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Dopaminergic modulation of the default mode network in Parkinson's disease
Abstract
Default mode network (DMN) is characterized by a deactivation of several cortical areas (including medial prefrontal cortex and posterior cingulate cortex) during goal-directed experimental tasks. Few findings are reported on DMN and the involvement of dopaminergic medication on this network in Parkinson's disease (PD). To evaluate the effect of levodopa on DMN deactivation, we conducted a randomized, crossover, placebo-controlled experiment consisting of two fMRI assessments in fourteen non-demented, non-depressed PD patients compared to thirteen healthy volunteers. They received either acute doses of levodopa or placebo in two fMRI sessions. Brain deactivation was evaluated during a facial emotion recognition task. While the control subjects showed a classical brain deactivation pattern during the emotional task, the PD patients taking placebo only deactivated the ventral medial prefrontal cortex. Patients failed to deactivate the posterior midline and lateral parts of DMN network. After levodopa administration, this network was restored conjointly with the improvement of motor dysfunction in PD patients. The levodopa effect on DMN is probably the consequence of a beneficial dopamine (DA) medication effect which leads to a fine tuning of the dopamine level in the motor part of striatum, resulting to a global improvement of physical state of PD patients and consequently an increased attentional resource to external stimuli. The absence of medial prefrontal deactivation impairment may suggest a preserved mesocortical DA system in these patients.
... In addition to the behavioral deficits, imaging studies indicated neural disturbances in emotional face processing in PD patients, yet studies remain scarce. During matching of negative facial expressions, PD patients showed greater activity in the amygdala and the posterior fusiform gyrus compared to controls in addition to decreased deactivation of the default mode network ( Delaveau et al., 2010 ). During passive viewing of dynamic facial expressions, reduced neural activity was found in PD patients on medication compared to healthy controls, in diverse brain regions across emotion categories. ...
... However, the effects of dopaminergic medication on emotion recognition in PD remain unclear with inconsistent behavioral findings ( Argaud et al., 2018 ;Gray and Tickle-Degnen, 2010 ). The few imaging studies that compared PD patients on and off medication have suggested partial normalization of neural activity following dopaminergic medication ( Delaveau et al., 2010 ;Fleury et al., 2014 ;Tessitore et al., 2002 ). In this context, it was proposed ( Argaud et al., 2018 ) that in early disease stages when mesocorticolimbic pathways are relatively intact, dopaminergic medication results with an overdose effect on mesolimibic projections to regions such as the amygdala. ...
... Subjects responded by pressing one of two possible buttons with their right hand and subject accuracy and reaction time were collected for each trial. Note that this task was previously used in PD patients, however past analyses were restricted to the amygdala or to deactivations ( Delaveau et al., 2010 ), and did not consider cognitive function. ...
Emotional and cognitive impairments in Parkinson's disease (PD) are prevalent, hamper interpersonal relations and reduce quality of life. It is however unclear to what extent these domains interplay in PD-related deficits and how they are influenced by dopaminergic availability. This study examined the effect of cognitive impairment and dopaminergic medication on neural and behavioral mechanisms of facial emotion recognition in PD patients. PD patients on and off dopaminergic medication and matched healthy controls underwent an emotional face matching task during functional MRI. In addition, a comprehensive neuropsychological evaluation of cognitive function was conducted. Increased BOLD response to emotional faces was found in the visual cortex of PD patients relative to controls irrespective of cognitive function and medication status. Administration of dopaminergic medication in PD patients resulted in restored behavioral accuracy for emotional faces relative to controls and decreased retrosplenial cortex BOLD response to emotion relative to off-medication state. Furthermore, cognitive impairment in PD patients was associated with reduced behavioral accuracy for non-emotional stimuli and predicted BOLD response to emotion in the anterior and posterior cingulate cortices, depending on medication status. Findings of aberrant visual and retrosplenial BOLD response to emotion are suggested to stem from altered attentional and/or emotion-driven modulation from subcortical and higher cortical regions. Our results indicate neural disruptions and behavioral deficits in emotion processing in PD patients that are dependent on dopaminergic availability and independent of cognitive function. Our findings highlight the importance of dopaminergic treatment not only for the motor symptoms but also the emotional disturbances in PD.
... In the same population, Delaveau et al. [26] investigated the effect of levodopa on default mode network (DMN) deactivation during the same FER task. Whereas the control group showed the classical deactivation of cortical areas (e.g., medial prefrontal cortex and posterior cingulate cortex), PD patients under placebo did not. ...
... The included studies have investigated multiple aspects of emotional processing in PD such as facial emotion recognition, physiological arousal, and emotional prosody. In the majority of studies, PD patients showed no behavioral deficits in the ability to accurately recognize and respond to emotional stimuli [22,24,[26][27][28][29]39,[41][42][43]. However, some studies did find impairments [23,30,31,35,40], and these overall inconsistencies are probably related to the large differences in sample characteristics and study designs, as well as on the specific aspect or phase of emotional processing that was measured. ...
... Measurements of both structural and functional correlates of emotional processing have provided direct and indirect evidence for the involvement of a number of brain structures, including the orbitofrontal cortices, amygdala, anterior cingulate cortices, and the basal ganglia ( [22,24]; Ibarretxte-Bilbao et al., 2009; [23,26,27,31,39]). Moreover, studies that used a dopaminergic intervention highlighted the importance of disrupted dopamine neurotransmission in emotional processing PD [22,24,26]. ...
Deficits in emotional processing in patients with Parkinson's disease (PD) have received increasing interest over the past decades. In this systematic review, we present the results of 18 behavioral studies that have examined the neurobiological base of emotional processing in PD. Multiple aspects of emotional processing have been studied, using a variety of research methods. Deficits in PD are mainly related to autonomic and perceptive processing of intense emotional stimuli, which is accompanied by structural and functional neurobiological abnormalities in predominantly ventral regions of affective neurocircuitry. These structures are more strongly dependent on dopaminergic neurotransmission than the dorsal structures of affective neurocircuitry, which are more related to the cognitive and regulatory aspects of emotion and appear to remain largely intact in PD patients. Considering the importance of active dopaminergic neurotransmission, PD can serve as a prolific model for studying the neurobiological correlates of normal human emotional behavior as well as psychiatric disorders such as anxiety, depression, and apathy. Moreover, the fact that PD patients are able to cognitively regulate or modulate their emotional responses despite reduced dopamine supplies, can have important implications for the treatment of affective disorders not only in PD patients but in the general population likewise.
... These findings are in line with previous evidence showing that the precuneus is a brain hub that plays an important role in memory, attention, and other cognitive functions (Cavanna and Trimble 2006). Several studies have shown changes in the functional connectivity patterns of the precuneus in PD participants (Delaveau et al. 2010;van Eimeren et al. 2009;Göttlich et al. 2013;Fang et al. 2017). Our findings offer an additional insight into the nature of these alterations. ...
... Therefore, although we tested the antisymmetric correlations on a well-characterized sample of participants with PD, our results should be interpreted with caution, and they should be replicated in larger and independent cohorts that would allow applying more stringent corrections. Furthermore, several participants in the current cohort underwent functional MRI while on medication, which has previously been shown to influence brain connectivity (Palmer et al. 2009;Wu et al. 2009;Delaveau et al. 2010). In this study, we assessed the effects of medication on our results by performing correlation analyses between the levodopa-equivalent doses and the topological graph measures, as well as comparing the networks of medicated and nonmedicated PD groups. ...
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by topological abnormalities in large-scale functional brain networks, which are commonly analyzed using undirected correlations in the activation signals between brain regions. This approach assumes simultaneous activation of brain regions, despite previous evidence showing that brain activation entails causality, with signals being typically generated in one region and then propagated to other ones. To address this limitation, here, we developed a new method to assess whole-brain directed functional connectivity in participants with PD and healthy controls using antisymmetric delayed correlations, which capture better this underlying causality. Our results show that whole-brain directed connectivity, computed on functional magnetic resonance imaging data, identifies widespread differences in the functional networks of PD participants compared with controls, in contrast to undirected methods. These differences are characterized by increased global efficiency, clustering, and transitivity combined with lower modularity. Moreover, directed connectivity patterns in the precuneus, thalamus, and cerebellum were associated with motor, executive, and memory deficits in PD participants. Altogether, these findings suggest that directional brain connectivity is more sensitive to functional network differences occurring in PD compared with standard methods, opening new opportunities for brain connectivity analysis and development of new markers to track PD progression.
... These findings are in line with previous evidence showing that the precuneus is a brain hub that plays an important role in memory, attention and other cognitive functions [12]. Several studies have shown changes in the functional connectivity patterns of the precuneus in PD patients [15,16,26,63]. Our findings offer an additional insight into the nature of these alterations. ...
... Although we tested the anti-symmetric correlations on a well characterized sample of PD patients, our findings should be replicated in larger and independent cohorts. In particular, several patients in the current cohort underwent functional MRI while on medication, which has previously been shown to influence brain connectivity [15,45,67]. In this study, we assessed the effects of medication on our results by performing correlation analyses between the levodopa-equivalent doses and the topological graph measures, as well as comparing the networks of medicated and non-medicated patient groups. ...
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by topological changes in large-scale functional brain networks. These networks are commonly analysed using undirected correlations between the activation signals of brain regions. However, this approach suffers from an important drawback: it assumes that brain regions get activated at the same time, despite previous evidence showing that brain activation features causality, with signals being typically generated in one region and then propagated to other ones. Thus, in order to address this limitation, in this study we developed a new method to assess whole-brain directed functional connectivity in patients with PD and healthy controls using anti-symmetric delayed correlations, which capture better this underlying causality. To test the potential of this new method, we compared it to standard connectivity analyses based on undirected correlations. Our results show that whole-brain directed connectivity identifies widespread changes in the functional networks of PD patients compared to controls, in contrast to undirected methods. These changes are characterized by increased global efficiency, clustering and transitivity as well as lower modularity. In addition, changes in the directed connectivity patterns in the precuneus, thalamus and superior frontal gyrus were associated with motor, executive and memory deficits in PD patients. Altogether, these findings suggest that directional brain connectivity is more sensitive to functional network changes occurring in PD compared to standard methods. This opens new opportunities for the analysis of brain connectivity and the development of new brain connectivity markers to track PD progression.
... This network mostly consists of hub-like brain structures including the medial prefrontal cortex (PFC), the precuneus, and the posterior cingulate cortex (Hagmann et al., 2008). In PD patients, there are PD specific changes in the DMN (Delaveau et al., 2010;van Eimeren et al., 2009). These changes were restored by DRT (Delaveau et al., 2010) and possibly will also be restored by DBS in the future (Kringelbach et al., 2011). ...
... In PD patients, there are PD specific changes in the DMN (Delaveau et al., 2010;van Eimeren et al., 2009). These changes were restored by DRT (Delaveau et al., 2010) and possibly will also be restored by DBS in the future (Kringelbach et al., 2011). ...
Oscillatory brain activities support many physiological functions from motor control to cognition. Disruptions of the normal oscillatory brain activities are commonly observed in neurological and psychiatric disorders including epilepsy, Parkinson's disease, Alzheimer's disease, schizophrenia, anxiety/trauma-related disorders, major depressive disorders, and drug addiction. Therefore, these disorders can be considered as common oscillation defects despite having distinct behavioral manifestations and genetic causes. Recent technical advances of neuronal activity recording and analysis have allowed us to study the pathological oscillations of each disorder as a possible biomarker of symptoms. Furthermore, recent advances in brain stimulation technologies enable time- and space-targeted interventions of the pathological oscillations of both neurological disorders and psychiatric disorders as possible targets for regulating their symptoms.
