariable Cox regressions were performed to identify predictors and their influence on PPS. RESULTS: Of 589 patients with progressive IDH wild-type GBM, 355 patients were included in analyses. Median PPS of all patients was 9 months (95% CI 8.0-10.0), with complete resection 12 months (95% CI 9.7-14.3, n=81), incomplete resection 11 months (95% CI 8.9-13.1, n=70) and without resection 7 months (95% CI 06-08, n=204). Multivariable Cox regression demonstrated a benefit for PPS with complete (HR 0.67, CI 0.49-0.90) and incomplete resection (HR 0.73, 95% CI 0.51-1.04) and confirmed methylation of the O6-methylguanine-DNA-methyltransferase (MGMT) gene promoter, lower age at diagnosis, absence of deep brain and multilocular localization, higher Karnofsky Performance Status (KPS) and recurrent therapies to be associated with longer PPS. In contrast, traditional eloquence and duration of progression-free survival had no effect on PPS. Subgroup analyses showed that all subgroups of confirmed predictors benefited from resection, except for patients in poor condition with a KPS <70. CONCLUSIONS: Out data suggest a role for complete and incomplete recurrent resection in progressive GBM patients regardless of methylation of MGMT, age, or adjuvant therapy but not in patients with a poor clinical condition with a KPS <70.

The contribution of mesiofrontal cortex to the preparation and execution of repetitive syllable productions: an fMRI study.

Clinical data indicate that the brain network of speech motor control can be subdivided into at least three functional-neuroanatomical subsystems: (i) planning of movement sequences (premotor ventrolateral-frontal cortex and/or anterior insula), (ii) preparedness for/initiation of upcoming verbal utterances (supplementary motor area, SMA), and (iii) on-line innervation of vocal tract muscles, i.e., motor execution (corticobulbar system, basal ganglia, cerebellum). Using an event-related design, this functional magnetic resonance imaging (fMRI) study sought to further delineate the contribution of SMA to pre-articulatory processes of speech production (preceding the innervation of vocal tract muscles) during an acoustically paced syllable repetition task forewarned by a tone signal. Hemodynamic activation across the whole brain and the time courses of the responses in five regions of interest (ROIs) were computed. First, motor preparation was associated with a widespread bilateral activation pattern, encompassing brainstem structures, SMA, insula, premotor ventrolateral-frontal areas, primary sensorimotor cortex (SMC), basal ganglia, and the superior cerebellum. Second, calculation of the time courses of BOLD ("blood oxygenation level-dependent") signal changes revealed the warning stimulus to elicit synchronous onset of hemodynamic activation in these areas. However, during 4-s intervals of syllable repetitions SMA and cerebellum showed opposite temporal activation patterns in terms of a shorter (SMA) and longer (cerebellum) latency of the entire BOLD response-as compared to SMC, indicating different pacing mechanisms during the initial and the ongoing phase of the task. Nevertheless, the contribution of SMA was not exclusively restricted to the preparation/initiation of verbal responses since the extension of mesiofrontal activation varied with task duration.

Work-Related Determinants of Burnout in a Nationally Representative Sample of German Employees: Results From the Study on Mental Health at Work.

OBJECTIVE: The aim of the study was to present first representative data on burnout measured as exhaustion in German employees. METHODS: Data were taken from the Study on Mental Health at Work (n = 4058). Computer-assisted personal interviews were conducted in 2011 to 2012. Multiple linear regression models were estimated to investigate the association between work-related and personal variables and burnout. RESULTS: Severe burnout was detected in nearly 3% of employees. Job demands were associated with higher burnout scores, more resources with lower scores. Independent of personal factors, higher quantitative demands (men: regression coefficient [ß] = 0.19; 95% confidence interval [CI], 0.16 to 0.23; women: ß = 0.24; 95% CI, 0.20 to 0.27) was identified as the strongest predictor of burnout measured as exhaustion. The model explained 28% to 33% of the total variance. CONCLUSIONS: Quantitative demands seem to be important risk factors for burnout independent of critical life events and general self-efficacy.

Dissociating oral motor capabilities: Evidence from patients with movement disorders.

