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Conventional treatments for pancreatic cancer are largely ineffective, and the prognosis for the vast majority of patients is poor. Clearly, new treatment options are desperately needed. Immunotherapy offers hope for the development of treatments for pancreatic cancer. A central requirement for the efficacy of this approach is the existence of cancer antigen-specific T cells, but these are often not present or difficult to isolate for most pancreatic tumors. Nevertheless, specific T cells can be generated using genetic modification to express chimeric antigen receptors (CAR), which can enable T cell responses against pancreatic tumor cells. CAR T cells can be produced ex vivo and expanded in vitro for infusion into patients. Remarkable responses have been documented using CAR T cells against several malignancies, including leukemias and lymphomas. Based on these successes, the extension of CAR T cell therapy for pancreatic cancer holds great promise. However, there are a number of challenges that limit the full potential of CAR T cell therapies for pancreatic cancer, including the highly immunosuppressive tumor microenvironment (TME). In this article, we will review the recent progress in using CAR T cells in pancreatic cancer preclinical and clinical settings, discuss hurdles for utilizing the full potential of CAR T cell therapy and propose research strategies and future perspectives. Research into the use of CAR T cell therapy in pancreatic cancer setting is rapidly gaining momentum and understanding strategies to overcome the current challenges in the pancreatic cancer setting will allow the development of effective CAR T cell therapies, either alone or in combination with other treatments to benefit pancreatic cancer patients.

Parkinson's disease (PD) is the fastest growing neurodegenerative disease, but at present there is no cure, nor any disease-modifying treatments. Synaptic biomarkers from in vivo imaging have shown promise in imaging loss of synapses in PD and other neurodegenerative disorders. Here, we provide new clinical insights from a cross-sectional, high-resolution positron emission tomography (PET) study of 30 PD individuals and 30 age- and sex-matched healthy controls (HC) with the radiotracer [ 11 C]UCB-J, which binds to synaptic vesicle glycoprotein 2A (SV2A), and is therefore, a biomarker of synaptic density in the living brain. We also examined a measure of relative brain perfusion from the early part of the same PET scan. Our results provide evidence for synaptic density loss in the substantia nigra that had been previously reported, but also extend this to other early-Braak stage regions known to be affected in PD (brainstem, caudate, olfactory cortex). Importantly, we also found a direct association between synaptic density loss in the nigra and severity of symptoms in patients. A greater extent and wider distribution of synaptic density loss in PD patients with longer illness duration suggests that [ 11 C]UCB-J PET can be used to measure synapse loss with disease progression. We also demonstrate lower brain perfusion in PD vs. HC groups, with a greater extent of abnormalities in those with longer duration of illness, suggesting that [ 11 C]UCB-J PET can simultaneously provide information on changes in brain perfusion. These results implicate synaptic imaging as a useful PD biomarker for future disease-modifying interventions., (© 2024. The Author(s).)

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons. Exercise has been reported to slow the clinical progression of PD. We evaluated the dopaminergic system of patients with mild and early PD before and after a six-month program of intense exercise. Using 18 F-FE-PE2I PET imaging, we measured dopamine transporter (DAT) availability in the striatum and substantia nigra. Using NM-MRI, we evaluated the neuromelanin content in the substantia nigra. Exercise reversed the expected decrease in DAT availability into a significant increase in both the substantia nigra and putamen. Exercise also reversed the expected decrease in neuromelanin concentration in the substantia nigra into a significant increase. These findings suggest improved functionality in the remaining dopaminergic neurons after exercise. Further research is needed to validate our findings and to pinpoint the source of any true neuromodulatory and neuroprotective effects of exercise in PD in large clinical trials., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background and Objectives: Ethanol has been reported to improve tremor severity in approximately two thirds of patients with essential tremor (ET), but the accuracy of that proportion is not certain and the mechanism of action is unknown. The goal of this study was to investigate alcohol response on tremor by applying an a priori objective response definition and subsequently to describe the responder rate to a standardized ethanol dose in a cohort of 85 ET patients. A secondary analysis evaluated other tremor and nontremor features, including demographics, tremor intensity, breath alcohol concentration, nontremor effects of alcohol, self-reported responder status to ethanol, and prior ethanol exposure., Methods: This was a prospective, open-label, single-dose challenge of oral ethanol during which motor and nonmotor measurements were obtained starting immediately prior to ethanol administration and subsequently every 20 min for 120 min. We defined tremor reduction as a 35% decline in power in the patient's tremor frequency recorded during spiral drawing 60 min after ethanol administration., Results: In total, 80% of patients were considered alcohol responsive using our objective definition. Responder status and change in the objective tremor metrics were significantly correlated with the change in breath alcohol concentration levels after ethanol administration, but no other relationships to nontremor metrics were found., Discussion: A high percentage of patients actually respond to acute ethanol. However, their self-reported response does not correlate well with their objective response. Objective response correlates with breath alcohol level but not with sedation, indicating a specific effect of ethanol on tremor., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Parkinson disease (PD) is the second most common neurodegenerative disease, affecting approximately 1% of the world's population. Increasing evidence suggests that aerobic physical exercise can be beneficial in mitigating both motor and nonmotor symptoms of the disease. In a recent pilot study of the role of exercise on PD, we sought to confirm exercise intensity by monitoring heart rate (HR). For this purpose, we asked participants to wear a chest strap HR monitor (Polar Electro Oy) and the Fitbit Charge 4 (Fitbit Inc) wrist-worn HR monitor as a potential proxy due to its convenience. Polar H10 has been shown to provide highly accurate R-R interval measurements. Therefore, we treated it as the gold standard in this study. It has been shown that Fitbit Charge 4 has comparable accuracy to Polar H10 in healthy participants. It has yet to be determined if the Fitbit is as accurate as Polar H10 in patients with PD during rest and exercise., Objective: This study aimed to compare Fitbit Charge 4 to Polar H10 for monitoring HR in patients with PD at rest and during an intensive exercise program., Methods: A total of 596 exercise sessions from 11 (6 male and 5 female) participants were collected simultaneously with both devices. Patients with early-stage PD (Hoehn and Yahr ≤2) were enrolled in a 6-month exercise program designed for patients with PD. They participated in 3 one-hour exercise sessions per week. They wore both Fitbit and Polar H10 during each session. Sessions included rest, warm-up, intense exercise, and cool-down periods. We calculated the bias in the HR of the Fitbit Charge 4 at rest (5 min) and during intense exercise (20 min) by comparing the mean HR during each of the periods to the respective means measured by Polar H10 (HRFitbit - HRPolar). We also measured the sensitivity and specificity of Fitbit Charge 4 to detect average HRs that exceed the threshold for intensive exercise, defined as 70% of an individual's theoretical maximum HR. Different types of correlations between the 2 devices were investigated., Results: The mean bias was 1.68 beats per minute (bpm) at rest and 6.29 bpm during high-intensity exercise, with an overestimation by Fitbit Charge 4 in both conditions. The mean bias of the Fitbit across both rest and intensive exercise periods was 3.98 bpm. The device's sensitivity in identifying high-intensity exercise sessions was 97.14%. The correlation between the 2 devices was nonlinear, suggesting Fitbit's tendency to saturate at high values of HR., Conclusions: The performance of Fitbit Charge 4 is comparable to Polar H10 for assessing exercise intensity in a cohort of patients with PD (mean bias 3.98 bpm). The device could be considered a reasonable surrogate for more cumbersome chest-worn devices in future studies of clinical cohorts., (©Giulia Colonna, Jocelyn Hoye, Bart de Laat, Gelsina Stanley, Alaaddin Ibrahimy, Sule Tinaz, Evan D Morris. Originally published in JMIR Biomedical Engineering (http://biomsedeng.jmir.org), 08.12.2023.)