... In patients with PD slower processing speeds were associated with decreased DMN connectivity at rest, specifically between the posterior cingulate, medial prefrontal and inferior parietal nodes ( Disbrow et al., 2014). Off medication, PD patients were unable to suppress DMN activity during a facial emotion recognition task ( Delaveau et al., 2010). In the Montreal card-sorting task, a task that involves manipulation of short-term memory, patients with PD showed less deactivation of the DMN as compared to healthy controls (van Eimeren et al., 2009). ...
... Engagement in a cognitive task is associated with significant posterior IPL deactivation ( Greicius et al., 2003;Buckner et al., 2008). Altered IPL and DMN connectivity in PD during task engagement (van Eimeren et al., 2009;Delaveau et al., 2010;Putcha et al., 2016) may represents a failure in activity transition between functional networks ( Putcha et al., 2016). Successful task engagement requires suppression of internally driven processes such as mind-wondering, and the salience network monitors external stimuli and facilitates the suppression of DMN activity and these internally driven processes. ...
Noradrenergic dysfunction contributes to cognitive impairment in Alzheimer's Disease (AD) and Parkinson's Disease (PD). Conventional therapeutic strategies seek to enhance cholinergic and dopaminergic neurotransmission in AD and PD, respectively, and few studies have examined noradrenergic dysfunction as a target for medication development. We review the literature of noradrenergic dysfunction in AD and PD with a focus on human imaging studies that implicate the locus coeruleus (LC) circuit. The LC sends noradrenergic projections diffusely throughout the cerebral cortex and plays a critical role in attention, learning, working memory, and cognitive control. The LC undergoes considerable degeneration in both AD and PD. Advances in magnetic resonance imaging have facilitated greater understanding of how structural and functional alteration of the LC may contribute to cognitive decline in AD and PD. We discuss the potential roles of the noradrenergic system in the pathogenesis of AD and PD with an emphasis on postmortem anatomical studies, structural MRI studies, and functional MRI studies, where we highlight changes in LC connectivity with the default mode network (DMN). LC degeneration may accompany deficient capacity in suppressing DMN activity and increasing saliency and task control network activities to meet behavioral challenges. We finish by proposing potential and new directions of research to address noradrenergic dysfunction in AD and PD.
... In addition, our findings revealed a decreased nodal degree in superior and inferior parietal lobule, whose crucial role in normal aging and neurodegenerative disorders has been reported by several fMRI studies (Delaveau et al. 2010;van Eimeren et al. 2009). A significantly lower degree in PD group was also detected in the inferior frontal gyrus, involved in suppression of habitual responses, an integral part of executive functions known to be affected in PD patients . ...
... Although no correlations were identified between graph parameters and LEDD, the lack of correlations between most of our functional metrics and motor scores could still be attributed to the potentially confounding effects of chronic dopaminergic medications, that can partially restore the deficits in the functional brain network (Delaveau et al. 2010). ...
Cognitive impairment in Parkinson’s disease (PD) is related to the reorganization of brain topology. Although drug challenge studies have proven how levodopa treatment can modulate functional connectivity in brain circuits, the role of chronic dopaminergic therapy on cognitive status and functional connectivity has never been investigated. We sought to characterize brain functional topology in mid-stage PD patients under chronic antiparkinson treatment and explore the presence of correlation between reorganization of brain architecture and specific cognitive deficits. We explored networks topology and functional connectivity in 16 patients with PD and 16 matched controls through a graph theoretical analysis of resting state-functional MRI data, and evaluated the relationships between network metrics and cognitive performance. PD patients showed a preserved small-world network topology but a lower clustering coefficient in comparison with healthy controls. Locally, PD patients showed lower degree of connectivity and local efficiency in many hubs corresponding to functionally relevant areas. Four disconnected subnetworks were also identified in regions responsible for executive control, sensory-motor control and planning, motor coordination and visual elaboration. Executive functions and information processing speed were directly correlated with degree of connectivity and local efficiency in frontal, parietal and occipital areas. While functional reorganization appears in both motor and cognitive areas, the clinical expression of network imbalance seems to be partially compensated by the chronic levodopa treatment with regards to the motor but not to the cognitive performance. In a context of reduced network segregation, the presence of higher local efficiency in hubs regions correlates with a better cognitive performance.
... DRT could influence the perception of facial expressions in two ways: (1) in the late stages of the disease, it may have a beneficial effect (Péron et al., 2014). (2) DRT activates the default mode network, enhancing attentional resources to external cues and emotion perception consequently (Delaveau et al., 2010). In the current investigation, individuals with PD were in the late stages of the disease and were examined while on their regular DRT. ...
Individuals with Parkinson's disease (PD) may exhibit impaired emotion perception. However, research demonstrating this decline has been based almost entirely on the recognition of isolated emotional cues. In real life, emotional cues such as expressive faces are typically encountered alongside expressive bodies. The current study investigated emotion perception in individuals with PD (n = 37) using emotionally incongruent composite displays of facial and body expressions, as well as isolated face and body expressions, and congruent composite displays as a baseline. In addition to a group of healthy controls (HC) (n = 50), we also included control individuals with schizophrenia (SZ) (n = 30), who display, as in PD, similar motor symptomology and decreased emotion perception abilities. The results show that individuals with PD showed an increased tendency to categorize incongruent face-body combinations in line with the body emotion, whereas those with HC showed a tendency to classify them in line with the facial emotion. No consistent pattern for prioritizing the face or body was found in individuals with SZ. These results were not explained by the emotional recognition of the isolated cues, cognitive status, depression, or motor symptoms of individuals with PD and SZ. As real-life expressions may include inconsistent cues in the body and face, these findings may have implications for the way individuals with PD and SZ interpret the emotions of others.
... Further, to address if turning the stimulation on immediately improves and restores global coherence and diffusion of information and helps restoring global dynamics back to a healthy state, we used several metrics that allowed the identification of global enhancements in communicability and synchrony of the network as well producing artificial local oscillatory conditions as a proxy for stimulation. In the light of earlier findings addressing large-scale changes caused by Parkinson's Disease (van Eimeren et al. 2009;Delaveau et al. 2010;Van Hartevelt et al. 2014) and previous research on DBS mechanisms (Kringelbach et al. 2010), we predicted that therapeutic DBS for Parkinson's Disease would create both global and local changes in the whole-brain dynamics. ...
Deep brain stimulation (DBS) for Parkinson's disease is a highly effective treatment in controlling otherwise debilitating symptoms yet the underlying brain mechanisms are currently not well understood. We used whole-brain computational modeling to disclose the effects of DBS ON and OFF during collection of resting state fMRI in ten Parkinson's Disease patients. Specifically, we explored the local and global impact of DBS in creating asynchronous, stable or critical oscillatory conditions using a supercritical bifurcation model. We found that DBS shifts the global brain dynamics of patients nearer to that of healthy people by significantly changing the bifurcation parameters in brain regions implicated in Parkinson's Disease. We also found higher communicability and coherence brain measures during DBS ON compared to DBS OFF. Finally, by modeling stimulation we identified possible novel DBS targets. These results offer important insights into the underlying effects of DBS, which may in time offer a route to more efficacious treatments.
... In addition, neurotoxic beta amyloid has a tendency to cluster in the posterior cingulate (Mihaescu et al., 2022). The DMN is also affected by dopamine depletion such that less dopamine leads to a lack of suppression of the DMN (Delaveau et al., 2010). Multiple characteristics of the SAL, FPN, and DMN are altered in PD. ...
Parkinson’s disease (PD) is a neurodegenerative disease with cognitive as well as motor impairments. While much is known about the brain networks leading to motor impairments in PD, less is known about the brain networks contributing to cognitive impairments. Here, we leveraged resting-state functional magnetic resonance imaging (rs-fMRI) data from the Parkinson’s Progression Marker Initiative (PPMI) to examine network dysfunction in PD patients with cognitive impairment. We focus on canonical cortical networks linked to cognition, including the salience network (SAL), frontoparietal network (FPN), and default mode network (DMN), as well as a subcortical basal ganglia network (BGN). We used the Montreal Cognitive Assessment (MoCA) as a continuous index of coarse cognitive function in PD. In 82 PD patients, we found that lower MoCA scores were linked with lower intra-network connectivity of the FPN. We also found that lower MoCA scores were linked with lower inter-network connectivity between the SAL and the BGN, the SAL and the DMN, as well as the FPN and the DMN. These data elucidate the relationship of cortical and subcortical functional connectivity with cognitive impairments in PD.
... The network described in this article as a frontal network approximates the well-known DMN (Mantini et al., 2007;Brookes et al., 2011), which has been investigated in the context of several diseases, revealing altered DMN activity in various neurological diseases like Alzheimer's disease, epilepsy, and also PD (Mohan et al., 2016). Since dopamine has a modulatory effect on the DMN in face recognition (Delaveau et al., 2010), an influence on the frontal network described by us was expected due to the spatial similarity. Although there was no difference between PD-OFF and PD-ON for the frontal network, there were partially changes of coupling strength between PD-OFF and PD-ON compared to HC, suggesting an influence of dopamine on the network. ...
Introduction
Parkinson’s disease (PD) is a neurodegenerative disorder affecting the whole brain, leading to several motor and non-motor symptoms. In the past, it has been shown that PD alters resting state networks (RSN) in the brain. These networks are usually derived from fMRI BOLD signals. This study investigated RSN changes in PD patients based on maximum phase-amplitude coupling (PAC) throughout the cortex. We also tested the hypothesis that levodopa medication shifts network activity back toward a healthy state.
Methods
We recorded 23 PD patients and 24 healthy age-matched participants for 30 min at rest with magnetoencephalography (MEG). PD patients were measured once in the dopaminergic medication ON and once in the medication OFF state. A T1-MRI brain scan was acquired from each participant for source reconstruction. After correcting the data for artifacts and performing source reconstruction using a linearly constrained minimum variance beamformer, we extracted visual, sensorimotor (SMN), and frontal RSNs based on PAC.
Results
We found significant changes in all networks between healthy participants and PD patients in the medication OFF state. Levodopa had a significant effect on the SMN but not on the other networks. There was no significant change in the optimal PAC coupling frequencies between healthy participants and PD patients.
Discussion
Our results suggest that RSNs, based on PAC in different parts of the cortex, are altered in PD patients. Furthermore, levodopa significantly affects the SMN, reflecting the clinical alleviation of motor symptoms and leading to a network normalization compared to healthy controls.
... Among these 8 FNs, PCUN, as a functional hub of the default mode network (DMN) (Andrews-Hanna et al. 2014), was discriminative for neurological WD. Neurological WD patients had altered DMN's functional brain connectivity (Han et al. 2016), and other existing findings also demonstrated that Parkinson's disease (PD), HD patients and other basal ganglia disorders have disrupted FC in the DMN (Tessitore et al. 2012;Delaveau et al. 2010;Wolf et al. 2012;Quarantelli et al. 2013). The PCUN was involved in visual, sensorimotor, and attentional information. ...
... The PD and HD patients with attention deficits have disrupted functional connectivity in DMN [13,14]. Furthermore, recent functional MRI (fMRI) studies have indicated that default mode network (DMN), particularly the posterior cingulate cortex (PCC), is associated with attention [15,16]. ...
... Previous work has reported functional decoupling of the DMN in PD during rest and tasks [71][72][73][74] . These abnormal manifestations of the DMN have been related to the dopaminergic system, as they can be normalized with levodopa treatment 75,76 . Levodopa and dopamine agonists may therefore help normalize brain activity in DMN regions and consequently, contribute to standardizing neurophysiological signaling across patients. ...
