Effects of transcranial direct current stimulation on neural activity and functional connectivity during fear extinction.

Background/Objective: Anxiety disorders are highly prevalent and negatively impact daily functioning and quality of life. Transcranial direct current stimulation (tDCS) targeting the dorsolateral prefrontal cortex (dlPFC), especially in the right hemisphere impacts extinction learning; however, the underlying neural mechanisms are elusive. Therefore, we aimed to investigate the effects of cathodal tDCS stimulation to the right dlPFC on neural activity and connectivity patterns during delayed fear extinction in healthy participants. Methods: We conducted a two-day fear conditioning and extinction procedure. On the first day, we collected fear-related self-reports, clinical questionnaires, and skin conductance responses during fear acquisition. On the second day, participants in the tDCS group (n = 16) received 20-min offline tDCS before fMRI and then completed the fear extinction session during fMRI. Participants in the control group (n = 18) skipped tDCS and directly underwent fMRI to complete the fear extinction procedure. Whole-brain searchlight classification and resting-state functional connectivity analyses were performed. Results: Whole-brain searchlight classification during fear extinction showed higher classification accuracy of threat and safe cues in the left anterior dorsal and ventral insulae and hippocampus in the tDCS group than in the control group. Functional connectivity derived from the insula with the dlPFC, ventromedial prefrontal cortex, and inferior parietal lobule was increased after tDCS. Conclusion: tDCS over the right dlPFC may function as a primer for information exchange among distally connected areas, thereby increasing stimulus discrimination. The current study did not include a sham group, and one participant of the control group was not randomized. Therefore, to address potential allocation bias, findings should be confirmed in the future with a fully randomized and sham controlled study.

Multi-band whole-body diffusion-weighted imaging with inversion recovery fat saturation: Effects of respiratory compensation.

PURPOSE: To prospectively compare artefacts and image quality in testicular stage I cancer patients using different combinations of breathing schemes and Multi-band (MB) in whole-body DWIBS at 1.5 T.Diffusion-Weighted whole-body Imaging with Background body signal Suppression (DWIBS) using inversion recovery (IR) fat saturation is a cornerstone in oncologic whole-body MRI, but implementation is restrained by long acquisition times. The new Multi-Band (MB) technique reduces scan time which can be reinvested in respiratory compensation. METHODS: Thirty testicular cancer stage I patients were included. Three variations of whole-body DWIBS were tested: Standard free Breathing (FB)-DWIBS, FB-MB-DWIBS and Respiratory triggered (RT)-MB-DWIBS. Artefacts and image quality of b = 800 s/mm2 images were evaluated using a Likert scale. No pathology was revealed. SNR was calculated in a healthy volunteer. RESULTS: RT-MB-DWIBS was rated significantly better than FB-DWIBS in the thorax (p < 0.001) and abdomen (p < 0.001), but not in the pelvis (p = 0.569). FB-MB-DWIBS was ranked significantly lower than both FB-DWIBS (p < 0.001) and RT-MB-DWIBS (p < 0.001) at all locations. However, FB-MB-DWIBS was scanned in half the time without being less than "satisfactory". Few artefacts were encountered. SNR was similar for low-intensity tissues, but the SNR in high-intensity and respiratory-prone tissue (spleen) was slightly lower for FB-DWIBS than the other sequences. CONCLUSION: Images produced by the sequences were similar. MB enables the use of respiratory trigger or can be used to produce very fast free-breathing DWI with acceptable image quality.

New acquisition techniques and their prospects for the achievable resolution of fMRI.

This work reviews recent advances in technologies for functional magnetic resonance imaging (fMRI) of the human brain and highlights the push for higher functional specificity based on increased spatial resolution and specific MR contrasts to reveal previously undetectable functional properties of small-scale cortical structures. We discuss how the combination of MR hardware, advanced acquisition techniques and various MR contrast mechanisms have enabled recent progress in functional neuroimaging. However, these advanced fMRI practices have only been applied to a handful of neuroscience questions to date, with the majority of the neuroscience community still using conventional imaging techniques. We thus discuss upcoming challenges and possibilities for fMRI technology development in human neuroscience. We hope that readers interested in functional brain imaging acquire an understanding of current and novel developments and potential future applications, even if they don't have a background in MR physics or engineering. We summarize the capabilities of standard fMRI acquisition schemes with pointers to relevant literature and comprehensive reviews and introduce more recent developments.