Parkinson's disease (PD) is the fastest growing neurological disorder and one of the leading neurological causes of disability worldwide following stroke. An overall aging global population, as well as general changes in lifestyle associated with mass industrialization in the last century, may be linked to both increased incidence rates of PD and an increase in cumulative cardiovascular risk. Recent epidemiological studies show an increased risk of stroke, post-stroke complications, and subclinical ischemic insults in PD. PD patients have a host of characteristics that might contribute to increasing the risk of developing ischemic stroke including motor impairment, dysautonomia, and sleep disorders. This increases the urgency to study the interplay between PD and other neurological disorders, and their combined effect on mortality, morbidity, and quality of life. In this review, we provide a comprehensive overview of the studied etiological factors and pathological processes involved in PD, specifically with regard to their relationship to stroke. We hope that this review offers an insight into the relationship between PD and ischemic stroke and motivates further studies in this regard., (© 2023. The Author(s) under exclusive licence to Belgian Neurological Society.)

Mental imagery is the mental re-creation of perceptual experiences, events and scenarios, and motor acts. In our previous study, we assessed whether motor imagery (MI) training combined with functional magnetic resonance imaging-based neurofeedback could improve the motor function of nondemented subjects with mild Parkinson's disease (PD) (N = 22). We used visual imagery (VI) (e.g., of scenes or events, but not of self-movements) training without neurofeedback for the control group (N = 22). Notably, both groups showed significant and comparable improvement in motor function after four weeks of daily imagery practice. In this study, we further examined the neural correlates of the motor enhancement as a result of the VI training by analyzing the self-reported VI content during daily practice and relating its quality to the functional connectivity characteristics of the same subjects. We demonstrated that the VI practice encompassed multisensory, spatial, affective, and executive processes all of which are also important for motor function in real life. Subjects with worse global disease severity also showed poorer quality of the VI content. Finally, the quality of the VI content showed significant positive correlations with the functional connectivity changes during the VI tasks in brain areas supporting visuospatial and sensorimotor processes. Our findings suggest that mental imagery training combining VI and MI may enhance motor function in patients with mild PD, and more broadly, underline the importance of incorporating self-reports of thoughts and experiences in neuroimaging studies that examine the brain mechanisms of complex cognitive processes especially in neuropsychiatric patient populations., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Accurate and timely diagnosis of atypical parkinsonian syndromes (APS) remains a challenge. Especially early in the disease course, the clinical manifestations of the APS overlap with each other and with those of idiopathic Parkinson's disease (PD). Recent advances in magnetic resonance imaging (MRI) technology have introduced promising imaging modalities to aid in the diagnosis of APS. Some of these MRI modalities are also included in the updated diagnostic criteria of APS. Importantly, MRI is safe for repeated use and more affordable and accessible compared to nuclear imaging. These advantages make MRI tools more appealing for diagnostic purposes. As the MRI field continues to advance, the diagnostic use of these techniques in APS, alone or in combination, are expected to become commonplace in clinical practice., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tinaz.)

Parkinson's disease (PD) is a common and complex neurodegenerative disorder with five stages on the Hoehn and Yahr scaling. Characterizing brain function alterations with progression of early stage disease would support accurate disease staging, development of new therapies, and objective monitoring of disease progression or treatment response. Functional magnetic resonance imaging (fMRI) is a promising tool in revealing functional connectivity (FC) differences and developing biomarkers in PD. While fMRI and FC data have been utilized for diagnosis of PD through application of machine learning approaches such as support vector machine and logistic regression, the characterization of FC changes in early-stage PD has not been investigated. Given the complexity and non-linearity of fMRI data, we propose the use of a long short-term memory (LSTM) network to distinguish the early stages of PD and understand related functional brain changes. The study included 84 subjects (56 in stage 2 and 28 in stage 1) from the Parkinson's Progression Markers Initiative (PPMI), the largest-available public PD dataset. Under a repeated 10-fold stratified cross-validation, the LSTM model reached an accuracy of 71.63%, 13.52% higher than the best traditional machine learning method and 11.56% higher than a CNN model, indicating significantly better robustness and accuracy compared with other machine learning classifiers. Finally, we used the learned LSTM model weights to select the top brain regions that contributed to model prediction and performed FC analyses to characterize functional changes with disease stage and motor impairment to gain better insight into the brain mechanisms of PD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Guo, Tinaz and Dvornek.)

Clinical scores (disease rating scales) are ordinal in nature. Longitudinal studies which use clinical scores produce ordinal time series. These time series tend to be noisy and often have a short-duration. This paper proposes a denoising method for such time series. The method uses a hierarchical approach to draw statistical power from the entire population of a study's patients to give reliable, subject-specific results. The denoising method is applied to MDS-UPDRS motor scores for Parkinson's disease.

