Mental imagery is the mental recreation of perceptual experiences, events and scenarios, and moto... more Mental imagery is the mental recreation 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.
Please check your proof carefully and mark all corrections at the appropriate place in the proof ... more Please check your proof carefully and mark all corrections at the appropriate place in the proof (e.g., by using on-screen annotation in the PDF file) or compile them in a separate list. Note: if you opt to annotate the file with software other than Adobe Reader then please also highlight the appropriate place in the PDF file. To ensure fast publication of your paper please return your corrections within 48 hours.
Parkinson’s disease (PD) is a common and complex neurodegenerative disorder with 5 stages in the ... more Parkinson’s disease (PD) is a common and complex neurodegenerative disorder with 5 stages in the Hoehn and Yahr scaling. Given the heterogeneity of PD, it is challenging to classify early stages 1 and 2 and detect brain function alterations. Functional magnetic resonance imaging (fMRI) is a promising tool in revealing functional connectivity (FC) differences and developing biomarkers in PD. Some machine learning approaches like support vector machine and logistic regression have been successfully applied in the early diagnosis of PD using fMRI data, which outperform classifiers based on manually selected morphological features. However, the early-stage characterization in FC changes has not been fully investigated. Given the complexity and non-linearity of fMRI data, we propose the use of a long short-term memory (LSTM) network to characterize the early stages of PD. The study included 84 subjects (56 in stage 2 and 28 in stage 1) from the Parkinson’s Progression Markers Initiative ...
ABSTRACTParkinson’s disease (PD) is characterized clinically by various motor and nonmotor sympto... more ABSTRACTParkinson’s disease (PD) is characterized clinically by various motor and nonmotor symptoms. The underlying neuroanatomical correlates of nonmotor symptoms in PD remain poorly understood. We investigated the differences and commonalities in the neuroanatomical correlates 1) between highly prevalent nonmotor features including fatigue, anxiety, depression, and apathy, and 2) between these nonmotor features and motor severity in nondemented subjects with mild PD (Hoehn & Yahr disease stage 2) using structural and functional magnetic resonance imaging. Compared to matched controls, the PD group showed atrophy in the basal ganglia and superior frontal cortex. Motor severity correlated with cortical thinning in frontotemporal regions, as well as with reduced functional connectivity between the frontostriatal and cerebellar networks. The composite nonmotor symptom severity did not show any correlation with the structural brain data, but correlated with reduced functional connectiv...
Parkinson disease is characterized by motor and nonmotor symptoms, reduced striatal dopamine sign... more 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.
Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PD-D) are Lewy body-related... more 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 ...
Neurofeedback-Guided Motor Imagery in PD After 10-12 neurofeedback sessions and "off-line" practi... more Neurofeedback-Guided Motor Imagery in PD 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.
Parkinson's disease (PD) leads to dysfunction in multiple cortico-striatal circuits. The neurodeg... more 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.
Decision-making is the process of choosing an appropriate series of goal-directed actions. It is ... more Decision-making is the process of choosing an appropriate series of goal-directed actions. It is a multidisciplinary topic that has been approached from different angles in various research fields including psychology, neuroscience, and economics. Our decisions are informed by our past (memory), dependent on the current situation (context), and are motivated by rewards. Basic reward features including magnitude, probability, and time play a central role in decision-making processes. Extensive research has explored the elements of decision-making in detailed computational models and demonstrated the potential neurophysiological mechanisms for decision-making using functional neuroimaging methods. There is an extensive literature on the role of basal ganglia-cortical circuits and dopamine in decision-making in healthy people and individuals with neuropsychiatric disorders. In this chapter, we provide an overview of terms used in decision-making research and an overview of the behavioral and neural correlates of decision-making. This is followed by a description of how different aspects of decision-making are affected in a number of neuropsychiatric conditions. Basic research provides a framework for analyzing potential pathological mechanisms within the basal ganglia-cortical circuits that contribute to decision-making deficits across different neuropsychiatric disorders. In particular, disturbances in dopaminergic pathways and the regulation of these pathways could contribute to alterations in decision-making in disorders including Parkinson’s disease, Attention Deficit Hyperactivity Disorder, Obsessive Compulsive Disorder, Tourette syndrome, Schizophrenia, and Mood disorders.
Bradykinesia is the most disabling motor symptom of Parkinson's disease (PD). The sequence effect... more 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 essenti... more 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 (E max) 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 NCT01468948 FUNDING.
Background-The mid-posterior part of the insula is involved in processing bodily sensations and u... more 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, on the other hand, 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. The current 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 to 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
Tourette syndrome (TS) is a neuropsychiatric disorder characterized by motor and vocal tics. Most... more 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 betwe...
Neurodegeneration in clinically manifest Parkinson's disease affects the substantia nigra pars co... more 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.