In this study, we investigate the clinical potential of brain-fingerprints derived from electrophysiological brain activity for diagnostics and progression monitoring of Parkinson’s disease (PD). We obtained brain-fingerprints from PD patients and age-matched healthy controls using short, task-free magnetoencephalographic recordings. The rhythmic components of the individual brain-fingerprint distinguished between patients and healthy participants with approximately 90% accuracy. The most prominent cortical features of the Parkinson’s brain-fingerprint mapped to polyrhythmic activity in unimodal sensorimotor regions. Leveraging these features, we also show that Parkinson’s disease stages can be decoded directly from cortical neurophysiological activity. Additionally, our study reveals that the cortical topography of the Parkinson’s brain-fingerprint aligns with that of neurotransmitter systems affected by the disease’s pathophysiology. We further demonstrate that the arrhythmic components of cortical activity are more variable over short periods of time in patients with Parkinson’s disease than in healthy controls, making individual differentiation between patients based on these features more challenging and explaining previous negative published results. Overall, we outline patient-specific rhythmic brain signaling features that provide insights into both the neurophysiological signature and clinical staging of Parkinson’s disease. For this reason, the proposed definition of a rhythmic brain-fingerprint of Parkinson’s disease may contribute to novel, refined approaches to patient stratification and to the improved identification and testing of therapeutic neurostimulation targets.
Lay summary
We propose a new method to help diagnose and monitor Parkinson’s disease (PD) using patients’ unique brain-fingerprint . These fingerprints are based on the brain’s electrical activity, which we measured without any specific tasks, using a technique called magnetoencephalography. Remarkably, we found that these brain-fingerprints can differentiate between people with Parkinson’s and those without, with about 90% accuracy. Specifically, we noticed that certain rhythmic patterns in the brain, particularly in areas involved in sensory and motor functions, were key indicators of Parkinson’s. Interestingly, these patterns also helped us identify the different stages of the disease.
Additionally, our research shows that the arrangement of these brain-fingerprints in Parkinson’s patients corresponds to how the neurochemistry of the brain is impacted by the disease. We also observed that certain irregular patterns in the brain’s activity, which vary more from moment to moment in Parkinson’s patients, make it harder to distinguish between individuals based on these features alone. This finding sheds light on why previous studies reported challenges with similar approaches.
Overall, our study offers new insights into the unique brain activity patterns in Parkinson’s disease and suggests that individual brain-fingerprints could be valuable in tailoring treatment plans and developing new therapies for this condition.
... However, results are inconsistent, with some studies reporting detrimental effects [28,29] whereas others show beneficial effects of Ldopa on emotion recognition [30,31], suggesting that L-dopa partially restores amygdala response but in dependence on disease progression [32]. Furthermore, malfunctioning neural synchronizations within and between the basal ganglia have also been discussed as a neurophysiological underpinning of these deficits in PD [33]. ...
Background:
Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects the motor system but also involves deficits in emotional processing such as facial emotion recognition. In healthy participants, it has been shown that facial mimicry, the automatic imitation of perceived facial expressions, facilitates the interpretation of the emotional states of our counterpart. In PD patients, recent studies revealed reduced facial mimicry and consequently reduced facial feedback, suggesting that this reduction might contribute to the prominent emotion recognition deficits found in PD.
Methods:
We investigate the influence of facial mimicry on facial emotion recognition. Twenty PD patients and 20 healthy controls (HC) underwent a classical facial mimicry manipulation (holding a pen with the lips, teeth or non-dominant hand) while performing an emotional change detection task with faces.
Results:
As expected, emotion recognition was significantly influenced by facial mimicry manipulation in HC further supporting the hypothesis of facial feedback and the related theory of embodied simulation. Importantly, patients with PD generally and independent from the facial mimicry manipulation were impaired in their ability to detected emotion changes. Our data further show that PD patients facial emotional recognition abilities are completely unaffected by mimicry manipulation, assuming that PD patients cannot profit from an artificial modulation of the already impaired facial feedback.
Conclusions:
These findings suggest that it is not the hypomimia and the absence of the facial feedback per se, but a disruption of the facial feedback loop, which leads to the prominent emotion recognition deficit in PD patients.
... [28] Though only a few studies have conducted with cross-over design to assess PD patients under ON and OFF medication state [29] accuracy improves after administration of DRT as it activates default mode network. [30] Role of STN-DBS is not widely studied where few studies report STN-DBS does not affect emotion recognition performance [31][32][33] while other reports a contrary finding. [34] In conclusion, facial emotion recognition studies found that mild to moderate PD individuals appear to have deficits in perception of negative emotions while advanced PD patients report of broad emotion perception deficits. ...
Non-motor symptoms (NMS) are common among Parkinson's disease (PD) patients and have a significant impact on quality of life. NMS such as deficits in emotion perception are gaining due focus in the recent times. As emotion perception and cognitive functions share certain common neural substrates, it becomes pertinent to evaluate existing emotion perception deficits in view of underlying cognitive deficits. The current systematic review aimed at examining studies on emotion perception PD in the last decade. We carried out a systematic review of 44 studies from the PubMed database. We reviewed studies examining emotion perception and associated cognitive deficits, especially executive function and visuospatial function in PD. This review also examines how early and advanced PD differ in emotion perception deficits and how the presence of common neuropsychiatric conditions such as anxiety, apathy, and depression as well as neurosurgical procedure such as deep brain stimulation affect emotion perception. The need for future research employing a comprehensive evaluation of neurocognitive functions and emotion perception is underscored as it has a significant bearing on planning holistic intervention strategies.
... This over-activation has been reported in the medial prefrontal cortex 18,19 and precuneus 21,25 while performing motor and cognitive tasks. During cognitive tasks, reduced deactivation in the default mode network, including the anterior and posterior midline structure, has also been reported in PD patients [54][55][56] . This might include a dopamine component, and upregulation of dopaminergic projections in the anterior cingulate cortex are associated with PD motor dysfunction 14 . ...
Functional neuroimaging studies of patients with Parkinson’s disease (PD) have repeatedly identified over-activations in midline structures (medial prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, and precuneus), especially in those without comorbid dementia. Here, we investigated whether the different cognitive profiles in PD were linked to measures of diffusion microstructure in medial regions of the brain. Using magnetic resonance based diffusion weighted imaging (DWI) in healthy volunteers (HV) and PD patients with and without mild cognitive impairment (PD-nonMCI and PD-MCI), applying diffusion tensor imaging (DTI) and high angular resolution diffusion imaging (HARDI) techniques, we observed: 1) increased fractional anisotropy (FA) in the precuneus and the anterior cingulate in the PD-nonMCI participants compared with the HV; 2) an association between precuneus FA and executive and memory function, respectively, in PD and HV; 3) a negative correlation between age and midline structure FA in PD but not HV; and 4) a differential association between cognitive scores and apparent fiber density (AFD) of the posterior cingulate-precuneus bundle in HV vs. PD. Together, these findings suggest that white matter reorganization of the posterior medial microstructures might serve a compensatory role for damaged basal ganglia function in PD-nonMCI.
... This review provides an overview of three widely used ways of rs-fMRI analysing techniques applied particularly to assess Alzheimer's disease. Other significant rs-fMRI methods applied to AD/non AD cohorts includes hierarchical clustering, regional homogeneity (ReHo) [69], the amplitude of low frequency fluctuation (ALFF) [86] Granger Causality Analysis (GCA) [87]. Rs-fMRI has a number of advantages when compared to other functional imaging methods. ...
Physiological changes due to blood oxygen level dependent (BOLD) signals from the brain can be probed by functional MRI (fMRI). Especially, several resting-state fMRI (rs-fMRI) studies have evidenced the alterations in the default mode network (DMN), which is a fundamental network among the resting state networks (RSNs) with respect to progressing diminished brain function due to various disease conditions such as Alzheimer's disease (AD). Recently, there are several techniques developed to analyze the rs-fMRI data such as voxel-based morphometry (VBM), i.e., seed-based analysis, independent component analysis (ICA), clustering algorithm, graph method, neural networks, pattern classification method and statistical parametric mapping. Though these techniques are promising, their application on routine clinical practice is not yet developed. However, it may play a vital role in future for diagnostic and prognosticating various dementia conditions. In this review, fundamentals of rs-fMRI, different data analysis techniques such as seed-based, independent component analysis and graph theory analysis, regional homogeneity analysis and amplitudes of low-frequency fluctuations of the rs-fMRI BOLD signal are discussed.
... The study demonstrated that subjects treated with a daily administration of levodopa increased the functional connectivity of the PCC and decreased the DMN activation in the left parahippocampal gyrus upon the execution of a cognitive task (Krajcovicova et al., 2012). Another study revealed that PD patients deactivate the ventral mPFC of the DMN but failed to deactivate the posterior medial and lateral areas of the network, a pattern restored by the introduction of levodopa (Delaveau et al., 2010). ...
Visual hallucinations (VH) are commonly found in the course of synucleinopathies like Parkinson's disease and dementia with Lewy bodies. The incidence of VH in these conditions is so high that the absence of VH in the course of the disease should raise questions about the diagnosis. VH may take the form of early and simple phenomena or appear with late and complex presentations that include hallucinatory production and delusions. VH are an unmet treatment need. The review analyzes the past and recent hypotheses that are related to the underlying mechanisms of VH and then discusses their pharmacological modulation. Recent models for VH have been centered on the role played by the decoupling of the default mode network (DMN) when is released from the control of the fronto-parietal and salience networks. According to the proposed model, the process results in the perception of priors that are stored in the unconscious memory and the uncontrolled emergence of intrinsic narrative produced by the DMN. This DMN activity is triggered by the altered functioning of the thalamus and involves the dysregulated activity of the brain neurotransmitters. Historically, dopamine has been indicated as a major driver for the production of VH in synucleinopathies. In that context, nigrostriatal dysfunctions have been associated with the VH onset. The efficacy of antipsychotic compounds in VH treatment has further supported the notion of major involvement of dopamine in the production of the hallucinatory phenomena. However, more recent studies and growing evidence are also pointing toward an important role played by serotonergic and cholinergic dysfunctions. In that respect, in vivo and post-mortem studies have now proved that serotonergic impairment is often an early event in synucleinopathies. The prominent cholinergic impairment in DLB is also well established. Finally, glutamatergic and gamma aminobutyric acid (GABA)ergic modulations and changes in the overall balance between excitatory and inhibitory signaling are also contributing factors. The review provides an extensive overview of the pharmacology of VH and offers an up to date analysis of treatment options.
... Gray and Tickle-Degnen (2010) reported emotion perception to be largely unaffected by medication status; other studies supported this assumption ( Yip et al., 2003;Péron et al., 2009;Cohen et al., 2010;Roca et al., 2010;Enrici et al., 2015). Contrastingly, several publications demonstrated beneficial effects of L-Dopa on emotion recognition (Tessitore et al., 2002;Sprengelmeyer et al., 2003;Delaveau et al., 2010), suggesting that L-Dopa partially restores amygdala response but in dependence of disease progression ( Delaveau et al., 2009). In fact, in the early disease stages, mesocorticolimbic pathways are described to be relatively spared compared with the motor pathway ( Braak et al., 2004), and L-Dopa needed to improve motor symptoms would at the same time overdose mesolimbic projections to subcortical structures involved in emotion processing like the amygdala, leading to detrimental effects in emotion perception, whereas in later disease stages, these effects would be beneficial. ...