Beware (Surprisingly Common) Left-Right Flips in Your MRI Data: An Efficient and Robust Method to Check MRI Dataset Consistency Using AFNI.

Knowing the difference between left and right is generally assumed throughout the brain MRI research community. However, we note widespread occurrences of left-right orientation errors in MRI open database repositories where volumes have contained systematic left-right flips between subject EPIs and anatomicals, due to having incorrect or missing file header information. Here we present a simple method in AFNI for determining the consistency of left and right within a pair of acquired volumes for a particular subject; the presence of EPI-anatomical inconsistency, for example, is a sign that dataset header information likely requires correction. The method contains both a quantitative evaluation as well as a visualizable verification. We test the functionality using publicly available datasets. Left-right flipping is not immediately obvious in most cases, so we also present visualization methods for looking at this problem (and other potential problems), using examples from both FMRI and DTI datasets.

Impact of gender and genetics on emotion processing in Parkinson's disease - A multimodal study.

•Understanding of the phenotypic heterogeneity of Parkinson's disease is needed.•Gender and genetics determine manifestation and progression of Parkinson's disease.•Altered emotion processing in Parkinson's disease is specific to male patients.•This is influenced by endocrinal and genetic factors in both genders.•This finding may impact the diagnosis and treatment of emerging clinical features.

Anatomic & metabolic brain markers of the m.3243A>G mutation: A multi-parametric 7T MRI study.

One of the most common mitochondrial DNA (mtDNA) mutations, the A to G transition at base pair 3243, has been linked to changes in the brain, in addition to commonly observed hearing problems, diabetes and myopathy. However, a detailed quantitative description of m.3243A>G patients' brains has not been provided so far. In this study, ultra-high field MRI at 7T and volume- and surface-based data analyses approaches were used to highlight morphology (i.e. atrophy)-, microstructure (i.e. myelin and iron concentration)- and metabolism (i.e. cerebral blood flow)-related differences between patients (N = 22) and healthy controls (N = 15). The use of quantitative MRI at 7T allowed us to detect subtle changes of biophysical processes in the brain with high accuracy and sensitivity, in addition to typically assessed lesions and atrophy. Furthermore, the effect of m.3243A>G mutation load in blood and urine epithelial cells on these MRI measures was assessed within the patient population and revealed that blood levels were most indicative of the brain's state and disease severity, based on MRI as well as on neuropsychological data. Morphometry MRI data showed a wide-spread reduction of cortical, subcortical and cerebellar gray matter volume, in addition to significantly enlarged ventricles. Moreover, surface-based analyses revealed brain area-specific changes in cortical thickness (e.g. of the auditory cortex), and in T1, T2* and cerebral blood flow as a function of mutation load, which can be linked to typically m.3243A>G-related clinical symptoms (e.g. hearing impairment). In addition, several regions linked to attentional control (e.g. middle frontal gyrus), the sensorimotor network (e.g. banks of central sulcus) and the default mode network (e.g. precuneus) were characterized by alterations in cortical thickness, T1, T2* and/or cerebral blood flow, which has not been described in previous MRI studies. Finally, several hypotheses, based either on vascular, metabolic or astroglial implications of the m.3243A>G mutation, are discussed that potentially explain the underlying pathobiology. To conclude, this is the first 7T and also the largest MRI study on this patient population that provides macroscopic brain correlates of the m.3243A>G mutation indicating potential MRI biomarkers of mitochondrial diseases and might guide future (longitudinal) studies to extensively track neuropathological and clinical changes.

Disruption to functional networks in neonates with perinatal brain injury predicts motor skills at 8 months.

