Neural substrates of the interaction between effort-expenditure reward decision-making and outcome anticipation.

OBJECTIVE: Reward anticipation is important for future decision-making, possibly due to re-evaluation of prior decisions. However, the exact relationship between reward anticipation and prior effort-expenditure decision-making, and its neural substrates are unknown. METHOD: Thirty-three healthy participants underwent fMRI scanning while performing the Effort-based Pleasure Experience Task (E-pet). Participants were required to make effort-expenditure decisions and anticipate the reward. RESULTS: We found that stronger anticipatory activation at the posterior cingulate cortex was correlated with slower reaction time while making decisions with a high-probability of reward. Moreover, the substantia nigra was significantly activated in the prior decision-making phase, and involved in reward-anticipation in view of its strengthened functional connectivity with the mammillary body and the putamen in trial conditions with a high probability of reward. CONCLUSIONS: These findings support the role of reward anticipation in re-evaluating decisions based on the brain-behaviour correlation. Moreover, the study revealed the neural interaction between reward anticipation and decision-making.

Magnetic resonance imaging assessment of substantia nigral iron deposition in Parkinson's disease: a meta-analysis.

OBJECTIVE: The pathogenesis of Parkinson's disease (PD) is associated with abnormal iron accumulation. Magnetic resonance imaging (MRI) studies have shown that patients with Parkinson's disease have an increased amount of iron in their substantia nigra (SN). We have undertaken a meta-analysis of studies using MRI in PD, to explore the potential role of MRI in diagnosing PD using abnormal iron deposition in SN as a candidate biomarker. MATERIALS AND METHODS: Searches of PubMed, Embase, and Medline databases revealed 16 studies that compared PD patients and healthy controls (HC). A sensitivity analysis and subgroup analysis were performed to evaluate the reliability of our results. Estimates were pooled by the fixed-effects model. As an expression of I2, we computed the proportion of variation due to heterogeneity. RESULTS: We included 16 studies with sample sizes of 435 PD and 355 HC in our meta-analysis. Results showed that SN iron deposition was significantly elevated (p<0.00001) in patients with PD compared to HC ones (SMD=0.72, 95% confidence interval 0.57 to 0.87, p<0.00001). CONCLUSIONS: Our findings, based on a homogeneous group-level analysis, suggest that MRI-based SN iron deposition could be used to distinguish PD from HC. For a more rigorous investigation of SN iron deposition in PD, larger cohort studies are needed.

Automated assessment of the substantia nigra on susceptibility map-weighted imaging using deep convolutional neural networks for diagnosis of Idiopathic Parkinson's disease.

OBJECTIVES: Despite its use in determining nigrostriatal degeneration, the lack of a consistent interpretation of nigrosome 1 susceptibility map-weighted imaging (SMwI) limits its generalized applicability. To implement and evaluate a diagnostic algorithm based on convolutional neural networks for interpreting nigrosome 1 SMwI for determining nigrostriatal degeneration in idiopathic Parkinson's disease (IPD). METHODS: In this retrospective study, we enrolled 267 IPD patients and 160 control subjects (125 patients with drug-induced parkinsonism and 35 healthy subjects) at our institute, and 24 IPD patients and 27 control subjects at three other institutes on approval of the local institutional review boards. Dopamine transporter imaging served as the reference standard for the presence or absence of abnormalities of nigrosome 1 on SMwI. Diagnostic performance was compared between visual assessment by an experienced neuroradiologist and the developed deep learning-based diagnostic algorithm in both internal and external datasets using a bootstrapping method with 10000 re-samples by the "pROC" package of R (version 1.16.2). RESULTS: The area under the receiver operating characteristics curve (AUC) (95% confidence interval [CI]) per participant by the bootstrap method was not significantly different between visual assessment and the deep learning-based algorithm (internal validation, .9622 [0.8912-1.0000] versus 0.9534 [0.8779-0.9956], P = .1511; external validation, 0.9367 [0.8843-0.9802] versus 0.9208 [0.8634-0.9693], P = .6267), indicative of a comparable performance to visual assessment. CONCLUSIONS: Our deep learning-based algorithm for assessing abnormalities of nigrosome 1 on SMwI was found to have a comparable performance to that of an experienced neuroradiologist.

Multimodal assessment of nigrosomal degeneration in Parkinson's disease.