Background-The Essential Tremor (ET) Rating Assessment Scale (TETRAS) has shown excellent inter-a... more Background-The Essential Tremor (ET) Rating Assessment Scale (TETRAS) has shown excellent inter-and intra-rater reliability. To assess the scale's ability to detect changes in tremor severity, we compared TETRAS performance with standard postural tremor accelerometry during a standardized ethanol challenge. Methods-Fifteen adult ET patients received a single oral ethanol dose calculated to reach 0.05 g/dl breath alcohol content (brAC) on two different study days. Two investigators independently assessed the effects with accelerometry on one day and with TETRAS on another day. Measurements were taken at 8 time-points (2 time-points baseline and 6 time-points up to 2 hours post ethanol). Further outcome measures included brAC readings at the same time points. Results-Because correlation between TETRAS and accelerometry revealed a logarithmic relation, for all comparisons, accelerometry data were log-transformed and a cumulative score logACC(R+L) was calculated. Correlation between logACC(R+L) and TETRAS was significant (r= 0.57, p<0.01). Repeated measures ANOVA for both TETRAS and accelerometry before and after ethanol showed a significant effect of time-point (F=34.6, p<0.01; F=13.5, p<0.01). Corrected post-hoc tests showed a difference between baseline and each of the following 6 timepoints. TETRAS and brAC were significantly correlated (r=−0.29, p<0.01). Intra-rater test-retest analysis between baseline measures showed high correlation (ICC=0.974, p<0.001). The ethanol challenge showed excellent reproducibility. Conclusion-We demonstrated sensitivity of the TETRAS performance scale to change after a therapeutic intervention. Our study provides responsiveness validity for TETRAS, further establishing its potential as a valid instrument for ET evaluation in both clinical and research settings.
Sequence learning depends on the striatal system, but recent findings also implicate the mediotem... more Sequence learning depends on the striatal system, but recent findings also implicate the mediotemporal lobe (MTL) system. Schendan, Searl, Melrose, & 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 magnetic resonance imaging (fMRI) study capitalized on this task to determine how changes in MTL function observed in aging and compromised frontostriatal function characteristic of Parkinson's disease (PD) patients impacts sequence learning and memory under implicit instructions. Brain activity was compared between "Sequence" and "Random" conditions in 12 non-demented PD patients 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
BackgroundParkinson’s disease (PD) causes difficulty with maintaining the speed, size, and vigor ... more BackgroundParkinson’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.MethodsWe 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 base...
Dementia with Lewy Bodies (DLB) and Parkinson's disease dementia (PD-D) are Lewy body (LB)-relate... more Dementia with Lewy Bodies (DLB) and Parkinson's disease dementia (PD-D) are Lewy body (LB)-related neurodegen-erative dementias sharing many clinical and neuropatholo-gical features. Both conditions affect cognition, behavior, movement, and autonomic functions. When the clinical picture is fully developed, DLB and PD-D are practically indistinguishable. Regarding molecular pathology, both are synucleinopathies, characterized by the accumulation of misfolded α-synuclein protein in the form of LBs and Lewy neurites. DLB and PD-D are believed to represent two entities on the same disease spectrum. The main difference between these two conditions is the temporal sequence of symptoms. Motor symptoms precede dementia in PD-D, whereas it coincides with or follows dementia in DLB within 1 year. Dementia with Lewy Bodies DLB is the second most common neurodegenerative dementia following Alzheimer's disease (AD). In contrast to AD, motor and behavioral symptoms appear early in the course of the disease in DLB and may be the major burden of the disease. Epidemiology and Risk Factors DLB accounts for 5% of all dementia cases over the age of 75. 1 In a systematic review, the prevalence of DLB was found to be between 0.02 and 33.3 per 1,000. 1 The incidence rate of DLB is 3.5 per 100,000 person-years overall, 2 and the incidence increases with age. 3 Risk factors associated with DLB are old age, mutations in the glucocerebrosidase (GBA) and α-synuclein genes, and carrying the H1 haplotype of the microtubule-associated protein tau (MAPT). 4-6 There are also new candidate risk genes associated with DLB such as BCL7C and GABRB3. 7 Compared with AD, the findings on apolipoprotein E4 (APOE) polymorphisms in DLB are inconclusive. Vascular risk factors are less associated with DLB compared with AD. Clinical Features The cardinal clinical features of DLB consist of motor, cog-nitive, behavioral, and autonomic symptoms. The cognitive profile is characterized by particularly severe deficits in attention as well as executive and visuospatial functions. In early phases of the disease, memory may be relatively Keywords ► dementia with Lewy bodies ► Parkinson's disease dementia ► synucleinopathy ► imaging Abstract 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.