Background: Parkinson's disease (PD) causes difficulty with maintaining the speed, size, and vigor of movements, especially when they are internally generated. We previously proposed that the insula is important in motivating intentional movement via its connections with the dorsomedial frontal cortex (dmFC). We demonstrated that subjects with PD can increase the right insula-dmFC functional connectivity using fMRI-based neurofeedback (NF) combined with kinesthetic motor imagery (MI). The current study is a randomized clinical trial testing whether NF-guided kinesthetic MI training can improve motor performance and increase task-based and resting-state right insula-dmFC functional connectivity in subjects with PD., Methods: We assigned nondemented subjects with mild PD (Hoehn & Yahr stage ≤ 3) to the experimental kinesthetic MI with NF (MI-NF, n = 22) and active control visual imagery (VI, n = 22) groups. Only the MI-NF group received NF-guided MI training (10-12 runs). The NF signal was based on the right insula-dmFC functional connectivity strength. All subjects also practiced their respective imagery tasks at home daily for 4 weeks. Post-training changes in 1) task-based and resting-state right insula-dmFC functional connectivity were the primary imaging outcomes, and 2) MDS-UPDRS motor exam and motor function scores were the primary and secondary clinical outcomes, respectively., Results: The MI-NF group was not significantly different from the VI group in any of the primary imaging or clinical outcome measures. The MI-NF group reported subjective improvement in kinesthetic body awareness. There was significant and comparable improvement only in motor function scores in both groups (secondary clinical outcome). This improvement correlated with NF regulation of the right insula-dmFC functional connectivity only in the MI-NF group. Both groups showed specific training effects in whole-brain functional connectivity with distinct neural circuits supporting kinesthetic motor and visual imagery (exploratory imaging outcome)., Conclusions: The functional connectivity-based NF regulation was unsuccessful, however, both kinesthetic MI and VI practice improved motor function in our cohort with mild PD., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Wilson disease (WD) can manifest with hepatic or neuropsychiatric symptoms. Our understanding of the in vivo brain changes in WD, particularly in the hepatic phenotype, is limited. Thirty subjects with WD and 30 age- and gender-matched controls participated. WD group underwent neuropsychiatric assessment. Unified WD Rating Scale neurological exam scores were used to determine neurological (WDN, score > 0) and hepatic-only (WDH, score 0) subgroups. All subjects underwent 3 Tesla anatomical and resting-state functional MRI. Diffusion tensor imaging (DTI) and susceptibility-weighted imaging (SWI) were performed only in the WD group. Volumetric, DTI, and functional connectivity analyses were performed to determine between-group differences. WDN and WDH groups were matched in demographic and psychiatric profiles. The entire WD group compared to controls showed significant thinning in the bilateral superior frontal cortex. The WDN group compared to control and WDH groups showed prominent structural brain changes including significant striatal and thalamic atrophy, more subcortical hypointense lesions on SWI, and diminished white matter integrity in the bilateral anterior corona radiata and corpus callosum. However, the WDH group also showed significant white matter volume loss compared to controls. The functional connectivity between the frontostriatal nodes was significantly reduced in the WDN group, whereas that of the hippocampus was significantly increased in the WDH group compared to controls. In summary, structural and functional brain changes were present even in neurologically non-manifesting WD patients in this cross-sectional study. Longitudinal brain MRI scans may be useful as biomarkers for prognostication and optimization of treatment strategies in WD., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Parkinson's disease (PD) can present with neuropsychiatric symptoms (here, anxiety, depression, and apathy) at any stage of the disease. We investigated the neural correlates of subclinical neuropsychiatric symptoms in relation to motor and cognitive symptoms in a high-functioning PD cohort., Methods: Brain morphometry of the cognitively intact, early-stage (Hoehn & Yahr 2) PD group (n = 48) was compared to matched controls (n = 37). Whole-brain, pairwise, resting-state functional connectivity measures were correlated with neuropsychiatric symptom, motor exam, and global cognitive scores of the PD group., Results: Factor analysis of highly collinear anxiety, depression, and apathy scores revealed a single principal component (i.e., composite neuropsychiatric symptom score) explaining 71.6% of variance. There was no collinearity between the neuropsychiatric, motor, and cognitive scores. Compared to controls, PD group showed only subcortical changes including amygdala and nucleus accumbens atrophy, and greater pallidal volume. Reduced functional connectivity in the limbic cortical-striatal circuits and increased functional connectivity between the cerebellum and occipito-temporal regions were associated with a more impaired neuropsychiatric profile. This functional connectivity pattern was distinct from those associated with motor deficits and global cognitive functioning. The individual components of the neuropsychiatric symptoms also exhibited unique connectivity patterns., Limitations: Patients were scanned in "on-medication" state only and a control group with similar neuropsychiatric symptoms was not included., Conclusion: Abnormal functional connectivity of distinct neural circuits is present even at the subclinical stage of neuropsychiatric symptoms in PD. Neuropsychiatric phenotyping is important and may facilitate early interventions to "reorganize" these circuits and delay/prevent clinical symptom onset., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose of Review: There has been an exponential growth in functional connectomics research in neurodegenerative disorders. This review summarizes the recent findings and limitations of the field in Parkinson's disease (PD) and atypical parkinsonian syndromes., Recent Findings: Increasingly more sophisticated methods ranging from seed-based to network and whole-brain dynamic functional connectivity have been used. Results regarding the disruption in the functional connectome vary considerably based on disease severity and phenotypes, and treatment status in PD. Non-motor symptoms of PD also link to the dysfunction in heterogeneous networks. Studies in atypical parkinsonian syndromes are relatively scarce. An important clinical goal of functional connectomics in neurodegenerative disorders is to establish the presence of pathology, track disease progression, predict outcomes, and monitor treatment response. The obstacles of reliability and reproducibility in the field need to be addressed to improve the potential of the functional connectome as a biomarker for these purposes in PD and atypical parkinsonian syndromes.

This paper proposes a mixture of linear dynamical systems model for quantifying the heterogeneous progress of Parkinson's disease from DaTscan Images. The model is fitted to longitudinal DaTscans from the Parkinson's Progression Marker Initiative. Fitting is accomplished using robust Bayesian inference with collapsed Gibbs sampling. Bayesian inference reveals three image-based progression subtypes which differ in progression speeds as well as progression trajectories. The model reveals characteristic spatial progression patterns in the brain, each pattern associated with a time constant. These patterns can serve as disease progression markers. The subtypes also have different progression rates of clinical symptoms measured by MDS-UPDRS Part III scores.