BACKGROUND: Approximately forty percent of all dopaminergic neurons in SNpc are located in five dense neuronal clusters, named nigrosomes. T2- or T2*-weighted images are used to delineate the largest nigrosome, named nigrosome-1. In these images, nigrosome-1 is a hyperintense region in the caudal and dorsal portion of the T2- or T2*-weighted substantia nigra. In PD, nigrosome-1 experiences iron accumulation, which leads to a reduction in T2-weighted hyperintensity. Here, we examine neuromelanin-depletion and iron deposition in regions of interest (ROIs) derived from quantitative-voxel based morphometry (qVBM) on neuromelanin-sensitive images and compare the ROIs with nigrosome-1 identified in T2*-weighted images. METHODS: Neuromelanin-sensitive and multi-echo gradient echo imaging data were obtained. R2* was calculated from multi-echo gradient echo imaging data. qVBM analysis was performed on neuromelanin-sensitive images and restricted to SNpc. Mean neuromelanin-sensitive contrast and R2* was measured from the resulting qVBM clusters. Nigrosome-1 was segmented in T2*-weighted images of control subjects and its location was compared to the spatial location of the qVBM clusters. RESULTS: Two bilateral clusters emerged from the qVBM analysis. These clusters showed reduced neuromelanin-sensitive contrast and increased mean R2* in PD as compared to controls. Cluster-1 from the qVBM analysis was in a similar spatial location as nigrosome-1, as seen in T2*-weighted images. CONCLUSION: qVBM cluster-1 shows reduced neuromelanin-sensitive contrast and is in a similar spatial position as nigrosome-1. This region likely corresponds to nigrosome-1 while the second cluster may correspond to nigrosome-2.

Effectiveness of QSM over R2* in assessment of parkinson's disease - A systematic review.

The incidence and prevalence of Parkinson's (PD) are increasing rapidly in developing countries. PD is difficult to diagnose based on clinical assessment. Presently, magnetic resonance imaging (MRI) methods such as R2* and Quantitative Susceptibility Mapping (QSM) were found to be useful in diagnosing the PD based on the iron deposition in different regions of the brain. The objective of this review was to evaluate the efficacy of QSM over R2* in assessment of PD. A comprehensive literature search was made on PubMed-Medline, CINAHL, Science Direct, Scopus, Web of Science, and the Cochrane library databases for original research articles published between 2000 and 2018. Original articles that reported the efficacy of QSM and R2* in assessment of PD were included. A total of 327 studies were identified in the literature search. However, only ten studies were eligible for analysis. Of the ten studies, five studies compared the accuracy of QSM over R2* in measuring the iron deposition in different regions of brain in PD. Our review found that QSM has better accuracy in identifying iron deposition in PD patients compared to R2*. However, there is discrepancy in the results between MRI Imaging methods and Postmortem studies. Additional longitudinal research studies are needed to provide a strong evidence base for the use of MRI imaging methods such as R2*and QSM in accurately measuring iron deposition in different regions of brain and serve as biomarkers in PD.

Reproducibility assessment of neuromelanin-sensitive magnetic resonance imaging protocols for region-of-interest and voxelwise analyses.

Neuromelanin-sensitive MRI (NM-MRI) provides a noninvasive measure of the content of neuromelanin (NM), a product of dopamine metabolism that accumulates with age in dopamine neurons of the substantia nigra (SN). NM-MRI has been validated as a measure of both dopamine neuron loss, with applications in neurodegenerative disease, and dopamine function, with applications in psychiatric disease. Furthermore, a voxelwise-analysis approach has been validated to resolve substructures, such as the ventral tegmental area (VTA), within midbrain dopaminergic nuclei thought to have distinct anatomical targets and functional roles. NM-MRI is thus a promising tool that could have diverse research and clinical applications to noninvasively interrogate in vivo the dopamine system in neuropsychiatric illness. Although a test-retest reliability study by Langley et al. using the standard NM-MRI protocol recently reported high reliability, a systematic and comprehensive investigation of the performance of the method for various acquisition parameters and preprocessing methods has not been conducted. In particular, most previous studies used relatively thick MRI slices (~3 â€‹mm), compared to the typical in-plane resolution (~0.5 â€‹mm) and to the height of the SN (~15 â€‹mm), to overcome technical limitations such as specific absorption rate and signal-to-noise ratio, at the cost of partial-volume effects. Here, we evaluated the effect of various acquisition and preprocessing parameters on the strength and test-retest reliability of the NM-MRI signal to determine optimized protocols for both region-of-interest (including whole SN-VTA complex and atlas-defined dopaminergic nuclei) and voxelwise measures. Namely, we determined a combination of parameters that optimizes the strength and reliability of the NM-MRI signal, including acquisition time, slice-thickness, spatial-normalization software, and degree of spatial smoothing. Using a newly developed, detailed acquisition protocol, across two scans separated by 13 days on average, we obtained intra-class correlation values indicating excellent reliability and high contrast, which could be achieved with a different set of parameters depending on the measures of interest and experimental constraints such as acquisition time. Based on this, we provide detailed guidelines covering acquisition through analysis and recommendations for performing NM-MRI experiments with high quality and reproducibility. This work provides a foundation for the optimization and standardization of NM-MRI, a promising MRI approach with growing applications throughout clinical and basic neuroscience.

Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study.

BACKGROUND: Findings from longitudinal follow-up studies in patients with idiopathic rapid-eye-movement sleep behaviour disorder (IRBD) have shown that most patients will eventually develop the synucleinopathies Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Neuroinflammation in the form of microglial activation is present in synucleinopathies and is a potential therapeutic target to halt or delay the neurodegenerative process. We aimed to investigate whether neuroinflammation is present in patients with IRBD and its possible relation to nigrostriatal dopamine function. METHODS: In this prospective, case-control, PET study, patients with IRBD and no clinical evidence of parkinsonism and cognitive impairment were recruited from tertiary sleep centres in Spain (Barcelona) and Denmark (Aarhus). We included patients with polysomnography-confirmed IRBD according to established criteria. Healthy controls were recruited through newspaper advertisements. Controls had no motor or cognitive complaints, a normal neurological examination, and a mean group age similar to the IRBD group. In patients with IRBD, we assessed microglial activation in the substantia nigra, putamen, and caudate with 11C-PK11195 PET, and dopaminergic axon terminal function in the putamen and caudate with 18F-DOPA PET. Controls underwent either 11C-PK11195 PET or 18F-DOPA PET. We compared 18F-DOPA uptake and 11C-PK11195 binding potential between groups with an unpaired, two-tailed Student's t test. FINDINGS: Between March 23, 2015, and Oct 19, 2016, we recruited 20 consecutive patients with IRBD and 19 healthy controls. 11C-PK11195 binding was increased on the left side of the substantia nigra in patients with IRBD compared with controls (Student's t test, mean difference 0·153 [95% CI 0·055 to 0·250], p=0·003), but not on the right side (0·121 [-0·007 to 0·250], p=0·064). 11C-PK11195 binding was not significantly increased in the putamen and caudate of patients with IRBD. 18F-DOPA uptake was reduced in IRBD in the left putamen (-0·0032 [-0·0044 to -0·0021], p<0·0001) and right putamen (-0·0032 [-0·0044 to -0·0020], p<0·0001), but not in the caudate. INTERPRETATION: In patients with IRBD, increased microglial activation was detected by PET in the substantia nigra along with reduced dopaminergic function in the putamen. Further studies, including more participants than were in this study and longitudinal follow-up, are needed to support our findings and evaluate whether the presence of activated microglia in patients with IRBD represents a marker of short-term conversion to a clinically defined synucleinopathy in the near future. FUNDING: Danish Council for Independent Research, Instituto de Salud Carlos III (Spain).

Region-Specific Iron Measured by MRI as a Biomarker for Parkinson's Disease.

The identification of sensitive and specific biomarkers for Parkinson's disease (PD) poses an important clinical challenge. A potential biomarker for early diagnosis and disease monitoring of PD is region-specific iron. Iron accumulation in the substantia nigra pars compacta is considered a main characteristic of PD. However, questions remain, such as the relationship between nigral iron and clinical indices of PD (motor impairment or disease duration). Further, previous studies have suggested the influence of iron on other nuclei. Iron quantification using magnetic resonance imaging (MRI) allows for studies of the relationship between regional iron and clinical symptoms in vivo. Thus, in this review we discuss the following topics: the technological development of MRI in measuring brain iron, nigral iron as a potential marker for PD in both clinical and prodromal stages, other influences of regional iron on PD, and clinical translation and future perspectives.

Diagnostic value of combined assessment of olfaction and sustantia nigra hyperechogenicity for Parkinson's disease.