Abnormal articulation rate is a frequent symptom in neurogenic speech disorders. Performance rates in speech-like or nonspeech tasks involving the vocal motor apparatus are commonly accepted predictors of speech motor function in general and of articulation rate in particular. However, theoretical arguments and behavioral observations in populations with disordered speech indicate that different oral motor behaviors may be governed by distinct mechanisms. The objective of the present study was to expand our knowledge of the relationship between speech movements, on the one hand, and speech-like and nonspeech oral motor behaviors, on the other, by using a rate paradigm. 130 patients with neurological movement disorders of different origins and 130 neurologically healthy subjects participated in the study. Rate data was collected in a speech task (oral reading/repetition), in speech-like tasks (rapid syllable repetitions), and in nonspeech tasks (rapid single articulator movements of the tongue/lips). The main analyses involved a multiple single-case method, by which we tested for differences among each patient's performance rates on the three task types. The results disclosed statistically significant (classical and strong) dissociations between movement rates obtained from the speech task and those obtained from speech-like and nonspeech oral motor tasks in a number of patients. The findings can be interpreted as reflecting major differences in task demands and underlying control mechanisms. The validity of diagnostic indices for speech obtained from speech-like or nonspeech tasks must thus be called into question.

Oral Motor Abilities Are Task Dependent: A Factor Analytic Approach to Performance Rate.

Measures of performance rates in speech-like or volitional nonspeech oral motor tasks are frequently used to draw inferences about articulation rate abnormalities in patients with neurologic movement disorders. The study objective was to investigate the structural relationship between rate measures of speech and of oral motor behaviors different from speech. A total of 130 patients with neurologic movement disorders and 130 healthy subjects participated in the study. Rate data was collected for oral reading (speech), rapid syllable repetition (speech-like), and rapid single articulator movements (nonspeech). The authors used factor analysis to determine whether the different rate variables reflect the same or distinct constructs. The behavioral data were most appropriately captured by a measurement model in which the different task types loaded onto separate latent variables. The data on oral motor performance rates show that speech tasks and oral motor tasks such as rapid syllable repetition or repetitive single articulator movements measure separate traits.

An investigation into the influences of age, pathology and cognition on speech production.

Changes in speech rate have long been identified as a prominent sign of dysarthria. At the same time, such changes have been reported in the literature on normal ageing. This study aimed to provide information on the speech rate behaviour in the three participant groups, comprising speakers with Parkinson's Disease (PD), healthy age matched control speakers (CON), and an older non-dysarthric group with mild cognitive decline (DEM).The analysis revealed that the CON and PD group performed similarly for articulation rate whereas the DEM speakers spoke significantly more slowly. This relationship was reversed for pausing behaviour, where the DEM and CON groups performed similarly whilst the PD speakers produced a higher degree of pause time. All groups could change their articulation rate significantly from habitual to slow and fast conditions. However, the groups differed in the amount of change, with CON speakers showing the greatest and DEM the smallest amount of differences in articulation rate. The data did not identify clear performance predictors. However, there was a suggestion that the speakers' cognitive skills had an impact on their speech performance.

Comparing speech characteristics in spinocerebellar ataxias type 3 and type 6 with Friedreich ataxia.

Patterns of dysarthria in spinocerebellar ataxias (SCAs) and their discriminative features still remain elusive. Here we aimed to compare dysarthria profiles of patients with (SCA3 and SCA6 vs. Friedreich ataxia (FRDA), focussing on three particularly vulnerable speech parameters (speaking rate, prosodic modulation, and intelligibility) in ataxic dysarthria as well as on a specific oral non-speech variable of ataxic impairment, i.e., the irregularity of oral motor diadochokinesis (DDK). 30 Patients with SCA3, SCA6, and FRDA, matched for group size (n = 10 each), disease severity, and disease duration produced various speech samples and DDK tasks. A discriminant analysis was used to differentiate speech and non-speech parameters between groups. Regularity of DDK was specifically impaired in SCA3, whereas impairments of speech parameters, i.e., rate and modulation were stronger affected in SCA6. Speech parameters are particularly vulnerable in SCA6, while non-speech oral motor features are notably impaired in SCA3.

The effects of delayed and frequency shifted feedback on speakers with Parkinson's Disease.