Objective: We aimed to determine suicide risk and lifetime suicidal ideation in Parkinson disease (PD) patients versus controls and how depression, demoralization, and insomnia are associated with suicidality., Methods: In this case-control study, PD patients and matched controls were recruited from movement disorder clinics, Michael J. Fox Foundation, and Research Match websites. Suicide risk and suicidal ideation were assessed using the Suicidal Behavior Questionnaire-revised (SBQ-R) and Columbia-Suicide Severity Rating Scale. Lifetime depression was assessed using the Brief Lifetime Depression Scale, sleep using Insomnia Severity Index (ISI), demoralization using Diagnostic Criteria for Psychosomatic Research and Kissane Demoralization Scales, and non-motor symptoms using UPDRS Non-Motor Aspects of Experiences of Daily Living scale (nM-EDL)., Results: 186 PD participants and 177 controls were matched for age (64.2 ± 7.7 years), sex (48.8% female), and socioeconomics. PD participants were not more likely than controls to have high suicide risk (SBQ-R ≥ 7) (7.5% vs. 11.3%; p = 0.22) or to have had a lifetime suicide plan or attempt (2.7% vs. 5.1%; p = 0.24), but were less likely to have had lifetime suicidal ideation (23.1% vs. 35.0%; p = 0.01). PD participants were more likely than controls to have lifetime depression history (34.4% vs. 20.9%; p = 0.004), and demoralization (19.9% vs. 10.7%; p = 0.02), and had higher ISI scores (8.7 ± 5.8 vs. 5.1 ± 4.5; p < 0.0001). PD patients with high versus normal suicide risk had higher nM-EDL scores (16.5 ± 6.8 vs. 10.7 ± 5.9; p = 0.002), and more demoralization (71.4% vs. 21.5%; p < 0.0001)., Conclusions: Suicide risk is not elevated and suicidal ideation is uncommon in PD, despite the high prevalence of depression and demoralization.

Objective: Parkinson disease is characterized by motor and nonmotor symptoms, reduced striatal dopamine signaling, and loss of dopamine neurons in the substantia nigra. It is now known that the pathological process in Parkinson disease may begin decades before the clinical diagnosis and include a variety of neuronal alterations in addition to the dopamine system., Methods: This study examined the density of all synapses with synaptic vesicle glycoprotein 2A (SV2A) in Parkinson disease subjects with mild bilateral disease (n = 12) and matched normal controls (n = 12) using in vivo high-resolution positron emission tomographic imaging as well as postmortem autoradiography in an independent sample with Parkinson disease (n = 15) and normal controls (n = 13) in the substantia nigra and putamen., Results: A group-by-brain region interaction effect (F 10, 22 = 3.52, p = 0.007) was observed in the primary brain areas with in vivo SV2A binding. Post hoc analyses revealed that the Parkinson disease group exhibited lower SV2A in the substantia nigra (-45%; p < 0.001), red nucleus (-31%; p = 0.03), and locus coeruleus (-17%; p = 0.03). Exploratory analyses also revealed lower SV2A binding in clinically relevant cortical areas. Using autoradiography, we confirmed lower SV2A in the substantia nigra (-17%; p < 0.005) and nonsignificant findings in the putamen (-4%; p = 0.06)., Interpretation: This work provides the first evidence of synaptic loss in brainstem nuclei involved in the pathogenesis of Parkinson disease in living patients. SV2A imaging holds promise for understanding synaptic changes central to the disease. Ann Neurol 2020;87:329-338., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Introduction: In many neurology residency programs, outpatient neurology subspecialties are underrepresented. Trainee exposure to these subspecialties, including movement disorders, is limited by paucity and variability of clinical experiences. We designed a structured educational tool to address this variability and allow for standardization of elements of movement disorders teaching., Methods: We designed and implemented a web-based curriculum in movement disorders for neurology housestaff, in order to improve participant knowledge. The curriculum includes an introduction with a structured framework for the description of abnormal movements and 10 interactive modules focusing on common movement disorders. The curriculum was piloted with nine neurology housestaff at Yale-New Haven Hospital. Evaluation of the curriculum was performed using pre- and post-tests, a survey, and semi-structured interviews., Results: The mean pre-test score was 0.7 (±0.19), and the mean post-test score was 0.95 (±0.05) ( t  = 3.27). Surveys demonstrated mean Likert values >4/5 for all questions in all categories (knowledge acquisition, quantity, enthusiasm and technical). Semi-structured interviews revealed the following themes: 1) the modules increased participant comfort with the topic, 2) the format was engaging, and 3) the curriculum accommodated different learning styles. All participants remarked that the structured framework was a particular strength., Conclusion: We have created, implemented, and evaluated a foundational curriculum in movement disorders for neurology trainees, using readily-available technology. Housestaff responded positively to the curriculum, both in terms of content and format. This curriculum can be implemented in a variety of educational settings, as a central component of a standardized approach to movement disorders teaching., Competing Interests: Nothing to declare., (© 2020 The Authors.)

Introduction: Deficits in goal-directed behavior are common in individuals with Parkinson's disease (PD) and have been ascribed to apathy. In addition to apathy, individuals' beliefs in their competence (self-efficacy) and capacity to regulate emotions, thoughts, and actions (self-regulation) are critical skills for goal-directed behavior. We investigated these skills and their relationship to motor and non-motor symptoms in individuals with PD. We also examined the neural correlates of these skills using functional magnetic resonance imaging (fMRI)., Methods: We enrolled 35 subjects with mild PD (Hoehn and Yahr stage ≤2.5) and used the new general self-efficacy (NGSES) and self-regulation scales (SRS). We correlated the scores on these scales with measures of cognition, anxiety, depression, apathy, fatigue, quality of life, and disease burden using stepwise regression analyses. We collected resting-state fMRI data in a 3-Tesla scanner and computed the pairwise functional connectivity among nodes of major networks. We correlated the connectivity maps with the NGSES and SRS scores., Results: Our PD cohort demonstrated intact NGSES and SRS scores compared with respective population data. These scores showed significant negative correlation with apathy and disease burden. Stronger connectivity in the salience network and decoupling from the default mode network supported self-efficacy and self-regulation., Conclusions: Self-efficacy and self-regulation capacity seems preserved, but vulnerable to disease-related factors in individuals with mild PD. Educational programs cultivating this capacity could improve the coping skills of these individuals. Functional connectivity changes in salience and default mode networks may serve as neurobiological markers to demonstrate the effectiveness of such interventions.