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor symptoms following dopaminergic depletion in the substantia nigra. Besides motor impairments, however, several non-motor detriments can have the potential to considerably impact subjectively perceived quality of life in patients. Particularly emotion recognition of facial expressions has been shown to be affected in PD, and especially the perception of negative emotions like fear, anger, or disgust is impaired. While emotion processing generally refers to automatic implicit as well as conscious explicit processing, the focus of most previous studies in PD was on explicit recognition of emotions only, while largely ignoring implicit processing deficits. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is widely accepted as a therapeutic measure in the treatment of PD and has been shown to advantageously influence motor problems. Among various concomitant non-motor effects of STN-DBS, modulation of facial emotion recognition under subthalamic stimulation has been investigated in previous studies with rather heterogeneous results. Although there seems to be a consensus regarding the processing of disgust, which significantly deteriorates under STN stimulation, findings concerning emotions like fear or happiness report heterogeneous data and seem to depend on various experimental settings and measurements. In the present review, we summarized previous investigations focusing on STN-DBS influence on recognition of facial emotional expressions in patients suffering from PD. In a first step, we provide a synopsis of disturbances and problems in facial emotion processing observed in patients with PD. Second, we present findings of STN-DBS influence on facial emotion recognition and especially highlight different impacts of stimulation on implicit and explicit emotional processing.
... van Eimeren, Monchi, Ballanger, and Strafella (2009), in a study with patients taken off antiparkinsonian medication before scanning (type/regimen not reported), showed that while performing an executive task the mPFC normally deactivated, whereas PCC and precuneus failed to deactivate. Studies with PD patients on levodopa, both alone or in combination with DA agonists, also show failure of deactivation in the vmPFC while performing a sequence learning task (Argyelan et al., 2008), and in both the vmPFC and PCC during resting state (Tinaz, Lauro, Hallett, & Horovitz, 2016; however, see Delaveau et al., 2010). The PCC may also be a candidate for more direct changes brought about by PD pathology, for example increasing the resting receptivity to DA (see also Nagano-Saito, Liu, Doyon, & Dagher, 2009;Tomasi et al., 2009). ...
... (d) ongoing dopaminergic treatment and fMRI scan performed in the ON state (e.g., (Peraza et al., 2014;Schumacher et al., 2018))-since, notably, dopaminergic medications have been shown to have a normalizing effect on DMN connectivity (Delaveau et al., 2010). ...
Aberrations of large‐scale brain networks are found in the majority of neurodegenerative disorders. The brain connectivity alterations underlying dementia with Lewy bodies (DLB) remain, however, still elusive, with contrasting results possibly due to the pathological and clinical heterogeneity characterizing this disorder. Here, we provide a molecular assessment of brain network alterations, based on cerebral metabolic measurements as proxies of synaptic activity and density, in a large cohort of DLB patients (N = 72). We applied a seed‐based interregional correlation analysis approach (p < .01, false discovery rate corrected) to evaluate large‐scale resting‐state networks' integrity and their interactions. We found both local and long‐distance metabolic connectivity alterations, affecting the posterior cortical networks, that is, primary visual and the posterior default mode network, as well as the limbic and attention networks, suggesting a widespread derangement of the brain connectome. Notably, patients with the lowest visual and attention cognitive scores showed the most severe connectivity derangement in regions of the primary visual network. In addition, network‐level alterations were differentially associated with the core clinical manifestations, namely, hallucinations with more severe metabolic dysfunction of the attention and visual networks, and rapid eye movement sleep behavior disorder with alterations of connectivity of attention and subcortical networks. These multiple network‐level vulnerabilities may modulate the core clinical and cognitive features of DLB and suggest that DLB should be considered as a complex multinetwork disorder.
... Among these 8 FNs, PCUN, as a functional hub of the default mode network (DMN) (Andrews-Hanna et al. 2014), was discriminative for neurological WD. Neurological WD patients had altered DMN's functional brain connectivity (Han et al. 2016), and other existing findings also demonstrated that Parkinson's disease (PD), HD patients and other basal ganglia disorders have disrupted FC in the DMN (Tessitore et al. 2012;Delaveau et al. 2010;Wolf et al. 2012;Quarantelli et al. 2013). The PCUN was involved in visual, sensorimotor, and attentional information. ...
Wilson’s disease patients with neurological symptoms have motor symptoms and cognitive deficits, including frontal executive, visuospatial processing, and memory impairments. Although the brain structural abnormalities associated with Wilson’s disease have been documented, it remains largely unknown how Wilson’s disease affects large-scale functional brain networks. In this study, we investigated functional brain networks in Wilson’s disease. Particularly, we analyzed resting state functional magnetic resonance images of 30 Wilson’s disease patients and 26 healthy controls. First, functional brain networks for each participant were extracted using an independent component analysis method. Then, a computationally efficient pattern classification method was developed to identify discriminative brain functional networks associated with Wilson’s disease. Experimental results indicated that Wilson’s disease patients, compared with healthy controls, had altered large-scale functional brain networks, including the dorsal anterior cingulate cortex and basal ganglia network, the middle frontal gyrus, the dorsal striatum, the inferior parietal lobule, the precuneus, the temporal pole, and the posterior lobe of cerebellum. Classification models built upon these networks distinguished between neurological WD patients and HCs with accuracy up to 86.9% (specificity: 86.7%, sensitivity: 89.7%). The classification scores were correlated with the United Wilson’s Disease Rating Scale measures and durations of disease of the patients. These results suggest that Wilson’s disease patients have multiple aberrant brain functional networks, and classification scores derived from these networks are associated with severity of clinical symptoms.
... In the same vein, numerous studies propose a fundamental role of the RSN, and especially the DMN, with normal brain function across the lifespan. A relationship between the RSN and various neurological and psychiatric conditions has been established [32][33][34][35][36], as have changes in RSN patterns during normal aging [37] and in mild cognitive impairment [38]. Finally, genetic studies have shown that RSN patterns have a hereditary component [38], and animal studies suggest that RSN are phylogenetically conserved in primates [38] and rats [39]. ...
Aging is a physiological process accompanied by cognitive decline, principally in memory and executive functions. Alterations in the connectivity of the default mode network (DMN) have been found to participate in cognitive decline, as well as in several neurocognitive disorders. The DMN has antisynchronic activity with attentional networks (task-positive networks (TPN)), which are critical to executive function and memory. Findings pointing to the regulation of the DMN via activation of TPN suggest that it can be used as a strategy for neuroprotection. Meditation is a noninvasive and nonpharmacological technique proven to increase meta-awareness, a cognitive ability which involves the control of both networks. In this review, we discuss the possibility of facilitating healthy aging through the regulation of networks through meditation. We propose that by practicing specific types of meditation, cognitive decline could be slowed, promoting a healthy lifestyle, which may enhance the quality of life for the elderly.
... The association between increasing levels of social amotivation and reduced functional connectivity of mesocorticolimbic dopamine circuits suggests a pathological lack of functional integration/interaction of multiple brain processes, which may be caused by impaired anatomical connectivity and/or synaptic plasticity (Stephan et al., 2009). Given the role of dopamine in modulation of the default mode network (Cole et al., 2013a;Cole et al., 2013b;Delaveau et al., 2010), decreased connectivity between the SN/VTA and the default mode network along with increased social amotivation in our study may contribute to disturbances of thought in schizophrenia. Although the dysconnectivity hypothesis has been implied for schizophrenia as a diagnostic group and specifically for positive symptomatology (for a review, see Pettersson-Yeo et al., 2011), our results show that functional disintegration of reward and cognitive-control brain systems may be of importance for negative symptomatology as well. ...
Background:
Social amotivation is a core element of the negative symptoms of schizophrenia. However, it is still largely unknown which neural substrates underpin social amotivation in people with schizophrenia, though deficiencies in the mesocorticolimbic dopamine system have been proposed.
Methods:
We examined the association between social amotivation and substantia nigra/ventral tegmental area-seeded intrinsic connectivity in 84 people with schizophrenia using resting state functional magnetic resonance imaging.
Results:
Spontaneous fluctuations of midbrain dopaminergic regions were positively associated with striatal and prefrontal fluctuations in people with schizophrenia. Most importantly, social amotivation was negatively associated with functional connectivity between the midbrain's substantia nigra/ventral tegmental area and medial- and lateral prefrontal cortex, the temporoparietal junction, and dorsal and ventral striatum. These associations were observed independently of depressive and positive symptoms.
Conclusions:
Our findings suggest that social amotivation in people with schizophrenia is associated with altered intrinsic connectivity of mesocorticolimbic pathways linked to cognitive control and reward processing. Dysconnectivity of dopaminergic neuronal ensembles that are fundamental to approach behavior and motivation may help explain the lack of initiative social behavior in people with social amotivation.
... Other brain regions that might be mentioned, although with less clear hypotheses, include the default mode network (DMN). Presently, there is a lack of clear understanding regarding the role of DMN and DA neurotransmission in PD patients (Delaveau et al., 2010). In a study by van Eimeren et al. (2009) PD patients were asked to perform an executive task 12-18 h after stopping their PD medication (type/regimen not reported). ...
Parkinson's disease (PD) is a devastating diagnosis with, however, potential for an extremely intriguing aesthetic component. Despite motor and cognitive deficits, an emerging collection of studies report a burst of visual artistic output and alterations in produced art in a subgroup of patients. This provides a unique window into the neurophysiological bases for why and how we might create and enjoy visual art, as well as into general brain function and the nature of PD or other neurodegenerative diseases. However, there has not been a comprehensive organization of literature on this topic. Nor has there been an attempt to connect case evidence and knowledge on PD with present understanding of visual art making in psychology and neuroaesthetics in order to propose hypotheses for documented artistic changes. Here, we collect the current research on this topic, tie this to PD symptoms and neurobiology, and provide new theories focusing on dopaminergic neuron damage, over-stimulation from dopamine agonist therapy, and context or genetic factors revealing the neurobiological basis of the visual artistic brain.
... Dopamine depletion is observed in L-dopa naïve PD and DLB cases, which correlates with reduction in attention and cognition (68,70,72), and this is likely to derive from changes to the dopaminergic VTA (74). Improved cognition and mood in PD is observed following L-dopa therapy (56) and correlates with a basal failure to inactivate the default mode network (22). Structural changes to basal ganglia circuitry in LBD are minimal (15) or absent (101) suggesting that changes within specific nuclei may be the major contributors of psychiatric symptoms (2,15,20,46). ...
Aims
Depression is commonly observed even in prodromal stages of Lewy body disorders (LBD), and is associated with cognitive impairment and a faster rate of cognitive decline. Given the role of dopamine in the development of movement disorders, but also in motivation and reward, we investigated neurodegenerative pathology in dopaminergic circuitry in Parkinson's disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB) patients in relation to depressive symptoms.
Methods
α‐synuclein, hyperphosphorylated tau and amyloid beta pathology was assessed in 17 DLB, 14 PDD and 8 PD cases within striatal and midbrain subregions, with neuronal cell density assessed in substantia nigra and ventral tegmental area. Additionally, we used a structural equation modelling (SEM) approach to investigate the extent to which brain connectivity might influence the deposition of pathological proteins within dopaminergic pathways.
Results
A significantly higher α‐synuclein burden was observed in the substantia nigra (p=0.006), ventral tegmental area (p=0.011) and nucleus accumbens (p=0.031) in LBD patients with depression. Significant negative correlations were observed between cell density in SN with LB Braak stage (p=0.013), whereas cell density in VTA showed negative correlations with LB Braak stage (p=0.026) and NFT Braak stage (p=0.007).
Conclusions
Dopaminergic α‐syn pathology appears to drive depression. Selective targeting of dopaminergic pathways may therefore provide symptomatic relief for depressive symptoms in LBD patients.
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... Differences in the intensity of spontaneous brain activity between AR and HC but also AR and TD (Karunanayaka et al., 2016) can be observed in the left IPC and PCC (less intensity in AR). This represents an important advance with regard to former variable results about DMN functional integrity in PD (Delaveau et al., 2010;Ibarretxe-Bilbao et al., 2011;Krajcovicova et al., 2012;van Eimeren et al., 2009). Unfortunately, whole brain analyses have not been performed and differences have only been tested within the DMN. ...