Mental imagery is the mental recreation of perceptual experiences, events and scenarios, and moto... more Mental imagery is the mental recreation 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.
Please check your proof carefully and mark all corrections at the appropriate place in the proof ... more Please check your proof carefully and mark all corrections at the appropriate place in the proof (e.g., by using on-screen annotation in the PDF file) or compile them in a separate list. Note: if you opt to annotate the file with software other than Adobe Reader then please also highlight the appropriate place in the PDF file. To ensure fast publication of your paper please return your corrections within 48 hours.
Parkinson’s disease (PD) is a common and complex neurodegenerative disorder with 5 stages in the ... more Parkinson’s disease (PD) is a common and complex neurodegenerative disorder with 5 stages in the Hoehn and Yahr scaling. Given the heterogeneity of PD, it is challenging to classify early stages 1 and 2 and detect brain function alterations. Functional magnetic resonance imaging (fMRI) is a promising tool in revealing functional connectivity (FC) differences and developing biomarkers in PD. Some machine learning approaches like support vector machine and logistic regression have been successfully applied in the early diagnosis of PD using fMRI data, which outperform classifiers based on manually selected morphological features. However, the early-stage characterization in FC changes has not been fully investigated. Given the complexity and non-linearity of fMRI data, we propose the use of a long short-term memory (LSTM) network to characterize the early stages of PD. The study included 84 subjects (56 in stage 2 and 28 in stage 1) from the Parkinson’s Progression Markers Initiative ...
ABSTRACTParkinson’s disease (PD) is characterized clinically by various motor and nonmotor sympto... more ABSTRACTParkinson’s disease (PD) is characterized clinically by various motor and nonmotor symptoms. The underlying neuroanatomical correlates of nonmotor symptoms in PD remain poorly understood. We investigated the differences and commonalities in the neuroanatomical correlates 1) between highly prevalent nonmotor features including fatigue, anxiety, depression, and apathy, and 2) between these nonmotor features and motor severity in nondemented subjects with mild PD (Hoehn & Yahr disease stage 2) using structural and functional magnetic resonance imaging. Compared to matched controls, the PD group showed atrophy in the basal ganglia and superior frontal cortex. Motor severity correlated with cortical thinning in frontotemporal regions, as well as with reduced functional connectivity between the frontostriatal and cerebellar networks. The composite nonmotor symptom severity did not show any correlation with the structural brain data, but correlated with reduced functional connectiv...
Parkinson disease is characterized by motor and nonmotor symptoms, reduced striatal dopamine sign... more 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.
Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PD-D) are Lewy body-related... more 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 ...
Neurofeedback-Guided Motor Imagery in PD After 10-12 neurofeedback sessions and "off-line" practi... more Neurofeedback-Guided Motor Imagery in PD 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.
Parkinson's disease (PD) leads to dysfunction in multiple cortico-striatal circuits. The neurodeg... more 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.
Decision-making is the process of choosing an appropriate series of goal-directed actions. It is ... more Decision-making is the process of choosing an appropriate series of goal-directed actions. It is a multidisciplinary topic that has been approached from different angles in various research fields including psychology, neuroscience, and economics. Our decisions are informed by our past (memory), dependent on the current situation (context), and are motivated by rewards. Basic reward features including magnitude, probability, and time play a central role in decision-making processes. Extensive research has explored the elements of decision-making in detailed computational models and demonstrated the potential neurophysiological mechanisms for decision-making using functional neuroimaging methods. There is an extensive literature on the role of basal ganglia-cortical circuits and dopamine in decision-making in healthy people and individuals with neuropsychiatric disorders. In this chapter, we provide an overview of terms used in decision-making research and an overview of the behavioral and neural correlates of decision-making. This is followed by a description of how different aspects of decision-making are affected in a number of neuropsychiatric conditions. Basic research provides a framework for analyzing potential pathological mechanisms within the basal ganglia-cortical circuits that contribute to decision-making deficits across different neuropsychiatric disorders. In particular, disturbances in dopaminergic pathways and the regulation of these pathways could contribute to alterations in decision-making in disorders including Parkinson’s disease, Attention Deficit Hyperactivity Disorder, Obsessive Compulsive Disorder, Tourette syndrome, Schizophrenia, and Mood disorders.
Bradykinesia is the most disabling motor symptom of Parkinson's disease (PD). The sequence effect... more 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 essenti... more 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 (E max) 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 NCT01468948 FUNDING.
Background-The mid-posterior part of the insula is involved in processing bodily sensations and u... more 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, on the other hand, 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. The current 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 to 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
Tourette syndrome (TS) is a neuropsychiatric disorder characterized by motor and vocal tics. Most... more 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 betwe...
Neurodegeneration in clinically manifest Parkinson's disease affects the substantia nigra pars co... more 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.