Objective: Functional connectivity magnetic resonance imaging (fcMRI) of neonates with perinatal brain injury could improve prediction of motor impairment before symptoms manifest, and establish how early brain organization relates to subsequent development. This cohort study is the first to describe and quantitatively assess functional brain networks and their relation to later motor skills in neonates with a diverse range of perinatal brain injuries. Methods: Infants (n = 65, included in final analyses: n = 53) were recruited from the neonatal intensive care unit (NICU) and were stratified based on their age at birth (premature vs. term), and on whether neuropathology was diagnosed from structural MRI. Functional brain networks and a measure of disruption to functional connectivity were obtained from 14 min of fcMRI acquired during natural sleep at term-equivalent age. Results: Disruption to connectivity of the somatomotor and frontoparietal executive networks predicted motor impairment at 4 and 8 months. This disruption in functional connectivity was not found to be driven by differences between clinical groups, or by any of the specific measures we captured to describe the clinical course. Conclusion: fcMRI was predictive over and above other clinical measures available at discharge from the NICU, including structural MRI. Motor learning was affected by disruption to somatomotor networks, but also frontoparietal executive networks, which supports the functional importance of these networks in early development. Disruption to these two networks might be best addressed by distinct intervention strategies.

Impaired emotion processing in functional (psychogenic) tremor: A functional magnetic resonance imaging study.

BACKGROUND: Despite its high prevalence and associated disability, the neural correlates of emotion processing in patients with functional (psychogenic) tremor (FT), the most common functional movement disorder, remain poorly understood. METHODS: In this cross sectional functional magnetic resonance imaging (fMRI) study at 4T, 27 subjects with FT, 16 with essential tremor (ET), and 25 healthy controls (HCs) underwent a finger-tapping motor task, a basic-emotion task, and an intense-emotion task to probe motor and emotion circuitries. Anatomical and functional MRI data were processed with FSL (FMRIB Software Library) and AFNI (Analysis of Functional Neuroimages), followed by seed-to-seed connectivity analyses using anatomical regions defined from the Harvard-Oxford subcortical atlas; all analyses were corrected for multiple comparisons. RESULTS: After controlling for depression scores and correcting for multiple comparisons, the FT group showed increased activation in the right cerebellum compared to ET during the motor task; and increased activation in the paracingulate gyrus and left Heschl's gyrus compared with HC with decreased activation in the right precentral gyrus compared with ET during the basic-emotion task. No significant differences were found after adjusting for multiple comparisons during the intense-emotion task but increase in connectivity between the left amygdala and left middle frontal gyrus survived corrections in the FT subjects during this task, compared to HC. CONCLUSIONS: In response to emotional stimuli, functional tremor is associated with alterations in activation and functional connectivity in networks involved in emotion processing and theory of mind. These findings may be relevant to the pathophysiology of functional movement disorders.

5-Year imaging sequelae of concussive blast injury and relation to early clinical outcome.

Current imaging diagnostic techniques are often insensitive to the underlying pathological changes following mild traumatic brain injury (TBI) or concussion so much so that the explicit definition of these uncomplicated mild brain injuries includes the absence of radiological findings. In the US military, this is complicated by the natural tendency of service members to down play symptoms for fear of removal from their unit particularly in combat making it challenging for clinicians to definitively diagnose and determine course of treatment. Questions remain regarding the long-term impact of these war-time brain injuries. The objective of the current study was to evaluate the long-term imaging sequelae of blast concussion in active-duty US military and leverage previous longitudinal data collected in these same patients to identify predictors of sustained DTI signal change indicative of chronic neurodegeneration. In total, 50 blast TBI and 44 combat-deployed controls were evaluated at this 5-year follow up by advanced neuroimaging techniques including diffusion tensor imaging and quantitative volumetry. While cross-sectional analysis of regions of white matter on DTI images did not reveal significant differences across groups after statistical correction, an approach flexible to the heterogeneity of brain injury at the single-subject level identified 74% of the concussive blast TBI cohort to have reductions in fractional anisotropy indicative of chronic brain injury. Logistic regression leveraging clinical and demographic data collected in the acute/sub-acute and 1-year follow up to determine predictors of these long-term imaging changes determined that brain injury diagnosis, older age, verbal memory and verbal fluency best predicted the presence of DTI abnormalities 5 years post injury with an AUC of 0.78 indicating good prediction strength. These results provide supporting evidence for the evolution not resolution of this brain injury pathology, adding to the growing body of literature describing imaging signatures of chronic neurodegeneration even after mild TBI and concussion.