Akinesia is a major manifestation of Parkinson's disease (PD) related to difficulties or failures of willed movement to occur. Akinesia is still poorly understood and is not fully alleviated by standard therapeutic strategies. One reason is that the area of the clinical concept has blurred boundaries referring to confounded motor symptoms. Here, we review neuroimaging studies which, by providing access to finer-grained mechanisms, have the potential to reveal the dysfunctional brain processes that account for akinesia. It comes out that no clear common denominator could be identified across studies that are too heterogeneous with respect to the clinical/theoretical concepts and methods used. Results reveal, however, that various abnormalities within but also outside the motor and dopaminergic pathways might be associated with akinesia in PD patients. Notably, numerous yet poorly reproducible neural correlates were found in different brain regions supporting executive control by means of resting-state or task-based studies. This includes for instance the dorsolateral prefrontal cortex, the inferior frontal cortex, the supplementary motor area, the medial prefrontal cortex, the anterior cingulate cortex or the precuneus. This observation raises the issue of the multidimensional nature of akinesia. Yet, other open issues should be considered conjointly to drive future investigations. Above all, a unified terminology is needed to allow appropriate association of behavioral symptoms with brain mechanisms across studies. We adhere to a use of the term akinesia restricted to dysfunctions of movement initiation, ranging from delayed response to freezing or even total abolition of movement. We also call for targeting more specific neural mechanisms of movement preparation and action triggering with more sophisticated behavioral designs/event-related neurofunctional analyses. More work is needed to provide reliable evidence, but answering these still open issues might open up new prospects, beyond dopaminergic therapy, for managing this disabling symptom.
... In AD, reduced connectivity between the hippocampus and the posterior cingulate accounts for aMCI presentation [21,23,24]. Likewise, patients with PD have reduced connectivity between the posterior cingulate and medial prefrontal regions [22], and this appears responsive to dopamine therapy [25,26]. A limited number of studies have investigated the association between APOE-ε4 and the default mode network region in PD either with respective to functional or structural integrity. ...
Introduction
Alzheimer's and Parkinson's disease (AD and PD) are distinct disorders but share similar biomarker profiles. The regions of the default mode network are implicated in these diseases and are associated with amnestic symptoms. The role of apolipoprotein-ε4 (APOE-ε4), which is associated with cognitive function, is unclear in PD.
Methods
In this work, we evaluated cortical thickness of default mode network regions that are likely affected in both early AD and PD individuals, that is, with amnestic mild cognitive impairment. We identified the prevalence of APOE-ε4 and evaluated its association with cortical atrophy.
Results
We observed significant parahippocampal atrophy and hippocampal atrophy rates in amnestic mild cognitive impairment subjects, regardless of disease origins (AD or PD). Similarly, mild cognitive impairment ε4 carriers showed significant precuneal atrophy compared with noncarriers.
Discussion
This work supports that converging changes to default mode network regions, especially the temporal lobe and precuneus, are shared in AD and PD.
... One study observed the restoration of the DMN after levodopa administration and postulated that the dopaminergic system modulates the DMN in Parkinson's disease. 31 Indeed, the change can be attributed to the loss of dopaminergic neurons in the substantia nigra, which is connected to the mPFC via the striatum. Thus, the impact of PD progression can indirectly cause certain functional disconnections in this circuit and may cause a possible impairment in the activity of the PD seed on mPFC NC seed on mPFC frontal regions of the brain. ...
Objective:
Parkinson's disease (PD) is a neurodegenerative disorder that mainly leads to the impairment of patients' motor function, as well as of cognition, as it progresses. This study tried to investigate the impact of PD on the resting state functional connectivity of the default mode network (DMN), as well as of the entire brain.
Methods:
Sixty patients with PD were included and compared to 60 matched normal control (NC) subjects. For the local connectivity analysis, the resting state fMRI data were analyzed by seed-based correlation analyses, and then a novel persistent homology analysis was implemented to examine the connectivity from a global perspective.
Results:
The functional connectivity of the DMN was decreased in the PD group compared to the NC, with a stronger difference in the medial prefrontal cortex. Moreover, the results of the persistent homology analysis indicated that the PD group had a more locally connected and less globally connected network compared to the NC.
Conclusion:
Our findings suggest that the DMN is altered in PD, and persistent homology analysis, as a useful measure of the topological characteristics of the networks from a broader perspective, was able to identify changes in the large-scale functional organization of the patients' brain.
... However, recent studies in cognitively intact Parkinson's disease have found no effect of levodopa on choice reaction times, despite improvements to bradykinesia (Michely et al., 2012;Michely et al., 2015). Similarly, the reported effect of levodopa is to restore to normality a reduced DMN deactivation, rather than to enhance it (Delaveau et al., 2010;Spetsieris et al., 2015). Thus we believe that the slow RT and greater DMN deactivation we see are unlikely to be due to dopaminergic medication. ...
A significant symptom of Lewy body dementia (LBD) is slow cognitive processing or bradyphrenia. In a previous fMRI task-based study, we found slower responses in LBD, accompanied by greater deactivation in the default mode network. In this study, we investigated the timing and magnitude of the activations and deactivations with respect to reaction time to determine whether the slower responses in LBD were associated with delayed neuronal activity. Using fMRI, we examined the magnitude and latency of activations and deactivations during an event-related attention task in 32 patients with LBD and 23 healthy controls using predefined regions of interest. Default mode network deactivations did not significantly differ in their timing between groups or task conditions, while the task-related activations in the parietal, occipital, frontal, and motor cortex were all significantly later in the LBD group. Repeating the analysis with reaction time as a parametric modulator of activation magnitude produced similar findings, with the reaction time modulator being significant in a number of regions including the default mode network, suggesting that the increased deactivation in LBD is partly explained by slower task completion. Our data suggest that the default mode network deactivation is initiated at the start of the task, and remains deactivated until its end, with the increased magnitude of deactivation in LBD reflecting the more prolonged cognitive processing in these patients. These data add substantially to our understanding of the neural origins of bradyphrenia, which will be essential for determining optimum therapeutic strategies for cognitive impairment in LBD. Hum Brain Mapp, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.
... We found four connections with lower connectivity when Parkinson's disease patients were ON dopaminergic medications, each of which connected a motor region (striatum, cerebellum, SMA/premotor cortex) to a posterior cortical integration hub, including key regions of the default mode network (PCC and angular gyrus) (Greicius et al., 2003) and the salience network (insula) (Menon and Uddin, 2010). Dopaminergic modulation of default mode connectivity has been shown in both task and resting state fMRI studies (de Leeuw et al., 2013;Delaveau et al., 2010;Flodin et al., 2012;Poston and Eidelberg, 2012;Putcha et al., 2015), but the mechanisms are still poorly understood. The default mode network is considered a 'task-negative' network that deactivates during goal-oriented activities and is negatively correlated with other brain networks, such as the frontal executive network. ...
Altered brain connectivity has been described in people with Parkinson's disease and in response to dopaminergic medications. However, it is unclear whether dopaminergic medications primarily ‘normalize’ disease related connectivity changes or if they induce unique alterations in brain connectivity. Further, it is unclear how these disease- and medication-associated changes in brain connectivity relate differently to specific motor manifestations of disease, such as bradykinesia/rigidity and tremor. In this study, we applied a novel covariance projection approach in combination with a bootstrapped permutation test to resting state functional MRI data from 57 Parkinson's disease and 20 healthy control participants to determine the Parkinson's medication-state and disease-state connectivity changes associated with different motor manifestations of disease. First, we identified brain connections that best classified Parkinson's disease ON versus OFF dopamine and Parkinson's disease versus healthy controls, achieving 96.9 ± 5.9% and 72.7 ± 12.4% classification accuracy, respectively. Second, we investigated the connections that significantly contribute to the classifications. We found that the connections greater in Parkinson's disease OFF compared to ON dopamine are primarily between motor (cerebellum and putamen) and posterior cortical regions, such as the posterior cingulate cortex. By contrast, connections that are greater in ON compared to OFF dopamine are between the right and left medial prefrontal cortex. We also identified the connections that are greater in healthy control compared to Parkinson's disease and found the most significant connections are associated with primary motor regions, such as the striatum and the supplementary motor area. Notably, these are different connections than those identified in Parkinson's disease OFF compared to ON. Third, we determined which of the Parkinson's medication-state and disease-state connections are associated with the severity of different motor symptoms. We found two connections correlate with both bradykinesia/rigidity severity and tremor severity, whereas four connections correlate with only bradykinesia/rigidity severity, and five connections correlate with only tremor severity. Connections that correlate with only tremor severity are anchored by the cerebellum and the supplemental motor area, but only those connections that include the supplemental motor area predict dopaminergic improvement in tremor. Our results suggest that dopaminergic medications do not simply ‘normalize’ abnormal brain connectivity associated with Parkinson's disease, but rather dopamine drives distinct connectivity changes, only some of which are associated with improved motor symptoms. In addition, the dissociation between of connections related to severity of bradykinesia/rigidity versus tremor highlights the distinct abnormalities in brain circuitry underlying these specific motor symptoms.
... It has been suggested that DMN disruption mainly arises as a direct consequence of PD pathology 57 and maximally as the result of PD dopaminergic impairment 58 . Consistently, it was shown that administration of drugs enhancing dopaminergic activity is able to restore normal DMN functioning in PD 58 . ...
To explore the effects of PD pathology on brain connectivity, we characterized with an emergent computational approach the brain metabolic connectome using [18F]FDG-PET in early idiopathic PD patients. We applied whole-brain and pathology-based connectivity analyses, using sparse-inverse covariance estimation in thirty-four cognitively normal PD cases and thirty-four age-matched healthy subjects for comparisons. Further, we assessed high-order resting state networks by interregional correlation analysis. Whole-brain analysis revealed altered metabolic connectivity in PD, with local decreases in frontolateral cortex and cerebellum and increases in the basal ganglia. Widespread long-distance decreases were present within the frontolateral cortex as opposed to connectivity increases in posterior cortical regions, all suggestive of a global-scale connectivity reconfiguration. The pathology-based analyses revealed significant connectivity impairment in the nigrostriatal dopaminergic pathway and in the regions early affected by α-synuclein pathology. Notably, significant connectivity changes were present in several resting state networks especially in frontal regions. These findings expand previous imaging evidence of altered connectivity in cognitively stable PD patients by showing pathology-based connectivity changes and disease-specific metabolic architecture reconfiguration at multiple scale levels, from the earliest PD phases. These alterations go well beyond the known striato-cortical connectivity derangement supporting in vivo an extended neural vulnerability in the PD synucleinopathy.
... Further, lower connectivity trends in PD patients in the striatal regions were found; however, these were not significant after multiple comparisons that matched the results by Li et al. (2016) and that have been previously shown to be highly significant in the de novo PD population (Nigro et al., 2016). The patients included in this study were not de novo and were on anti-Parkinsonian medication for few years, which might facilitate partial restoration of the connectivity deficits as demonstrated by previous b AU10 fMRI and MEG-based studies in patients with PD b AU11 (Delaveau et al., 2010;Luo et al., 2015). We also recognize few limitations of our study. ...