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PD-D) are Lewy body-related neurodegenerative disorders sharing common clinical and neuropathological findings. The clinical features of both conditions include cognitive impairment, behavioral symptoms, autonomic dysfunction, sleep disorders, and parkinsonism. The cognitive profile of both disorders is characterized by particularly severe deficits in executive and visuospatial functions as well as attention. Clinical differentiation between DLB and PD-D is based on an arbitrary distinction between the time of onset of parkinsonism and cognitive symptoms; extrapyramidal symptoms precede dementia in PD-D, whereas it coincides with or follows dementia within 1 year in DLB. When the clinical picture is fully developed, DLB and PD-D are practically indistinguishable. Although the diagnosis is basically clinical, structural and functional neuroimaging as well as cerebrospinal fluid biomarkers may help the clinician in the diagnosis. Placebo-controlled randomized trials of the cholinesterase inhibitors have shown modest but significant benefits in cognition, global function, and neuropsychiatric symptoms in both disorders. Behavioral symptoms such as hallucinations and delusions should be treated with caution with antipsychotics, as they have the potential to worsen motor and cognitive symptoms., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Quantitative assessment of dopamine transporter imaging can aid in diagnosing Parkinson disease (PD) and assessing disease progression in the context of therapeutic trials. Previously, the software program SBRquant was applied to 123 I-ioflupane SPECT images acquired on healthy controls and subjects with PD. Earlier work on optimization of the parameters for differentiating between controls and subjects with dopaminergic deficits is extended here for maximizing change measurements associated with disease progression on longitudinally acquired scans. Methods: Serial 123 I-ioflupane SPECT imaging for 51 subjects with PD (conducted approximately 1 y apart) were downloaded from the Parkinson Progression Markers Initiative database. The software program SBRquant calculates the striatal binding ratio (SBR) separately for the left and right caudates and putamen regions of interest (ROIs). Parameters were varied to evaluate the number of summed transverse slices and the positioning of the striatal ROIs for determining the signal-to-noise ratio associated with their annual rate of change in SBR. The parameters yielding the largest change in the lowest putamen's SBR from scan 1 to scan 2 were determined. Results: From scan 1 to scan 2 in the 51 subjects, the largest annual change was observed when the putamen ROI was placed 3 pixels away from the caudate and by summing 5 central striatal slices. This resulted in an 11.2% ± 4.3% annual decrease in the lowest putamen SBR for the group. Conclusion: Quantitative assessment of dopamine transporter imaging for assessing progression of PD requires specific, optimal parameters different from those for diagnostic accuracy., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Intentional movement is an internally driven process that requires the integration of motivational and sensory cues with motor preparedness. In addition to the motor cortical-basal ganglia circuits, the limbic circuits are also involved in the integration of these cues. Individuals with Parkinson's disease (PD) have a particular difficulty with internally generating intentional movements and maintaining the speed, size, and vigor of movements. This difficulty improves when they are provided with external cues suggesting that there is a problem with the internal motivation of movement in PD. The prevailing view attributes this difficulty in PD to the dysfunction of motor cortical-basal ganglia circuits. First, we argue that the standard cortical-basal ganglia circuit model of motor dysfunction in PD needs to be expanded to include the insula which is a major hub within the limbic circuits. We propose a neural circuit model highlighting the interaction between the insula and dorsomedial frontal cortex which is involved in generating intentional movements. The insula processes a wide range of sensory signals arising from the body and integrates them with the emotional and motivational context. In doing so, it provides the impetus to the dorsomedial frontal cortex to initiate and sustain movement. Second, we present the results of our proof-of-concept experiment demonstrating that the functional connectivity of the insula-dorsomedial frontal cortex circuit can be enhanced with neurofeedback-guided kinesthetic motor imagery using functional magnetic resonance imaging in subjects with PD. Specifically, we found that the intensity and quality of body sensations evoked during motor imagery and the emotional and motivational context of motor imagery determined the direction (i.e., negative or positive) of the insula-dorsomedial frontal cortex functional connectivity. After 10-12 neurofeedback sessions and "off-line" practice of the successful motor imagery strategies all subjects showed a significant increase in the insula-dorsomedial frontal cortex functional connectivity. Finally, we discuss the implications of these results regarding motor function in patients with PD and propose suggestions for future studies.

Background: Mild and transient head tremor may sometimes be observed in otherwise tremor-free relatives of essential tremor (ET) cases, although its prevalence is unclear. A diagnostic question is whether this transient, isolated head tremor, often observed as no more than a wobble, is an early manifestation of ET or whether it is a normal finding. A direct comparison with controls is needed. Methods: Two hundred and forty-one first-degree relatives of ET cases (FD-ET) and 77 spousal controls (Co) were enrolled in a study of ET. Each underwent a detailed evaluation that included a tremor history and videotaped neurological examination. None of the enrollees reported tremor, had a prior diagnosis of ET, or had significant tremor on screening spirals. All videotaped examinations were initially reviewed by a movement disorder neurologist blinded to subject type, and among those with head tremor on examination, co-reviewed by two additional movement disorders neurologists. Results: Twenty-six (10.8, 95% Confidence interval [CI] = 7.5-15.3%) of 241 FD-ET vs. 2 (2.6, 95% CI = 0.7-9.0%) of 77 Co had isolated, transient head tremor (odds ratio = 4.54, 95% CI = 1.05-19.57, p = 0.04). No enrollee had significant upper extremity tremor and none met inclusion criteria for ET based on the presence of upper extremity tremor. With one exception, head tremor occurred during or after phonation. It was always transient (generally a single back and forth wobble) and rare (observed briefly on one or two occasions during the videotaped examination) and had a faster frequency, lower amplitude and a different quality than voluntary head shaking. Conclusion: The basis for the observed isolated head tremor is unknown, but it could be an early feature of ET in ET families.Indeed, one-in-ten otherwise unaffected first-degree relatives of ET cases exhibited such tremor. To a far lesser extent it was also observed in "unaffected" controls. In both, it is likely a sign of early, emerging, undiagnosed ET, although follow-up studies are needed to confirm this. If it were ET, it would indicate that the prevalence of ET may be considerably higher than previously suspected.

Purpose: Dopamine transporter (DaT) imaging is an adjunct diagnostic tool in parkinsonian disorders. Interpretation of DaT scans is based on visual reads. SBRquant is an automated method that measures the striatal binding ratio (SBR) in DaT scans, but has yet to be optimized. We aimed to (1) optimize SBRquant parameters to distinguish between patients with Parkinson disease (PD) and healthy controls using the Parkinson's Progression Markers Initiative (PPMI) database and (2) test the validity of these parameters in an outpatient cohort., Methods: For optimization, 336 DaT scans (215 PD patients and 121 healthy controls) from the PPMI database were used. Striatal binding ratio was calculated varying the number of summed transverse slices (N) and positions of the striatal regions of interest (d). The resulting SBRs were evaluated using area under the receiver operating characteristic curve. The optimized parameters were then applied to 77 test patients (35 PD and 42 non-PD patients). Striatal binding ratios were also correlated with clinical measures in the PPMI-PD group., Results: The optimal parameters discriminated the training groups in the PPMI cohort with 95.8% sensitivity and 98.3% specificity (lowest putamen SBR threshold, 1.037). The same parameters discriminated the groups in the test cohort with 97.1% sensitivity and 100% specificity (lowest putamen SBR threshold, 0.875). A significant negative correlation (r = -0.24, P = 0.0004) was found between putamen SBRs and motor severity in the PPMI-PD group., Conclusions: SBRquant discriminates DaT scans with high sensitivity and specificity. It has a high potential for use as a quantitative diagnostic aid in clinical and research settings.