Differential involvement of corticospinal tract (CST) fibers in UMN-predominant ALS patients with or without CST hyperintensity: A diffusion tensor tractography study.

Diagnosis of amyotrophic lateral sclerosis (ALS) depends on clinical evidence of combined upper motor neuron (UMN) and lower motor neuron (LMN) degeneration, although ALS patients can present with features predominantly of one or the other. Some UMN-predominant patients show hyperintense signal along the intracranial corticospinal tract (CST) on T2- and proton density (PD)-weighted images (ALS-CST +), and appear to have faster disease progression when compared to those without CST hyperintensity (ALS-CST -). The reason for this is unknown. We hypothesized that diffusion tensor tractography (DTT) would reveal differences in DTI abnormalities along the intracranial CST between these two patient subgroups. Clinical DTI scans were obtained at 1.5T in 14 neurologic controls and 45 ALS patients categorized into two UMN phenotypes based on clinical measures and MRI. DTT was used to quantitatively assess the CST in control and ALS groups. DTT revealed subcortical loss ('truncation') of virtual motor CST fibers (presumably) projecting from the precentral gyrus (PrG) in ALS patients but not in controls; in contrast, virtual fibers (presumably) projecting to the adjacent postcentral gyrus (PoG) were spared. No significant differences in virtual CST fiber length were observed between controls and ALS patients. However, the frequency of CST truncation was significantly higher in the ALS-CST + subgroup (9 of 21) than in the ALS-CST - subgroup (4 of 24; p = 0.049), suggesting this finding could differentiate these ALS subgroups. Also, because virtual CST truncation occurred only in the ALS patient group and not in the control group (p = 0.018), this DTT finding could prove to be a diagnostic biomarker of ALS. Significantly shorter disease duration and faster disease progression rate were observed in ALS patients with CST fiber truncation than in those without (p < 0.05). DTI metrics of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were also determined in four regions of interest (ROIs) along the CST, namely: cerebral peduncle (CP), posterior limb of internal capsule (PLIC), centrum semiovale at top of lateral ventricle (CSoLV) and subcortical to primary motor cortex (subPMC). Of note, FA values along the left hemisphere virtual CST tract were significantly different between controls and ALS-CST + patients (p < 0.05) only at the PLIC level, but not at the CSoLV or subPMC level. Also, no significant differences in FA values were observed between ALS subgroups or between control and ALS-CST - groups (p > 0.05) in any of the ROIs. In addition, comparing FA values between ALS patients with CST truncation and those without in the aforementioned four ROIs, revealed no significant differences in either hemisphere. However, visual evaluation of DTT was able to identify UMN degeneration in patients with ALS, particularly in those with a more aggressive clinical disease course and possibly different pathologic processes.

Perfusion magnetic resonance imaging provides additional information as compared to anatomical imaging for decision-making in vestibular schwannoma.

OBJECTIVE: The added value of perfusion MRI for decision-making in vestibular schwannoma (VS) patients is unknown. MRI offers two perfusion methods: the first employing contrast agent (dynamic susceptibility contrast (DSC)-MRI) that provides information on cerebral blood volume (CBV) and cerebral blood flow (CBF), the second by magnetic labeling of blood (arterial spin labeling (ASL)-MRI), providing CBF-images. The goal of the current study is to investigate whether DSC and ASL perfusion MRI provides complimentary information to current anatomical imaging in treatment selection process of VS. METHODS: Nine patients with growing VS with extrameatal diameter >9 mm were included (>2 mm/year and 20% volume expansion/year) and one patient with 23 mm extrameatal VS without growth. DSC and ASL perfusion MRI were obtained on 3 T MRI. Perfusion in VS was scored as hyperintense, hypointense or isointense compared to the contralateral region. RESULTS: Seven patients showed hyperintense signal on DSC and ASL sequences. Three patients showed iso- or hypointense signal on at least one perfusion map (1 patient hypointense on both DSC-MRI and ASL; 1 patient isointense on DSC-CBF; 1 patient isointense on ASL). All patients showed enhancement on post-contrast T1 anatomical scan. CONCLUSION: Perfusion MR provides additional information compared to anatomical imaging for decision-making in VS.