Parkinson's disease (PD) is a neuro-degenerative disorder, which predominantly affects the motor system. Diffusion MRI has demonstrated deficits in anisotropy as well as increased diffusivity in the sub-cortical structures, primarily in the substantia nigra in PD. However, the clinical spectrum of PD is not limited to motor symptoms, rather it encompasses several non-motor symptoms such as depression, psychosis, olfactory dysfunction and cognitive impairment. These non-motor symptoms underscore PD as a complex neurological disorder arising from dysfunction of several network components. Therefore, to decipher the underlying neuropathology it is crucial to employ novel network based methods that can elucidate associations between specific network changes. This study aimed at assessing the large-scale structural network changes in PD. Structural connectomes were computed using probabilistic fiber tracking on diffusion MRI between 86 regions of interest. Graph theoretic analysis on the connectome was carried out at several levels of granularity: global, local (nodal) and lobar and edge-wise. Our findings demonstrate lower network clustering capability, overall lower neural connectivity as well as significantly reduced nodal influence of the hippocampus in PD. Additionally, extensive patterns of reduced connectivity were observed within and between the temporal, parietal and occipital areas. In summary, our findings corroborate widespread structural disconnectivity which has been linked to the non-motor symptoms in PD.
Aim:
Parkinson's disease is one of the most common neurodegenerative diseases. Excellent levodopa responsiveness has been proposed as a characteristic supporting feature in substantiating the PD diagnosis. However, a small portion of clinically established PD patients shows poor levodopa response. This study aims to investigate brain function alterations of PD patients with poor levodopa responsiveness by PET/MRI.
Method:
A total of 46 PD patients were recruited. They all completed 11C-CFT PET/MRI scans and the acute levodopa challenge test. Among these 46 PD patients, 42 participants further underwent 18F-FDG PET/MRI scans. Clinical variables regarding demographic data, disease features and cognition scales were also collected. Based on the improvement rate of UPDRS-III, PD patients were divided into non-responders (improvement rate < 33%) and responders (improvement rate ≥ 33%). Statistical parametric zapping was performed to analyze molecular imaging. Dopaminergic uptake and metabolism of 70 brain regions were converted to quantitative values and expressed as standard uptake value (SUV). SUV was further normalized by the cerebellum. The resulting SUV ratios and clinical variables were then compared by SPSS.
Results:
The difference between levodopa non-responders (n=17) and responders (n=29) in the UPDRS III baseline was statistically significant and the former had a lower UPDRS III baseline (19 (10, 32), p＜0.05). In contrast, no statistical difference between these two groups was found in age, gender, disease duration, cognition, motor subtype and Hoehn-Yahr stage. Dopaminergic uptake differences between levodopa non-responders (n = 17) and responders (n = 29) were shown in the left inferior frontal cortex (1.00 ± 0.09 vs 1.07 ± 0.08, p < 0.05 and FDR < 0.2), the right posterior cingulum (1.10 ± 0.10 vs 1.20 ± 0.13, p <0.05 and FDR < 0.2) and the right insula (1.21 ± 0.12 vs 1.30 ± 0.10, p < 0.05 and FDR < 0.2). The metabolic alterations between levodopa non-responders (n=16) and responders (n=26) were shown in the right supplementary motor area (1.30 (1.18, 1.39) vs 1.41 (1.31, 1.53), p < 0.05 and FDR < 0.2), right precuneus (1.37 ± 0.10 vs 1.47 ± 0.18, p < 0.05 and FDR < 0.2), right parietal cortex (1.14 ± 0.15 vs 1.27 ± 0.21, p < 0.05 and FDR < 0.2), right supramarginal gyrus (1.16 (1.12, 1.26) vs 1.25 (1.14, 1.46), p < 0.05 and FDR < 0.2), right postcentral gyrus (1.15 (1.08, 1.32) vs 1.24 (1.17, 1.39), p < 0.05 and FDR < 0.2), medulla (0.75 ± 0.07 vs 0.80 ± 0.07, p < 0.05 and FDR < 0.2), right rolandic operculum (1.25 (1.18, 1.32) vs 1.33 (1.25, 1.50), p < 0.05 and FDR < 0.2), right olfactory (0.95 (0.91, 1.01) vs 1.01 (0.95, 1.15), p < 0.05 and FDR < 0.2), the right insula (1.15 (1.06, 1.22) vs 1.21 (1.12, 1.35), p < 0.05 and FDR < 0.2) and the left cerebellum crus (0.96 (0.91, 1.01) vs 0.92 (0.86, 0.96), p < 0.05 and FDR < 0.2).
Conclusions:
PD patients with poor response to levodopa showed less severe impairment of baseline motor symptoms, more severe dopaminergic deficits in the left inferior frontal, right posterior cingulate cortex and the right insula, and lower metabolism in the right supplementary motor area, right precuneus, right parietal cortex, right supramarginal gyrus, right postcentral gyrus, medulla, right rolandic operculum, right olfactory, the right insula and higher metabolism in the left cerebellum crus.
Working memory (WM) impairments are reported to occur in patients with Parkinson's disease (PD). However, the mechanisms are unclear. Here, we investigate several putative factors that might drive poor performance, by examining the precision of recall, the order in which items are recalled and whether memories are corrupted by random guessing (attentional lapses). We used two separate tasks that examined the quality of WM recall under different loads and retention periods, as well as a traditional digit span test. Firstly, on a simple measure of WM recall, where patients were asked to reproduce the orientation of a centrally presented arrow, overall recall was not significantly impaired. However, there was some evidence for increased guessing (attentional lapses). On a new analogue version of the Corsi‐span task, where participants had to reproduce on a touchscreen the exact spatial pattern of presented stimuli in the order and locations in which they appeared, there was a reduction in the precision of spatial WM at higher loads. This deficit was due to misremembering item order. At the highest load, there was reduced recall precision, whereas increased guessing was only observed at intermediate set sizes. Finally, PD patients had impaired backward, but not forward, digit spans. Overall, these results reveal the task‐ and load‐dependent nature of WM deficits in PD. On simple low‐load tasks, attentional lapses predominate, whereas at higher loads, in the spatial domain, the corruption of mnemonic information—both order item and precision—emerge as the main driver of impairment.
Human and animal studies have shown that casein peptide (casein hydrolysate) has positive effects on cognitive function. This double-blind randomized controlled study aimed to investigate whether single ingestion of casein peptide could affect cognitive function (executive function) and cognitive neural activity in healthy older adults. We assigned 47 participants to one of the three dietary supplements as follows: casein peptide (TMP, n = 15), casein (TMC, n = 16), and indigestible dextrin (TMF, n = 16). Dietary supplements were ingested 30 min before starting the experiment; moreover, neural activity while performing the task-switching reaction time (SWT) trial was assessed through functional magnetic resonance imaging (fMRI). Additionally, we used a visual analog scale (VAS) test to assess the pre- and post-test feeling and mood. Regarding the parameters of the SWT trial, there were no significant among-group differences in the reaction time, accuracy rate, and %SwitchCost. Contrastingly, the fMRI experiment revealed among-group differences in the main effects in the medial frontal gyrus, Supplementary motor cortex (SMC), posterior cingulate gyrus (PCg), and amygdala (Amyg). Specifically, there was a significant decrease in the neural activities in the SMC and PCg in the TMP group than in the other two groups. Moreover, there was a significant increase in the neural activity in the Amyg in the TMP group compared with the TMF, but not the TMC, group. Furthermore, the VAS score was significantly higher in the TMP group than in the other two groups. There were no recorded adverse outcomes. Our findings suggested that TMP ingestion by older adults could temporarily suppress complementary neural activity in specific brain regions involved in executive functions, as well as default mode network activity, which could improve cognitive neural activities.
Tourette syndrome (TS) is a developmental neuropsychiatric disorder characterized by the presence of tics and is often associated with other comorbidities. Obsessive-compulsive disorder (OCD) is one of the most common comorbid disorders in TS with the majority of TS patients experiencing significant obsessive-compulsive symptoms (OCS) that often substantially contributes to the disease burden of TS. There are also striking phenomenological similarities between TS and OCD, as they are both characterized by repetitive behaviors that are frequently preceded by sensory phenomena; these similarities, coupled with the high prevalence of OCS in TS, raise questions as to the neural substrates of tics and OCS. There has been considerable research interest into the functional neuroactivity of patients with TS and those with OCD, but there is a paucity of research on comorbid TS + OCD, especially with regards to how it differs from its classical counterparts. This chapter will review the functional neuroimaging research on tics, OCS, sensory phenomena and functional connectivity that has been conducted in TS, OCD, and TS + OCD samples. As well, hypothesized neurobiological models of the above diagnostic groups will be reviewed with a special emphasis as to how the neurobiology of tics differs from OCS, and how TS + OCD may differ from TS and OCD.
Aims
The aim of this study was to identify brain regions with local, structural, and functional abnormalities in dementia with Lewy bodies (DLB) and uncover the differences between DLB and Alzheimer's disease (AD). The neural networks involved in the identified abnormal brain regions were further described.
Methods
PubMed, Web of Science, OVID, Science Direct, and Cochrane Library databases were used to identify neuroimaging studies that included DLB versus healthy controls (HCs) or DLB versus AD. The coordinate‐based meta‐analysis and functional meta‐analytic connectivity modeling were performed using the activation likelihood estimation algorithm.
Results
Eleven structural studies and fourteen functional studies were included in this quantitative meta‐analysis. DLB patients showed a dysfunction in the bilateral inferior parietal lobule and right lingual gyrus compared with HC patients. DLB patients showed a relative preservation of the medial temporal lobe and a tendency of lower metabolism in the right lingual gyrus compared with AD. The frontal‐parietal, salience, and visual networks were all abnormally co‐activated in DLB, but the default mode network remained normally co‐activated compared with AD.
Conclusions
The convergence of local brain regions and co‐activation neural networks might be potential specific imaging markers in the diagnosis of DLB. This might provide a pathway for the neural regulation in DLB patients, and it might contribute to the development of specific interventions for DLB and AD.
Background and purpose:
Lower urinary tract symptoms (LUTS) are the most common nonmotor symptoms usually occurring mid-stage of Parkinson's disease (PD); however, its underlying mechanisms are unknown. We aimed to assess whether corticometry or volumetry can identify a pattern of cerebral cortical changes in PD patients with LUTS.
Methods:
We recruited 85 idiopathic PD patients and performed corticometry and volumetry on various cortical regions using each patient's magnetic resonance imaging. To identify a correlation between the cortical thickness/volume and nonmotor symptoms scale domain 7 scores, which represent the severity of LUTS, we performed general linear model and region of interest analyses.
Results:
Significant regional thinning of the left precuneus, left temporal pole, left precentral, right precuneus, and right pars opercularis was correlated with nonmotor symptoms scale domain 7 scores. We also found that cortical volumes of left precuneus and left frontal pole were inversely correlated with the severity of urinary symptoms.
Conclusions:
This study showed that the thicknesses and volumes of several cortical regions were significantly correlated with the severity of LUTS in PD patients. The findings of regional atrophy and thinning of specific cortical regions in this study provide additional evidence that multiple cortical regions, especially the precuneus cortex, not only may be involved in urinary dysfunctions of PD patients but also may help to elucidate the exact underlying mechanisms for LUTS in PD patients.
Background:
Studies in aging older adults have shown the positive association between cognition and exercise related fitness, particularly cardiorespiratory fitness. These reports have also demonstrated the association of high cardiorespiratory fitness, as well as other types of fitness, on the reversal of age-related decline in neural network connectivity, highlighting the potential role of fitness on age- and disease-related brain changes. While the clinical benefits of exercise are well-documented in Parkinson's disease (PD), the extent to which cardiorespiratory fitness (assessed by estimated VO2max testing) or motor skill fitness (assessed by the Physical Performance Test (PPT)) affects neural network connectivity in PD remains to be investigated. The purpose of this study was to explore the hypothesis that higher fitness level is associated with an increase in the intrinsic network connectivity of cognitive networks commonly affected in PD.
Methods:
In this cross-sectional resting state fMRI, we used a multivariate statistical approach based on high-dimensional independent component analysis (ICA) to investigate the association between two independent fitness metrics (estimated VO2max and PPT) and resting state network connectivity.