Background-The Essential Tremor (ET) Rating Assessment Scale (TETRAS) has shown excellent inter-a... more Background-The Essential Tremor (ET) Rating Assessment Scale (TETRAS) has shown excellent inter-and intra-rater reliability. To assess the scale's ability to detect changes in tremor severity, we compared TETRAS performance with standard postural tremor accelerometry during a standardized ethanol challenge. Methods-Fifteen adult ET patients received a single oral ethanol dose calculated to reach 0.05 g/dl breath alcohol content (brAC) on two different study days. Two investigators independently assessed the effects with accelerometry on one day and with TETRAS on another day. Measurements were taken at 8 time-points (2 time-points baseline and 6 time-points up to 2 hours post ethanol). Further outcome measures included brAC readings at the same time points. Results-Because correlation between TETRAS and accelerometry revealed a logarithmic relation, for all comparisons, accelerometry data were log-transformed and a cumulative score logACC(R+L) was calculated. Correlation between logACC(R+L) and TETRAS was significant (r= 0.57, p<0.01). Repeated measures ANOVA for both TETRAS and accelerometry before and after ethanol showed a significant effect of time-point (F=34.6, p<0.01; F=13.5, p<0.01). Corrected post-hoc tests showed a difference between baseline and each of the following 6 timepoints. TETRAS and brAC were significantly correlated (r=−0.29, p<0.01). Intra-rater test-retest analysis between baseline measures showed high correlation (ICC=0.974, p<0.001). The ethanol challenge showed excellent reproducibility. Conclusion-We demonstrated sensitivity of the TETRAS performance scale to change after a therapeutic intervention. Our study provides responsiveness validity for TETRAS, further establishing its potential as a valid instrument for ET evaluation in both clinical and research settings.
Sequence learning depends on the striatal system, but recent findings also implicate the mediotem... more Sequence learning depends on the striatal system, but recent findings also implicate the mediotemporal lobe (MTL) system. Schendan, Searl, Melrose, & 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 magnetic resonance imaging (fMRI) study capitalized on this task to determine how changes in MTL function observed in aging and compromised frontostriatal function characteristic of Parkinson's disease (PD) patients impacts sequence learning and memory under implicit instructions. Brain activity was compared between "Sequence" and "Random" conditions in 12 non-demented PD patients 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
BackgroundParkinson’s disease (PD) causes difficulty with maintaining the speed, size, and vigor ... more BackgroundParkinson’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.MethodsWe 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 base...
Dementia with Lewy Bodies (DLB) and Parkinson's disease dementia (PD-D) are Lewy body (LB)-relate... more Dementia with Lewy Bodies (DLB) and Parkinson's disease dementia (PD-D) are Lewy body (LB)-related neurodegen-erative dementias sharing many clinical and neuropatholo-gical features. Both conditions affect cognition, behavior, movement, and autonomic functions. When the clinical picture is fully developed, DLB and PD-D are practically indistinguishable. Regarding molecular pathology, both are synucleinopathies, characterized by the accumulation of misfolded α-synuclein protein in the form of LBs and Lewy neurites. DLB and PD-D are believed to represent two entities on the same disease spectrum. The main difference between these two conditions is the temporal sequence of symptoms. Motor symptoms precede dementia in PD-D, whereas it coincides with or follows dementia in DLB within 1 year. Dementia with Lewy Bodies DLB is the second most common neurodegenerative dementia following Alzheimer's disease (AD). In contrast to AD, motor and behavioral symptoms appear early in the course of the disease in DLB and may be the major burden of the disease. Epidemiology and Risk Factors DLB accounts for 5% of all dementia cases over the age of 75. 1 In a systematic review, the prevalence of DLB was found to be between 0.02 and 33.3 per 1,000. 1 The incidence rate of DLB is 3.5 per 100,000 person-years overall, 2 and the incidence increases with age. 3 Risk factors associated with DLB are old age, mutations in the glucocerebrosidase (GBA) and α-synuclein genes, and carrying the H1 haplotype of the microtubule-associated protein tau (MAPT). 4-6 There are also new candidate risk genes associated with DLB such as BCL7C and GABRB3. 7 Compared with AD, the findings on apolipoprotein E4 (APOE) polymorphisms in DLB are inconclusive. Vascular risk factors are less associated with DLB compared with AD. Clinical Features The cardinal clinical features of DLB consist of motor, cog-nitive, behavioral, and autonomic symptoms. The cognitive profile is characterized by particularly severe deficits in attention as well as executive and visuospatial functions. In early phases of the disease, memory may be relatively Keywords ► dementia with Lewy bodies ► Parkinson's disease dementia ► synucleinopathy ► imaging Abstract 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.
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Papers by Sule Tinaz