Diffuse alterations in grey and white matter associated with cognitive impairment in Shwachman-Diamond syndrome: evidence from a multimodal approach.

Shwachman-Diamond syndrome is a rare recessive genetic disease caused by mutations in SBDS gene, at chromosome 7q11. Phenotypically, the syndrome is characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal dysplasia and variable cognitive impairments. Structural brain abnormalities (smaller head circumference and decreased brain volume) have also been reported. No correlation studies between brain abnormalities and neuropsychological features have yet been performed. In this study we investigate neuroanatomical findings, neurofunctional pathways and cognitive functioning of Shwachman-Diamond syndrome subjects compared with healthy controls. To be eligible for inclusion, participants were required to have known SBDS mutations on both alleles, no history of cranial trauma or any standard contraindication to magnetic resonance imaging. Appropriate tests were used to assess cognitive functions. The static images were acquired on a 3 × 0 T magnetic resonance scanner and blood oxygen level-dependent functional magnetic resonance imaging data were collected both during the execution of the Stroop task and at rest. Diffusion tensor imaging was used to assess brain white matter. The Tract-based Spatial Statistics package and probabilistic tractography were used to characterize white matter pathways. Nine participants (5 males), half of all the subjects aged 9-19 years included in the Italian Shwachman-Diamond Syndrome Registry, were evaluated and compared with nine healthy subjects, matched for sex and age. The patients performed less well than norms and controls on cognitive tasks (p = 0.0002). Overall, cortical thickness was greater in the patients, both in the left (+10%) and in the right (+15%) hemisphere, significantly differently increased in the temporal (left and right, p = 0.04), and right parietal (p = 0.03) lobes and in Brodmann area 44 (p = 0.04) of the right frontal lobe. The greatest increases were observed in the left limbic-anterior cingulate cortex (≥43%, p < 0.0004). Only in Broca's area in the left hemisphere did the patients show a thinner cortical thickness than that of controls (p = 0.01). Diffusion tensor imaging showed large, significant difference increases in both fractional anisotropy (+37%, p < 0.0001) and mean diffusivity (+35%, p < 0.005); the Tract-based Spatial Statistics analysis identified six abnormal clusters of white matter fibres in the fronto-callosal, right fronto-external capsulae, left fronto-parietal, right pontine, temporo-mesial and left anterior-medial-temporal regions. Brain areas activated during the Stroop task and those active during the resting state, are different, fewer and smaller in patients and correlate with worse performance (p = 0.002). Cognitive impairment in Shwachman-Diamond syndrome subjects is associated with diffuse brain anomalies in the grey matter (verbal skills with BA44 and BA20 in the right hemisphere; perceptual skills with BA5, 37, 20, 21, 42 in the left hemisphere) and white matter connectivity (verbal skills with alterations in the fronto-occipital fasciculus and with the inferior-longitudinal fasciculus; perceptual skills with the arcuate fasciculus, limbic and ponto-cerebellar fasciculus; memory skills with the arcuate fasciculus; executive functions with the anterior cingulated and arcuate fasciculus).

Mathematical models for the diffusion magnetic resonance signal abnormality in patients with prion diseases.