Results:
We found that increased estimated VO2max was associated with increased within network connectivity in cognitive networks known to be impaired in PD, including those sub-serving memory and executive function. There was a similar trend for high levels of PPT to be associated with increased within network connectivity in distinct resting state networks. The between functional network connectivity analysis revealed that cardiorespiratory fitness was associated with increased functional connectivity between somatosensory motor network and several cognitive networks sub-serving memory, attention, and executive function.
Conclusion:
This study provides important empirical data supporting the potential association between two forms of fitness and multiple resting state networks impacting PD cognition. Linking fitness to circuit specific modulation of resting state network connectivity will help establish a neural basis for the positive effects of fitness and specific exercise modalities and provide a foundation to identify underlying mechanisms to promote repair.
Motor disturbance is a major source of injury in older adults, a fact facilitated by the interfering action of cognitive activities on ongoing motor tasks. The present work studies the influence of aging on the functional interaction of the default mode network(DMN) and two key networks for motion, the somato-motor network(SMN) and the posterior motor circuit of basal ganglia(BGmC). The relationship between these networks was explored in young (31.3 ± 5.2;n = 12) and aged (58.7 ± 5.4;n = 15) groups by studying the co-activation (positive correlation)/co-inactivation (negative correlation) and unrelated fluctuations (no significant correlation) of the BOLD-signals recorded by functional magnetic resonance imaging in the motor/somatosensory primary cortex, basal ganglia(BG) centers, and the posterior cingulate cortex(DMN) which projects to the SMN and BGmC. Two experimental conditions were used, one with subjects performing hand movements (a condition which should activate the motor networks and block the DMN) and a resting condition with subjects not performing any particular task (a condition where the DMN is recruited and the motor networks should be less active). In the young group, the DMN showed co-inactivation with the SMN and a non-significant correlation with the BGmC. However, in the aged-group the DMN-BGmC co-inactivation decreased (particularly during the motor action), and the DMN-SMN co-inactivation was replaced by a co-activation (during both the resting and motor action). Present data show a marked effect of age on the functional relationship of DMN with these cortical (SMN) and subcortical(BG) motor networks, suggesting that a disorder of the DMN-motor network co-inactivation may facilitate the motor disturbances that often accompany aging.
Both functional connectivity (FC) and blood oxygen level-dependent (BOLD) signal variability (SDBOLD) are methods that are used for examining the physiological state of the brain. Although they are derived from signal changes and are related, a few studies have explored their relationship. Here, we examined the relationship between SDBOLD and FC within the default mode network (DMN) in healthy aging participants and those with Parkinson's disease (PD) ON and OFF dopaminergic medications. Dopaminergic medications had profound effects on both DMN FC and SDBOLD measured separately in PD. Analyzing DMN FC and SDBOLD in a joint independent component analysis, we identified joint components of DMN FC and SDBOLD that were separately associated with measurements of motor and cognitive impairment in PD and qualitatively similar to those in healthy aging. Dopaminergic medications had a differential effect on these components depending on these measures of disease severity, "normalizing" the relationships. Importantly, we show that dopaminergic medication status matters in imaging PD, and it can affect both connectivity and SDBOLD. Imaging PD ON may lead to inflated estimates of SDBOLD and diminish the ability to measure changes associated with declining motor and cognitive capacities.
Introduction:
Parkinson's disease (PD) is characterized with reduced dopamine level in the brain, resulting from the nigral degeneration. It is commonly accepted that the function of default mode network (DMN) is disturbed in PD, even in those who have no significant cognitive impairment. However, the relationship between the depletion of dopamine and DMN dysconnectivity is not fully clear. The aim of this study was to investigate the seed-based DMN connectivity and the influence of dopaminergic therapy on the DMN integrity in non-demented PD by using resting-state fMRI.
Material and methods:
Resting-state fMRI data was collected from 24 non-demented PD patients before and after taking levodopa and 36 healthy controls (HCs). Functional connectivity (FC) was examined by a seed-based correlation approach.
Results:
Compared with HCs, decreased DMN connectivity in PD patients was observed, a number of which were significantly improved after taking levodopa therapy. Moreover, by directly comparing the DMN connectivity between ON- and OFF-medication conditions, we found significantly enhanced FC in a set of regions of DMN in the ON- medication condition. Conversely, we also found that the PCC revealed decreased FC with left inferior temporal.
Conclusion:
DMN connectivity was found to be impaired in no-demented PD patients, and levodopa has the ability to impart a normalizing effect on DMN connectivity.
Background:
Cognitive impairment is a common non-motor symptom in Parkinson's disease. So far, the underlying pathophysiology remains unclear. Several alterations in functional network connectivity have been described in Parkinson's disease patients with cognitive impairment which are probably the result of the heterogenous pathophysiology underlying this cognitive decline, including dopaminergic and cholinergic deficits. Accordingly, the reported resting-state connectivity patterns vary greatly among studies.
Objective:
To evaluate the localization and magnitude of functional connectivity patterns in resting-state brain networks in Parkinson's disease patients with cognitive impairment by pooling data from available studies.
Methods:
We searched PubMed, the Cochrane Library, MEDLINE, Embase and PsycINFO to identify functional MRI studies in Parkinson's disease patients with cognitive impairment. A voxel-based meta-analysis combined with quality statistics was performed, using the anisotropic effect-size version of the signed differential mapping method.
Results:
Seventeen studies with cognitively impaired Parkinson's disease patients were included consisting of 222 Parkinson's disease patients with mild cognitive impairment, 68 patients with Parkinson's disease dementia, 289 cognitively unimpaired Parkinson's disease patients and 353 healthy controls. Parkinson's disease patients with cognitive impairment predominantly showed a reduced connectivity in specific brain regions that are part of the default mode network.
Conclusion:
Cognitive impairment in Parkinson's disease is associated with reduced connectivity in networks relevant to cognition, most prominently the default mode network. Specific alterations in functional connectivity may contribute to cognitive decline in Parkinson patients and may be a promising future biomarker.
Background: Parkinson's disease (PD) could be classified into akinetic-rigidity (PDAR), tremor-dominant (PDTD) and mixed subtypes. PDAR patients are more prone to develop cognitive deficits. The default mode network (DMN), fronto-parietal network (FPN) and dorsal attention network (DAN) play important roles in cognitive processing. Our aim was to evaluate changes in connectivity patterns of the DMN, and its interrelation with the FPN and DAN in cognitively unimpaired drug-naïve PDAR patients.
Method: Resting-state functional MRI (rs-fMRI) data was collected in 20 cognitively unimpaired early-stage drug-naïve PDAR patients and 20 age-, gender- and cognition- matched healthy controls (HCs). Group-level independent component analysis (ICA) was used to investigate changes in functional connectivity (FC) within the DMN between PDAR and HCs groups, and relationships between the DMN and FPN/DAN were evaluated by seed-based approach.
Results: In PDAR patients, a significantly decreased FC, as compared with HCs, was observed in the left inferior parietal lobule (IPL) within the DMN. And the left IPL had a reduced FC with the left anterior cingulate cortex (ACC), left superior frontal gyrus (SFG), and left precuneus. However, no differences were detected in the FC between the left IPL and FPN/DAN. In addition, cognitive scores on the brief visuospatial memory test revised (BVMT-R), representing for cognitive memory domain, were positively correlated with the FC of the left IPL with bilateral SFG.
Conclusions: Our study mainly revealed altered within-DMN connectivity in cognitively unimpaired PDAR patients, which could provide further insights into the mechanism underlying cognitive decline evolution in the PD subtype.
Parkinson's disease is a neurodegenerative disorder classically characterized by motor symptoms. Among them, hypomimia affects facial expressiveness and social communication and has a highly negative impact on patients' and relatives' quality of life. Patients also frequently experience nonmotor symptoms, including emotional-processing impairments, leading to difficulty in recognizing emotions from faces. Aside from its theoretical importance, understanding the disruption of facial emotion recognition in PD is crucial for improving quality of life for both patients and caregivers, as this impairment is associated with heightened interpersonal difficulties. However, studies assessing abilities in recognizing facial emotions in PD still report contradictory outcomes. The origins of this inconsistency are unclear, and several questions (regarding the role of dopamine replacement therapy or the possible consequences of hypomimia) remain unanswered. We therefore undertook a fresh review of relevant articles focusing on facial emotion recognition in PD to deepen current understanding of this nonmotor feature, exploring multiple significant potential confounding factors, both clinical and methodological, and discussing probable pathophysiological mechanisms. This led us to examine recent proposals about the role of basal ganglia-based circuits in emotion and to consider the involvement of facial mimicry in this deficit from the perspective of embodied simulation theory. We believe our findings will inform clinical practice and increase fundamental knowledge, particularly in relation to potential embodied emotion impairment in PD. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Deep brain stimulation (DBS) for Parkinson's disease is a highly effective treatment in controlling otherwise debilitating symptoms. Yet the underlying brain mechanisms are currently not well understood. Whole-brain computational modeling was used to disclose the effects of DBS during resting-state functional Magnetic Resonance Imaging in ten patients with Parkinson's disease. Specifically, we explored the local and global impact that DBS has in creating asynchronous, stable or critical oscillatory conditions using a supercritical bifurcation model. We found that DBS shifts global brain dynamics of patients towards a Healthy regime. This effect was more pronounced in very specific brain areas such as the thalamus, globus pallidus and orbitofrontal regions of the right hemisphere (with the left hemisphere not analyzed given artifacts arising from the electrode lead). Global aspects of integration and synchronization were also rebalanced. Empirically, we found higher communicability and coherence brain measures during DBS-ON compared to DBS-OFF. Finally, using our model as a framework, artificial in silico DBS was applied to find potential alternative target areas for stimulation and whole-brain rebalancing. These results offer important insights into the underlying large-scale effects of DBS as well as in finding novel stimulation targets, which may offer a route to more efficacious treatments.
Resting state studies in neuropsychiatric disorders have already provided much useful information, but the field is regarded as being at a relatively preliminary stage and subject to several design issues that set limits on the overall utility.
Background:
Resting state functional magnetic resonance imaging (rs-fMRI) has been applied to investigate topographic structure in Parkinson's disease (PD). Alteration of topographic architecture has been inconsistent in PD AIM: To investigate the network profile of PD using graph theoretical analysis.
Method:
Twenty six newly diagnosed PD and 19 age- and gender- matched healthy controls (HC) were included in our analysis. Small-world profile and topographic profiles (nodal degree, global efficiency, local efficiency, cluster coefficient, shortest path length, betweenness centrality) were measured and compared between groups, with age and gender as covariates. We also performed correlation analysis between topographic features with motor severity measured by UPDRS III.
Results:
Small-world property was present in PD. Nodal degree, global efficiency, local efficiency and characteristic path length consistently revealed disruptive sensorimotor network, and visual network to a less degree in PD. By contrast, default mode network (DMN) and cerebellum in PD showed higher nodal degree, global efficiency and local efficiency, and lower characteristic path length. Global and local efficiency in the midbrain was higher in PD excluding substantia nigra. PD group also exhibited lower cluster coefficient in the subcortical motor network (thalamus and caudate nucleus). No significant correlation was found between topographic properties and motor severity.
Conclusion:
PD exhibited disruptive sensorimotor and visual networks in early disease stage. DMN, a certain areas in the cerebellum and midbrain may compensate for disruptive sensorimotor and visual network in PD. Disruptive network architecture may be an early alteration of PD pathophysiology but may not serve as a valid biomarker yet.