INTRODUCTION: Hyposmia and substantia nigra hyperechogenicity (SN+) are characteristic markers of Parkinson's disease (PD), although their diagnostic value in isolation may be limited. We evaluated the combined prevalence of both disorders in patients diagnosed with PD and assessed their diagnostic yield compared to a sample with essential tremor (ET) and another group of healthy subjects. METHODS: Patients diagnosed with PD and ET and treated in our outpatient clinic were enrolled. Olfaction was assessed using the "Sniffin' Sticks" odour identification test (SS-12) and hyperechogenicity of the substantia nigra (SN+) was assessed by transcranial duplex ultrasound. RESULTS: A total of 98 subjects were analysed, comprising 30 with PD, 21 with ET, and 47 controls. The respective prevalence rates of hyposmia (SS-12 < 8) and SN+ (area > .24cm(2)) were 70% and 83.3% in PD, 33.3% and 9.5% in ET, and 17% and 10.6% in controls. Both markers were present in 63% of patients with PD, none of the patients with ET, and only 2 of the controls. CONCLUSIONS: Combined use of substantia nigra sonography and olfactory testing with SS-12, two rapid, safe, and accessible tests, was more specific than each isolated marker for distinguishing patients with PD from patients with ET and control subjects. Since both markers have been described in very early phases of PD, combined use may be helpful in providing early diagnosis of PD.

A new assessment tool for Parkinson disease: the nigral lesion load obtained by transcranial sonography.

OBJECTIVES: A sonographic method that provides for the measurement of a single frozen image and ignores the remaining portions of the midbrain has been used recently as a biological marker of Parkinson disease. We propose a new approach to evaluating the midbrain: obtaining the nigral lesion load, with which it is possible to acquire an estimate of the real damage to the substantia nigra. METHODS: We studied 60 patients with Parkinson disease and classified them according to the Hoehn and Yahr scale (Neurology 1967; 17:427-442). Magnetic resonance imaging of the brain, ioflupane-labeled single-photon emission computed tomography, and technetium Tc 99m-labeled single-photon emission computed tomography were performed. Assessment of the midbrain parenchyma was performed with transcranial sonography to quantify the extent of hyperechoic signals on 2 different scans (upper and lower substantia nigra). RESULTS: In 90% of patients (54), we found pathologic hyperechoic substantia nigra signals (>0.25 cm(2)). These data were similar to those described previously by other authors. However, the sum of the values obtained from each measurement (total of 4 per patient) showed that patients with severe disease had larger nigral lesion loads. In most cases, the study showed impairment of the nigrostriatal dopaminergic system when the hyperechoic pattern was more pronounced. CONCLUSIONS: Transcranial sonography is a useful tool for Parkinson disease workup. A single measurement of substantia nigra echogenicity may be insufficient for an optimal definition of the stage of the disease. A study of the entire midbrain may deliver more information than a single measurement.

Assessment of substantia nigra echogenicity in German and Filipino populations using a portable ultrasound system.

OBJECTIVES: Transcranial sonography of the substantia nigra for diagnosing premotor stages of Parkinson disease has been attracting increasing interest. Standard reference values defining an abnormal increased echogenic size (hyperechogenicity) of the substantia nigra have been established in several populations using high-end stationary ultrasound systems. It is unknown whether a portable ultrasound system can be appropriately used and how the Filipino population would compare with the well-studied white population. METHODS: We prospectively studied substantia nigra echogenic sizes and third ventricle widths in 71 healthy adult German participants and 30 age- and sex-matched Filipino participants using both a well-established stationary ultrasound system (in the German cohort) and a recently distributed portable ultrasound system (in both ethnic cohorts). RESULTS: Mean substantia nigra echogenic sizes, cutoff values defining abnormal hyperechogenicity, and intra-rater reliability were similar with both systems and in both ethnic cohorts studied. The Filipino and German participants did not differ with respect to the frequency of insufficient insonation conditions (each 3%) and substantia nigra hyperechogenicity (10% versus 9%; P = .80). However, third ventricle widths were smaller in the Filipino than the German participants (mean ± SD, 1.6 ± 1.1 versus 2.4 ± 1.0 mm; P = .004). CONCLUSIONS: The frequency of substantia nigra hyperechogenicity appears to be homogeneous in white and Asian populations. Screening for this feature may well be performed with a present-day portable ultrasound system.

Value of combined midbrain sonography, olfactory and motor function assessment in the differential diagnosis of early Parkinson's disease.