Parkinson's disease (PD) leads to dysfunction in multiple cortico-striatal circuits. The neurodegeneration has also been associated with impaired white matter integrity. This structural and functional "disconnection" in PD needs further characterization. We investigated the structural and functional organization of the PD whole brain connectome consisting of 200 nodes using diffusion tensor imaging and resting-state functional MRI, respectively. Data from 20 non-demented PD patients on dopaminergic medication and 20 matched controls were analyzed using graph theory-based methods. We focused on node strength, clustering coefficient, and local efficiency as measures of local network properties; and network modularity as a measure of information flow. PD patients showed reduced white matter connectivity in frontoparietal-striatal nodes compared to controls, but no change in modular organization of the white matter tracts. PD group also showed reduction in functional local network metrics in many nodes distributed across the connectome. There was also decreased functional modularity in the core cognitive networks including the default mode and dorsal attention networks, and sensorimotor network, as well as a lack of modular distinction in the orbitofrontal and basal ganglia nodes in the PD group compared to controls. Our results suggest that despite subtle white matter connectivity changes, the overall structural organization of the PD connectome remains robust at relatively early disease stages. However, there is a breakdown in the functional modular organization of the PD connectome.

Bradykinesia is the most disabling motor symptom of Parkinson's disease (PD). The sequence effect (SE), a feature of bradykinesia, refers to the rapid decrement in amplitude and speed of repetitive movements (e.g., gait, handwriting) and is a major cause of morbidity in PD. Previous research has revealed mixed results regarding the role of dopaminergic treatment in the SE. However, external cueing has been shown to improve it. In this study, we aimed to characterize the SE systematically and relate this phenomenon to the energetic cost of movement within the context of cost-benefit framework of motor control. We used a dynamic isometric motor task with auditory pacing to assess the SE in motor output during a 15-s task segment in PD patients and matched controls. All participants performed the task with both hands, and without and with visual feedback (VF). Patients were also tested in "on"- and "off"-dopaminergic states. Patients in the "off" state did not show higher SE compared to controls, partly due to large variance in their performance. However, patients in the "on" state and in the absence of VF showed significantly higher SE compared to controls. Patients expended higher total motor energy compared to controls in all conditions and regardless of their medication status. In this experimental situation, the SE in PD is associated with the cumulative energetic cost of movement. Dopaminergic treatment, critical for internal triggering of movement, fails to maintain the motor vigor across responses. The high motor cost may be related to failure to incorporate limbic/motivational cues into the motor plan. VF may facilitate performance by shifting the driving of movement from internal to external or, alternatively, by functioning as a motivational cue.

Background: Recently, 1-octanol has been shown to have efficacy in treating patients with essential tremor (ET). The primary metabolite of 1-octanol is octanoic acid (OA), which is now thought to be the active substance that mediates tremor suppression. Our aim was to describe the maximum tolerated dose (MTD) of oral OA in patients with ET and assess the pharmacokinetics (PK) and pharmacodynamics (PD) profile of OA., Methods: The MTD was studied using an open-label, single-ascending 3 + 3 dose-escalation design. Predefined single doses ranged from 8 to 128 mg/kg, with grade 2 adverse events (AEs) defined as dose-limiting toxicity. Tremor was assessed using accelerometry, digital spiral analysis, and a standard clinical rating scale at baseline and up to 600 minutes after intake. Safety assessments and PK sampling were also performed., Results: Dose-limiting toxicity was not reached. The most frequent AE was mild abdominal discomfort. Exposure (AUC) increased linearly with the dose. Secondary efficacy measures suggested a dose-dependent reduction of tremor. Accordingly, a single unified PK/PD model with an effect compartment and sigmoid maximum effect (Emax) response could be built that accounted well for the time profiles of plasma concentrations as well as effects on tremor severity across the 5 dose levels., Conclusion: Although our trial did not reach an MTD, a dose-dependent effect was demonstrated in the PK/PD model as well as in secondary efficacy outcomes. Future studies are needed to explore the safety in higher dose ranges and to confirm dose-dependent efficacy in a placebo-controlled design., Trial Registration: Clinicaltrials.gov NCT01468948FUNDING. NINDS Intramural Research Program; TG Therapeutics Inc.

Patients with Parkinson's disease have difficulties with self-initiating a task and maintaining a steady task performance. We hypothesized that these difficulties relate to reorganization in the sensorimotor execution, cingulo-opercular task-set maintenance, and frontoparietal adaptive control networks. We tested this hypothesis using graph theory-based network analysis of a composite network including a total of 86 nodes, derived from the three networks of interest. Resting-state functional magnetic resonance images were collected from 30 patients with Parkinson's disease (age 42-75 years, 11 females; Hoehn and Yahr score 2-3, average 2.4 ± 0.4) in their off-medication state and 30 matched control subjects (age 44-75 years, 10 females). For each node, we calculated strength as a general measure of connectivity, global efficiency and betweenness centrality as measures of functional integration, and clustering coefficient and local efficiency as measures of functional segregation. We found reduced node strength, clustering, and local efficiency in sensorimotor and posterior temporal nodes. There was also reduced node strength and betweenness centrality in the dorsal anterior insula and temporoparietal junction nodes of the cingulo-opercular network. These nodes are involved in integrating multimodal information, specifically related to self-awareness, sense of agency, and ultimately to intact perception of self-in-action. Moreover, we observed significant correlations between global disease severity and averaged graph metrics of the whole network. In addition to the well-known task-related frontostriatal mechanisms, we propose that the resting-state reorganization in the composite network can contribute to problems with self-initiation and task-set maintenance in Parkinson's disease.