In clinical practice signal hyperintensity in the cortex and/or in the striatum on magnetic resonance (MR) diffusion-weighted images (DWIs) is a marker of sporadic Creutzfeldt-Jakob Disease (sCJD). MR diagnostic accuracy is greater than 90%, but the biophysical mechanisms underpinning the signal abnormality are unknown. The aim of this prospective study is to combine an advanced DWI protocol with new mathematical models of the microstructural changes occurring in prion disease patients to investigate the cause of MR signal alterations. This underpins the later development of more sensitive and specific image-based biomarkers. DWI data with a wide a range of echo times and diffusion weightings were acquired in 15 patients with suspected diagnosis of prion disease and in 4 healthy age-matched subjects. Clinical diagnosis of sCJD was made in nine patients, genetic CJD in one, rapidly progressive encephalopathy in three, and Gerstmann-Sträussler-Scheinker syndrome in two. Data were analysed with two bi-compartment models that represent different hypotheses about the histopathological alterations responsible for the DWI signal hyperintensity. A ROI-based analysis was performed in 13 grey matter areas located in affected and apparently unaffected regions from patients and healthy subjects. We provide for the first time non-invasive estimate of the restricted compartment radius, designed to reflect vacuole size, which is a key discriminator of sCJD subtypes. The estimated vacuole size in DWI hyperintense cortex was in the range between 3 and 10 µm that is compatible with neuropathology measurements. In DWI hyperintense grey matter of sCJD patients the two bi-compartment models outperform the classic mono-exponential ADC model. Both new models show that T2 relaxation times significantly increase, fast and slow diffusivities reduce, and the fraction of the compartment with slow/restricted diffusion increases compared to unaffected grey matter of patients and healthy subjects. Analysis of the raw DWI signal allows us to suggest the following acquisition parameters for optimized detection of CJD lesions: b = 3000 s/mm(2) and TE = 103 ms. In conclusion, these results provide the first in vivo estimate of mean vacuole size, new insight on the mechanisms of DWI signal changes in prionopathies and open the way to designing an optimized acquisition protocol to improve early clinical diagnosis and subtyping of sCJD.

Cerebro-cerebellar connectivity is increased in primary lateral sclerosis.

Increased functional connectivity in resting state networks was found in several studies of patients with motor neuron disorders, although diffusion tensor imaging studies consistently show loss of white matter integrity. To understand the relationship between structural connectivity and functional connectivity, we examined the structural connections between regions with altered functional connectivity in patients with primary lateral sclerosis (PLS), a long-lived motor neuron disease. Connectivity matrices were constructed from resting state fMRI in 16 PLS patients to identify areas of differing connectivity between patients and healthy controls. Probabilistic fiber tracking was used to examine structural connections between regions of differing connectivity. PLS patients had 12 regions with increased functional connectivity compared to controls, with a predominance of cerebro-cerebellar connections. Increased functional connectivity was strongest between the cerebellum and cortical motor areas and between the cerebellum and frontal and temporal cortex. Fiber tracking detected no difference in connections between regions with increased functional connectivity. We conclude that functional connectivity changes are not strongly based in structural connectivity. Increased functional connectivity may be caused by common inputs, or by reduced selectivity of cortical activation, which could result from loss of intracortical inhibition when cortical afferents are intact.

Arterial spin labelling reveals prolonged arterial arrival time in idiopathic Parkinson's disease.

Idiopathic Parkinson's disease (IPD) is the second most common neurodegenerative disease, yet effective disease modifying treatments are still lacking. Neurodegeneration involves multiple interacting pathological pathways. The extent to which neurovascular mechanisms are involved is not well defined in IPD. We aimed to determine whether novel magnetic resonance imaging (MRI) techniques, including arterial spin labelling (ASL) quantification of cerebral perfusion, can reveal altered neurovascular status (NVS) in IPD. Fourteen participants with IPD (mean ± SD age 65.1 ± 5.9 years) and 14 age and cardiovascular risk factor matched control participants (mean ± SD age 64.6 ± 4.2 years) underwent a 3T MRI scan protocol. ASL images were collected before, during and after a 6 minute hypercapnic challenge. FLAIR images were used to determine white matter lesion score. Quantitative images of cerebral blood flow (CBF) and arterial arrival time (AAT) were calculated from the ASL data both at rest and during hypercapnia. Cerebrovascular reactivity (CVR) images were calculated, depicting the change in CBF and AAT relative to the change in end-tidal CO2. A significant (p = 0.005) increase in whole brain averaged baseline AAT was observed in IPD participants (mean ± SD age 1532 ± 138 ms) compared to controls (mean ± SD age 1335 ± 165 ms). Voxel-wise analysis revealed this to be widespread across the brain. However, there were no statistically significant differences in white matter lesion score, CBF, or CVR between patients and controls. Regional CBF, but not AAT, in the IPD group was found to correlate positively with Montreal cognitive assessment (MoCA) scores. These findings provide further evidence of alterations in NVS in IPD.