OBJECTIVE: Characteristic features of Parkinson's disease (PD) are asymmetric parkinsonian motor signs, hyposmia and substantia nigra (SN) hyperechogenicity on transcranial ultrasound. However, each of these features has limited diagnostic value as they may be present, albeit less frequently, in other parkinsonian disorders. Here, the diagnostic sensitivity and specificity of combined assessment of these three features are evaluated. METHODS: 632 patients with parkinsonism (PD, vascular parkinsonism, atypical parkinsonian syndromes, essential tremor and major depressive disorder with motor slowing) were assessed on the Unified Parkinson's disease Rating Scale for motor asymmetry (right-left score difference ≥2), the 12 item Sniffin' Sticks test (SS-12) and transcranial ultrasound. The derivation (validation) cohort consisted of 517 (115) subjects (193 (35) women; age 65.4±9.6 (62.3±10.3) years) of whom 385 (68) had PD and 132 (47) non-PD parkinsonism; another 21 (6) subjects were not included due to missing transcranial insonability. Of the validation cohort, all patients had a disease duration ≤2 years and observers were blind to diagnoses. RESULTS: The optimum cut-off values for discrimination of PD were SS-12 score <8 (hyposmia) and SN echogenic size ≥0.24 cm(2) (SN hyperechogenicity). Sensitivity, specificity and positive predictive values for the diagnosis of PD were as follows, for the derivation cohort: motor asymmetry 88%, 54% and 85%; hyposmia 75%, 70% and 88%; SN hyperechogenicity 90%, 63% and 88%; two features present 96%, 72% and 91%; three features present 57%, 94% and 97%; and for the validation cohort: two features present 91%, 77% and 85%; three features present 49%, 98% and 97%. CONCLUSION: The combined assessment of motor asymmetry, hyposmia and SN hyperechogenicity improves diagnostic specificity and allows early diagnosis of PD.

Hyperechogenicity of the substantia nigra: pitfalls in assessment and specificity for Parkinson's disease.

During the last decade, substantia nigra (SN) hyperechogenicity has been established as a valuable supplementary diagnostic marker for Parkinson's disease. As an increasing number of studies indicate that this ultrasound feature may even be evident before motor symptoms of Parkinson's disease occur, longitudinal studies revealing its value as a screening instrument for subjects at risk are awaited with great expectancy. At the same time, other studies have shown that SN hyperechogenicity is not only found in Parkinson's disease but also in other disease entities. Limitations and pitfalls of the method need to be considered to evaluate and compare these studies. Taking these into account, it is important to realize that in some other neurodegenerative diseases as well as in disorders associated with an increased risk for Parkinson's disease hyperechogenicity can be found--usually, however, less prevalent. Interestingly, even in subgroups of patients with non-neurodegenerative disorders, SN hyperechogenicity can be detected. This holds, for example, true for multiple sclerosis patients with a higher rate of disease progression. In this disorder, microglia activation is known to occur, which is also evident in Parkinson's disease. This pathomechanism as well as increased iron content is known to contribute to SN hyperechogenicity. From the studies published so far it can be concluded that, although SN hyperechogenicity is not only found in Parkinson's disease, assessment of the echogenicity of the SN and other ultrasound features is valuable in the differential diagnosis of Parkinsonian syndromes and most probably in subjects at risk. Further elucidation of the cause of the echosignal will not only contribute to the understanding of the pathophysiology of some neurodegenerative diseases but also to an even better implementation in the clinical routine and for scientific studies.

Assessment of idiopathic rapid-eye-movement sleep behavior disorder by transcranial sonography, olfactory function test, and FP-CIT-SPECT.

Idiopathic rapid-eye-movement (REM) sleep behavior disorder (iRBD) has been suggested to be a risk factor for subsequent development of neurodegenerative disorders, especially Parkinson's disease (PD) and other alpha-synucleinopathies. At present, it is not possible to predict whether or not an iRBD patient will eventually develop PD. Here, we report 5 iRBD patients who underwent a test battery comprising a neurological examination (including UPDRS rating), mini mental state examination testing, transcranial sonography, olfactory function testing, and presynaptic dopamine transporter imaging with FP-CIT-SPECT. Our preliminary data show the diverse pattern of individual combinations of pathological findings when a multimodal assessment approach is applied in this patient group. Large-size longitudinal studies in iRBD patients are required to evaluate the usefulness of diagnostic tests to identify the subgroup of iRBD patients that is prone to develop PD.