Delayed auditory feedback (DAF) has been assessed as a rate reduction and intelligibility enhancing tool in patients with Parkinson's Disease (PD) for some time. However, there are contradictory results in the literature regarding the success of this device. Also, little is known about the effects of DAF on speech other than influences on speech rate and intelligibility. Frequency shifted feedback (FSF) is known to produce more natural sounding speech than DAF and to improve the fluency of persons who stutter. However, there are currently no studies reporting how PD speakers perform under FSF.The aim of this study was to investigate the effects of both types of altered feedback on the speech of PD and control participants on a broad range of measures. The performance of 16 PD speakers and 11 control speakers in a reading task under DAF, FSF and no altered feedback (NAF) are reported in this paper.The results showed that all groups responded to altered feedback in a similar way and showed a prominent reduction of speech rate. The conditions evoked changes in pause frequency (increases), loudness levels (increases), pitch variation (increases) and intelligibility and naturalness (decreases) for all or some of the groups. Few effects could be observed on articulation/pause time ratio, pause duration, pitch range, and speech rhythm. Previous reports on differences in susceptibility of PD speaker to altered feedback were confirmed and some speakers benefited from the system despite the negative group results for intelligibility and naturalness. In general, FSF resulted in performance closer to the NAF state than DAF on all variables, and for those PD speakers who benefited from altered feedback, the FSF condition evoked the greatest improvement.

Do we have a "mental syllabary" in the brain? An FMRI study.

The present study combines functional magnetic resonance imaging (fMRI) and reaction time (RT) measurements to further elucidate the influence of syllable frequency and complexity on speech motor control processes, i.e., overt reading of pseudowords. Tying in with a recent fMRI-study of our group we focused on the concept of a mental syllabary housing syllable sized ready-made motor plans for high- (HF), but not low-frequency (LF) syllables. The RT-analysis disclosed a frequency effect weakened by a simultaneous complexity effect for HF-syllables. In contrast, the fMRI data revealed no effect of syllable frequency, but point to an impact of syllable structure: Compared with CV-items, syllables with a complex onset (CCV) yielded higher hemodynamic activation in motor "execution" areas (left sensorimotor cortex, right inferior cerebellum), which is at least partially compatible with our previous study. We discuss the role of the syllable in speech motor control.

The influence of syllable onset complexity and syllable frequency on speech motor control.

Functional imaging studies have delineated a "minimal network for overt speech production", encompassing mesiofrontal structures (supplementary motor area, anterior cingulate gyrus), bilateral pre- and postcentral convolutions, extending rostrally into posterior parts of the inferior frontal gyrus (IFG) of the language-dominant hemisphere, left anterior insula as well as bilateral components of the basal ganglia, the cerebellum, and the thalamus. In order to further elucidate the specific contribution of these cerebral regions to speech motor planning, subjects were asked to read aloud visually presented bisyllabic pseudowords during functional magnetic resonance imaging (fMRI). The test stimuli systematically varied in onset complexity (CCV versus CV) and frequency of occurrence (high-frequency, HF versus low-frequency, LF) of the initial syllable. A cognitive subtraction approach revealed a significant main effect of syllable onset complexity (CCV versus CV) at the level of left posterior IFG, left anterior insula, and both cerebellar hemispheres. Conceivably, these areas closely cooperate in the sequencing of subsyllabic aspects of the sound structure of verbal utterances. A significant main effect of syllable frequency (LF versus HF), by contrast, did not emerge. However, calculation of the time series of hemodynamic activation within the various cerebral structures engaged in speech motor control revealed this factor to enhance functional connectivity between Broca's area and ipsilateral anterior insula.

Cognitive Impairment in Parkinson's Disease: Is It a Unified Phenomenon?

Parkinson's disease (PD) has long been associated with dementia. This has been found to correlate with participant age, age at onset of PD and severity of PD. In addition, a large corpus of research points to the fact that participants with, as well as without, dementia can be impaired in a variety of cognitive tasks. Among these, set-shifting and dual-tasking skills have received particular focus. Most studies report that a reduction in attentional resources can lead to problems with these tasks. However, none have been able to determine exactly which systems are involved in these skills and which neurological impairments underlie the observed cognitive deficits. The current study set out to investigate how performance on tasks requiring set-shifting and dual tasking related to each other, as well as overall measures of cognition gained across a variety of tasks. Fifteen participants with PD and 12 control participants underwent screening tests for dementia, as well as specific tests to assess attention, set-shifting and dual tasking. The results indicate that set-shifting ability correlated well with other measures of cognitive performance, whereas dual-tasking skills did not. This could suggest that set-shifting and dual tasking are not necessarily controlled by the same process, or that a particular process is involved to different degrees. In addition, many participants showed individual performance variations and dissociations between tasks that were not necessarily evident from the statistical analysis. This indicates that it can be difficult to make assumptions on overall cognitive performance from specific tasks and vice versa. This observation has implications for clinical practice as well as research methodology.