Background: The mid-posterior part of the insula is involved in processing bodily sensations and urges and is activated during tic generation in Tourette syndrome. The dorsal anterior part of the insula, however, integrates sensory and emotional information with cognitive valuation and is implicated in interoception. The right dorsal anterior insula also participates in urge suppression in healthy subjects. This study examined the role of the right dorsal anterior insula in the urge to tic in Tourette syndrome., Methods: Resting-state functional magnetic resonance imaging was performed in 13 adult Tourette patients and 13 matched controls. The role of the right dorsal anterior insula within the urge-tic network was investigated using graph theory-based neural network analysis. The functional connectivity of the right dorsal anterior insula was also correlated with urge and tic severity., Results: Even though the patients did not exhibit any overt tics, the right dorsal anterior insula demonstrated higher connectivity, especially with the frontostriatal nodes of the urge-tic network in patients compared with controls. The functional connectivity between the right dorsal anterior insula and bilateral supplementary motor area also correlated positively with urge severity in patients., Conclusions: These results suggest that the right dorsal anterior insula is part of the urge-tic network and could influence the urge- and tic-related cortico-striato-thalamic regions even during rest in Tourette syndrome. It might be responsible for heightened awareness of bodily sensations generating premonitory urges in Tourette syndrome., Competing Interests: Sule Tinaz, Patrick Malone, and Silvina G. Horovitz have nothing to disclose and report no conflict of interest., (© 2015 International Parkinson and Movement Disorder Society.)

Dystonia is characterized by abnormal posturing due to sustained muscle contraction, which leads to pain and significant disability. New therapeutic targets are needed in this disorder. The objective of this randomized, sham-controlled, blinded exploratory study is to identify a specific motor system target for non-invasive neuromodulation and to evaluate this target in terms of safety and tolerability in the cervical dystonia (CD) population. Eight CD subjects were given 15-minute sessions of low-frequency (0.2 Hz) repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (MC), dorsal premotor cortex (dPM), supplementary motor area (SMA), anterior cingulate cortex (ACC) and a sham condition with each session separated by at least two days. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) score was rated in a blinded fashion immediately pre- and post-intervention. Secondary outcomes included physiology and tolerability ratings. The mean change in TWSTRS severity score by site was 0.25 ± 1.7 (ACC), -2.9 ± 3.4 (dPM), -3.0 ± 4.8 (MC), -0.5 ± 1.1 (SHAM), and -1.5 ± 3.2 (SMA) with negative numbers indicating improvement in symptom control. TWSTRS scores decreased from Session 1 (15.1 ± 5.1) to Session 5 (11.0 ± 7.6). The treatment was tolerable and safe. Physiology data were acquired on 6 of 8 subjects and showed no change over time. These results suggest rTMS can modulate CD symptoms. Both dPM and MC are areas to be targeted in further rTMS studies. The improvement in TWSTRS scores over time with multiple rTMS sessions deserves further evaluation.

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by motor and vocal tics. Most patients describe uncomfortable premonitory sensations preceding the tics and a subjective experience of increased sensitivity to tactile stimuli. These reports indicate that a sensory processing disturbance is an important component of TS together with motor phenomena. Thus, we focused our investigation on the role of the sensorimotor cortex (SMC) in TS using multimodal neuroimaging techniques. We measured the gamma-aminobutyric acid (GABA)+/Creatine (Cre) ratio in the SMC using GABA (1) H magnetic resonance spectroscopy. We recorded the baseline beta activity in the SMC using magnetoencephalography and correlated GABA+/Cre ratio with baseline beta band power. Finally, we examined the resting state functional connectivity (FC) pattern of the SMC using functional magnetic resonance imaging (fMRI). GABA+/Cre ratio in the SMC did not differ between patients and controls. Correlation between the baseline beta band power and GABA+/Cre ratio was abnormal in patients. The anterior insula showed increased FC with the SMC in patients. These findings suggest that altered limbic input to the SMC and abnormal GABA-mediated beta oscillations in the SMC may underpin some of the sensorimotor processing disturbances in TS and contribute to tic generation., (Published 2014. This article is a U.S. Government work and is in the public domain in the USA.)

Background: The ability of the Essential Tremor (ET) Rating Assessment Scale (TETRAS) to detect changes in tremor severity is unknown., Methods: Fifteen adult ET patients received a single oral ethanol dose calculated to reach 0.05 g/dL breath alcohol content (brAC). Effects were investigated independently with accelerometry and TETRAS., Results: Accelerometry data were log-transformed and a cumulative score logACC(R+L) was calculated. Correlation between logACC(R+L) and TETRAS was significant. TETRAS and accelerometry showed a significant effect of time point using repeated-measures analysis of variance. The difference between baseline and each of the following six time points as well as the correlation of TETRAS with brAC were significant. The calculated minimum detectable change of TETRAS was 8.9% and the effect size was d = 4.75 (95% confidence interval: 3.60-5.90)., Conclusion: We demonstrated sensitivity to change of the TETRAS performance scale after a therapeutic intervention, which further establishes its potential for use in both clinical and research settings., (© 2013 International Parkinson and Movement Disorder Society.)

Sequence learning depends on the striatal system, but recent findings also implicate the mediotemporal lobe (MTL) system. Schendan, Searl, Melrose, and Stern (2003) found higher-order associative, learning-related activation in the striatum, dorsolateral prefrontal cortex, and the MTL during the early acquisition phase of both implicit and explicit variants of a serial response time task. This functional MRI (fMRI) study capitalized on this task to determine how changes in MTL function observed in aging and compromised frontostriatal function characteristic of patients with Parkinson's disease (PD) impacts sequence learning and memory under implicit instructions. Brain activity was compared between "sequence" and "random" conditions in 12 nondemented patients with PD and education- and gender-matched healthy control participants of whom 12 were age matched (MC) and 14 were younger (YC). Behaviorally, sequence-specific learning of higher-order associations was reduced with aging and changed further with PD and resulted primarily in implicit knowledge in the older participants. fMRI revealed reduced intensity and extent of sequence learning-related activation in older relative to younger people in frontostriatal circuits and the MTL. This was because signal was greater for the sequence than random condition in younger people, whereas older people, especially those with PD, showed the opposite pattern. Both older groups also showed increased activation to the task itself relative to baseline fixation. In addition, right MTL showed hypoactivation and left MTL hyperactivation in PD relative to the MC group. The results suggest changes in frontostriatal and MTL activity occur during aging that affect task-related activity and the initial acquisition phase of implicit higher-order sequence learning. In addition, the results suggest that Parkinson's disease adversely affects processes in the MTL including sequence learning and memory.

Abstract Investigations into the neurobiological substrates underlying urge are important for developing better understanding and treatment for impulse-control disorders. We characterize the phenomenon based on normal bodily (interoceptive) urges. Features include the following: a preceding awareness of an uncomfortable bodily sensation, a sense of urgency that action must be taken, rising distress when action is delayed, a temporary (e.g., a few minutes in length) ability to suppress or manifest the action voluntarily, subsequent relief once action is taken, association with an action that is necessary to survival. We compare and contrast these characteristics with those described by Tourette syndrome patients as the urge to tic, and highlight several unknowns which merit further investigation.