Pathomechanisms and compensatory efforts related to Parkinsonian speech.

Voice and speech in Parkinson's disease (PD) patients are classically affected by a hypophonia, dysprosody, and dysarthria. The underlying pathomechanisms of these disabling symptoms are not well understood. To identify functional anomalies related to pathophysiology and compensation we compared speech-related brain activity and effective connectivity in early PD patients who did not yet develop voice or speech symptoms and matched controls. During fMRI 20 PD patients ON and OFF levodopa and 20 control participants read 75 sentences covertly, overtly with neutral, or with happy intonation. A cue-target reading paradigm allowed for dissociating task preparation from execution. We found pathologically reduced striato-prefrontal preparatory effective connectivity in early PD patients associated with subcortical (OFF state) or cortical (ON state) compensatory networks. While speaking, PD patients showed signs of diminished monitoring of external auditory feedback. During generation of affective prosody, a reduced functional coupling between the ventral and dorsal striatum was observed. Our results suggest three pathomechanisms affecting speech in PD: While diminished energization on the basis of striato-prefrontal hypo-connectivity together with dysfunctional self-monitoring mechanisms could underlie hypophonia, dysarthria may result from fading speech motor representations given that they are not sufficiently well updated by external auditory feedback. A pathological interplay between the limbic and sensorimotor striatum could interfere with affective modulation of speech routines, which affects emotional prosody generation. However, early PD patients show compensatory mechanisms that could help improve future speech therapies.

Diffusion tensor imaging of nigral degeneration in Parkinson's disease: A region-of-interest and voxel-based study at 3 T and systematic review with meta-analysis.

There is increasing interest in developing a reliable, affordable and accessible disease biomarker of Parkinson's disease (PD) to facilitate disease modifying PD-trials. Imaging biomarkers using magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) can describe parameters such as fractional anisotropy (FA), mean diffusivity (MD) or apparent diffusion coefficient (ADC). These parameters, when measured in the substantia nigra (SN), have not only shown promising but also varying and controversial results. To clarify the potential diagnostic value of nigral DTI in PD and its dependency on selection of region-of-interest, we undertook a high resolution DTI study at 3 T. 59 subjects (32 PD patients, 27 age and sex matched healthy controls) were analysed using manual outlining of SN and substructures, and voxel-based analysis (VBA). We also performed a systematic literature review and meta-analysis to estimate the effect size (DES) of disease related nigral DTI changes. We found a regional increase in nigral mean diffusivity in PD (mean ± SD, PD 0.80 ± 0.10 vs. controls 0.73 ± 0.06 · 10(- 3) mm(2)/s, p = 0.002), but no difference using a voxel based approach. No significant disease effect was seen using meta-analysis of nigral MD changes (10 studies, DES = + 0.26, p = 0.17, I(2) = 30%). None of the nigral regional or voxel based analyses of this study showed altered fractional anisotropy. Meta-analysis of 11 studies on nigral FA changes revealed a significant PD induced FA decrease. There was, however, a very large variation in results (I(2) = 86%) comparing all studies. After exclusion of five studies with unusual high values of nigral FA in the control group, an acceptable heterogeneity was reached, but there was non-significant disease effect (DES = - 0.5, p = 0.22, I(2) = 28%). The small PD related nigral MD changes in conjunction with the negative findings on VBA and meta-analysis limit the usefulness of nigral MD measures as biomarker of Parkinson's disease. The negative results of nigral FA measurements at regional, sub-regional and voxel level in conjunction with the results of the meta-analysis of nigral FA changes question the stability and validity of this measure as a PD biomarker.