Neurodegeneration in clinically manifest Parkinson's disease affects the substantia nigra pars compacta, and gradually spreads to the limbic cortices and the neocortex. We used MRI imaging coupled with automated surface reconstruction and segmentation methods to examine cortical thickness and subcortical volumes in nondemented, early-stage Parkinson's disease patients compared to matched healthy control participants. These methods, which have been previously used to document cortical thickness changes in patients with Alzheimer's disease and Huntington's disease but not Parkinson's disease, use MR signal intensity information and the geometric constraints of the cortical and subcortical structures for an accurate tissue classification. Parkinson's disease patients were matched to the control group in psychomotor processing speed and executive functioning, but showed higher anxiety state scores. Our results demonstrated focal cortical thinning in the Parkinson's disease group in the orbitofrontal cortex, ventrolateral prefrontal cortex, and occipito-parietal areas. Subcortically, striatal volume loss was noted. These results demonstrate that both cortical and subcortical structural changes occur at relatively early stages of the disease, and are discussed in terms of the emotional dysregulation that occurs early on in patients with Parkinson's disease., (Copyright © 2010 Movement Disorder Society.)

The human immunodeficiency virus (HIV) damages fronto-striatal regions, and is associated with deficits in executive functioning. We recently developed a semantic event sequencing task based on the Picture Arrangement subtest of the Wechsler Adult Intelligence Scale-III for use with functional magnetic resonance imaging (fMRI) and found recruitment of dorsolateral prefrontal cortex and basal ganglia in healthy participants. To assess the impact of HIV on the functioning of the basal ganglia and prefrontal cortex, we administered this task to 11 HIV+ and 11 Control participants matched for age and education. Neuropsychological evaluation demonstrated that the HIV+ group had mild impairment in memory retrieval and motor functioning, but was not demented. Morphometric measurements suggested no atrophy in basal ganglia regions. The results of the fMRI analysis revealed hypoactivation of the left caudate, left dorsolateral prefrontal cortex, and bilateral ventral prefrontal cortex in the HIV+ group. Functional connectivity analysis demonstrated less functional connectivity between the caudate and prefrontal cortex and basal ganglia regions in the HIV+ group. In contrast, the HIV+ group demonstrated increased activation of right postcentral/supramarginal gyrus, and greater connectivity between the caudate and this same anterior parietal region. The results of this study extend previous investigations by demonstrating compromised function of the caudate and connected prefrontal regions in HIV during cognition. This disruption of fronto-striatal circuitry likely precedes the development of cognitive impairment in HIV.

Studies of Parkinson's disease (PD) suggest that cognitive deficits accompany the classically recognized motor symptoms, and that these cognitive deficits may result from damage to frontal-basal ganglia circuits. PD patients are impaired on ordering events and action components into coherent sequences. In this study, we examined early-stage, nondemented, medicated PD subjects and matched control subjects during a semantic event sequencing task using functional MRI (fMRI). The task required subjects to examine four pictures of meaningful events, determine the correct temporal relationship between each picture, and re-order the pictures into a coherent sequence. There were two main findings. First, we found abnormal activation within the prefrontal cortex (PFC) and the "default" network in the PD group. Distinct areas of the PFC showed both hypoactivation and hyperactivation, whereas the "default" network showed reduced levels of resting activation in PD. Secondly, we observed left caudate hyperactivation in the PD group. The findings are discussed in relationship to how more activation may be compensatory, but does not necessarily mean efficient and correlated brain function.

Recent delayed matching studies have demonstrated that maintaining trial-unique stimuli in working memory modulates activity in temporal lobe structures. In contrast, most previous studies that focused on the role of the prefrontal cortex (PFC) used familiar stimuli. We combined fMRI with a delayed-match-to-sample (DMS) task in humans that allowed us to manipulate stimulus pre-exposure (trial-unique vs. familiar objects) and stimulus domain (object vs. location). A visually guided saccade task was used to localize the frontal eye fields (FEF). We addressed two questions: First, we examined whether delay-period activity within PFC regions was more strongly engaged when stimuli were familiar (pre-exposed) than when they were not seen previously (trial-unique). Second, we examined the role of regions within the PFC in object vs. location working memory. Subjects were instructed to remember one stimulus domain while ignoring the other over an 8-s delay period. Object-specific delay-period activity was greatest in the posterior orbitofrontal cortex (OFC) bilaterally, and was stronger for familiar than trial-unique objects. In addition, consistent with previous findings, right posterior superior frontal sulcus, and the FEF were specifically active during the delay period of the location DMS task. These activations outside FEF were not related to saccadic eye movements. In contrast to previous reports, object-specific delay activity was more prominent in the posterior OFC than in the ventrolateral PFC, and was found to be greater for familiar than for trial-unique objects. These results suggest a critical role for the orbitofrontal cortex for maintaining object information in working memory.

Semantic event sequencing is the ability to plan ahead and order meaningful events chronologically. To investigate the neural systems supporting this ability, an fMRI picture sequencing task was developed. Participants sequenced a series of four pictures presented in random order based on the temporal relationship among them. A control object discrimination task was designed to be comparable to the sequencing task regarding semantic, visuospatial, and motor processing requirements but without sequencing demands. fMRI revealed significant activation in the dorsolateral prefrontal cortex and globus pallidus internal part in the picture sequencing task compared with the control task. The findings suggest that circuits involving the frontal lobe and basal ganglia output nuclei are important for picture sequencing and more generally for the sequential ordering of events. This is consistent with the idea that the basal ganglia output nuclei are critical not only for motor but also for high-level cognitive function, including behaviors involving meaningful information. We suggest that the interaction between the frontal lobes and basal ganglia output nuclei in semantic event sequencing can be generalized to include the sequential ordering of behaviors in which the selective updating of neural representations is the key computation.

The objective is to study risk factors for Alzheimer disease (AD) in Istanbul, Turkey. This is a population-based case-control study. We screened people over age 70 in the community for cognitive impairment. The screen positives and a proportion of screen negatives underwent neurologic examination in the second phase. Cases were 57 "probable" AD patients and controls were 127 cognitively normal individuals identified by neurologic examination. Odds ratios (OR) were calculated using multivariate logistic regression analysis. Having a university/college degree had a protective effect on AD risk (OR = 0.10, 95% confidence interval [CI] = 0.02-0.50). Exposure to occupational electromagnetic field had an OR of 4.02 (95% CI = 1.02-15.78). Use of electricity for residential heating also showed elevated risk (OR = 2.77, 95% CI = 1.12-6.85). Our results suggest that having a higher education is protective from AD and that electromagnetic field exposure at work or at home is a significant risk factor.