Background: There are doubts wether generic medications have the same bioavailability and efficacy compared with the original drugs developed by pharmaceutical companies with research capabilities. Aim: To compare the pharmacokinetics and clinical (motor) responses of Sinemetâ and Grifoparkinâ(generic carbidopa/levodopa 250/25 mg) in patients with advanced Parkinson's disease. Patients and methods: Patients were randomly assigned to Sinemetâ (15 patients 62±12 years old; mean disease duration 11±7 years) or Grifoparkinâ (15 patients, 64±11 years old; mean disease duration 12±4 years) groups. Medication and food were withheld 12 h before the study. Fifteen blood samples were collected (starting 9 AM) immediately before (sample 1, t=0 min) and after (samples 2-15, t=20-360 min) oral administration of a single dose of Sinemetâ or Grifoparkinâ, and plasmatic L-DOPA was quantified using HPLC with electrochemical detection. Additionally, each patient was clinically evaluated every 20 minutes, using the tapping test and the unified Parkinson's disease scale Hoehn & Yarh. Results: Tmax (time at which the maximal L-DOPA concentration was reached) were 69±12 min and 64±11 min for Sinemetâ and Grifoparkinâ respectively (NS). Cmax (maximal L-DOPA concentration reached) was 3161±345 ng/ml for Sinemetâ and 3274±520 ng/ml for Grifoparkinâ (NS). The t1/2 (half life time), CL (clearance) and volume of distribution (Vd) values calculated were 159±32 min, 51.7±5.1 1/h and 3.6±1.2 l/kg for Sinemetâ and 161±48 min, 58.7±8 l/h and 3.0±0.7 l/kg for Grifoparkinâ (NS). UPDRS-III value for the best "on state" and for the worst "off state" were 23±11 and 50±19 for Sinemetâ and 20±7 and 46±13 for Grifoparkinâ respectively (NS). Conclusion: the results obtained showed that both drugs are bioequivalent in patients with advanced Parkinson's disease (Rev Méd Chile 2003; 131: 623-631)
To examine the integrity of the default mode network in patients with Parkinson disease (PD). Previous functional neuroimaging experiments have studied executive deficits in patients with PD with regard to task-related brain activation. However, recent studies suggest that executive performance also relies on the integrity of the default mode network (ie, medial prefrontal cortex, posterior cingulate cortex, precuneus, and lateral parietal and medial temporal cortices), characterized by a deactivation of these cortical areas during the performance of executive tasks.
We used functional magnetic resonance imaging to investigate cortical deactivations during a card-sorting task (retrieval and manipulation of short-term memory contents) compared with a simple sensory-motor matching task. In addition, a functional connectivity analysis was performed.
Tertiary outpatient clinic.
Seven patients with mild to moderate PD (not taking medication) and 7 healthy controls.
Cortical deactivations.
Both groups showed comparable deactivation of the medial prefrontal cortex but different deactivation in the posterior cingulate cortex and the precuneus. Compared with controls, patients with PD not only showed less deactivation of the posterior cingulate cortex and the precuneus, they even demonstrated a reversed pattern of activation and deactivation. Connectivity analysis yielded that in contrast to healthy individuals, medial prefrontal cortex and the rostral ventromedial caudate nucleus were functionally disconnected in PD.
We describe specific malfunctioning of the default mode network during an executive task in PD. This finding is plausibly linked to dopamine depletion and may critically contribute to the understanding of executive deficits in PD.
Dopamine and dopamine transporters (DAT, which regulate extracellular dopamine in the brain) are implicated in the modulation of attention but their specific roles are not well understood. Here we hypothesized that dopamine modulates attention by facilitation of brain deactivation in the default mode network (DMN). Thus, higher striatal DAT levels, which would result in an enhanced clearance of dopamine and hence weaker dopamine signals, would be associated to lower deactivation in the DMN during an attention task.
For this purpose we assessed the relationship between DAT in striatum (measured with positron emission tomography and [(11)C]cocaine used as DAT radiotracer) and brain activation and deactivation during a parametric visual attention task (measured with blood oxygenation level dependent functional magnetic resonance imaging) in healthy controls. We show that DAT availability in caudate and putamen had a negative correlation with deactivation in ventral parietal regions of the DMN (precuneus, BA 7) and a positive correlation with deactivation in a small region in the ventral anterior cingulate gyrus (BA 24/32). With increasing attentional load, DAT in caudate showed a negative correlation with load-related deactivation increases in precuneus.
These findings provide evidence that dopamine transporters modulate neural activity in the DMN and anterior cingulate gyrus during visuospatial attention. Our findings suggest that dopamine modulates attention in part by regulating neuronal activity in posterior parietal cortex including precuneus (region involved in alertness) and cingulate gyrus (region deactivated in proportion to emotional interference). These findings suggest that the beneficial effects of stimulant medications (increase dopamine by blocking DAT) in inattention reflect in part their ability to facilitate the deactivation of the DMN.
The aim of this study is to elucidate the clinical spectrum and frequency of non-motor symptoms during off periods (NMOS) in Parkinson's disease (PD) patients with motor fluctuation. We compared clinical characteristics between PD patients with motor symptoms only (M-off) and those with both motor and non-motor symptoms (NM-off) during off periods. The association of NMOS with parkinsonian clinical characteristics was also investigated. Sixty-seven consecutive PD patients of both M-off and NM-off groups were included in this study. We reviewed medical records, interviewed the patients, and administered a structured questionnaire. NMOS is classified into three categories: autonomic, neuropsychiatric and sensory. The frequency of NMOS and their individual manifestations were assessed. Of 67 patients with off symptoms, 20 were M-off group and 47 NM-off group. Among NMOS, diffuse pain was the most common manifestation, followed by anxiety and sweating. There were no significant differences between M-off and NM-off groups with regard to age, duration of disease and treatment, interval between onset of parkinsonian symptoms and off symptoms and off periods. Patients taking higher dosage of levodopa had fewer NMOS. NMOS is frequent in PD. Comprehensive recognition of NMOS can avoid unnecessary tests and is important for optimal treatment in PD.
Cognitive processing is associated with deactivation of the default mode network. The presence of dopaminoceptive neurons in proximity to the medial prefrontal node of this network suggests that this neurotransmitter may modulate deactivation in this region. We therefore used positron emission tomography to measure cerebral blood flow in 15 Parkinson's disease (PD) patients while they performed a motor sequence learning task and a simple movement task. Scanning was conducted before and during intravenous levodopa infusion; the pace and extent of movement was controlled across tasks and treatment conditions. In normal and unmedicated PD patients, learning-related deactivation was present in the ventromedial prefrontal cortex (p < 0.001). This response was absent in the treated condition. Treatment-mediated changes in deactivation correlated with baseline performance (p < 0.002) and with the val(158)met catechol-O-methyltransferase genotype. Our findings suggest that dopamine can influence prefrontal deactivation during learning, and that these changes are linked to baseline performance and genotype.
The major motor disturbances in Parkinson's disease are thought to be caused by overactivity of the internal segment of the globus pallidus (GPi), in large part due to excessive drive from the subthalamic nucleus. The excessive inhibitory activity of GPi is thought to "brake' the motor thalamus and the cortical motor system to produce the slowness, rigidity, and poverty of movement characteristic of parkinsonian states. To test the hypothesis that direct reduction of Gpi activity can improve motor function, we studied the effect of GPi pallidotomy in 14 patients. The location of the GPi nucleus was confirmed by microelectrode recording before lesion creation. Standardised videotape recordings before and after operation were randomised and scored by a "blinded' evaluator. 6 months after surgery, total motor score in the "off" state had improved by 30% and the total akinesia score by 33%. The gait score in the "off" state improved by 15% and a composite postural instability and gait score by 23%. After surgery there was almost total elimination of drug-induced involuntary movements (dyskinesias), with a 92% reduction on the side contralateral to the pallidotomy. No patient had visual or corticospinal complications. In these patients GPi pallidotomy enhanced motor performance, reduced akinesia, improved gait, and eliminated the neural elements responsible for levodopa-induced dyskinesias.
A baseline or control state is fundamental to the understanding of most complex systems. Defining a baseline state in the human brain, arguably our most complex system, poses a particular challenge. Many suspect that left unconstrained, its activity will vary unpredictably. Despite this prediction we identify a baseline state of the normal adult human brain in terms of the brain oxygen extraction fraction or OEF. The OEF is defined as the ratio of oxygen used by the brain to oxygen delivered by flowing blood and is remarkably uniform in the awake but resting state (e.g., lying quietly with eyes closed). Local deviations in the OEF represent the physiological basis of signals of changes in neuronal activity obtained with functional MRI during a wide variety of human behaviors. We used quantitative metabolic and circulatory measurements from positron-emission tomography to obtain the OEF regionally throughout the brain. Areas of activation were conspicuous by their absence. All significant deviations from the mean hemisphere OEF were increases, signifying deactivations, and resided almost exclusively in the visual system. Defining the baseline state of an area in this manner attaches meaning to a group of areas that consistently exhibit decreases from this baseline, during a wide variety of goal-directed behaviors monitored with positron-emission tomography and functional MRI. These decreases suggest the existence of an organized, baseline default mode of brain function that is suspended during specific goal-directed behaviors.
There are doubts wether generic medications have the same bioavailability and efficacy compared with the original drugs developed by pharmaceutical companies with research capabilities.
To compare the pharmacokinetics and clinical (motor) responses of Sinemet and Grifoparkin (generic carbidopa/levodopa 250/25 mg) in patients with advanced Parkinson's disease.
Patients were randomly assigned to Sinemet (15 patients 62 +/- 12 years old; mean disease duration 11 +/- 7 years) or Grifoparkin (15 patients, 64 +/- 11 years old; mean disease duration 12 +/- 4 years) groups. Medication and food were withheld 12 h before the study. Fifteen blood samples were collected (starting 9 AM) immediately before (sample 1, t = 0 min) and after (samples 2-15, t = 20-360 min) oral administration of a single dose of Sinemet or Grifoparkin, and plasmatic L-DOPA was quantified using HPLC with electrochemical detection. Additionally, each patient was clinically evaluated every 20 minutes, using the tapping test and the unified Parkinson's disease scale Hoehn & Yarh.
Tmax (time at which the maximal L-DOPA concentration was reached) were 69 +/- 12 min and 64 +/- 11 min for Sinemet and Grifoparkin respectively (NS). Cmax (maximal L-DOPA concentration reached) was 3161 +/- 345 ng/ml for Sinemet and 3274 +/- 520 ng/ml for Grifoparkin (NS). The t1/2 (half life time), CL (clearance) and volume of distribution (Vd) values calculated were 159 +/- 32 min, 51.7 +/- 5.1 1/h and 3.6 +/- 1.2 l/kg for Sinemet and 161 +/- 48 min, 58.7 +/- 8 l/h and 3.0 +/- 0.7 l/kg for Grifoparkin (NS). UPDRS-III value for the best "on state" and for the worst "off state" were 23 +/- 11 and 50 +/- 19 for Sinemet and 20 +/- 7 and 46 +/- 13 for Grifoparkin respectively (NS).
The results obtained showed that both drugs are bioequivalent in patients with advanced Parkinson's disease.
In addition to classic motor signs and symptoms, Parkinson's disease (PD) is characterized by neuropsychological and emotional deficits, including a blunted emotional response. In the present study, we explored both the neural basis of abnormal emotional behavior in PD and the physiological effects of dopaminergic therapy on the response of the amygdala, a central structure in emotion processing. PD patients and matched normal controls (NCs) were studied with blood oxygenation level-dependent functional magnetic resonance imaging during a paradigm that involved perceptual processing of fearful stimuli. PD patients were studied twice, once during a relatively hypodopaminergic state (i.e., > or =12 hr after their last dose of dopamimetic treatment) and again during a dopamine-replete state. The imaging data revealed a robust bilateral amygdala response in NCs that was absent in PD patients during the hypodopaminergic state. Dopamine repletion partially restored this response in PD patients. Our results demonstrate an abnormal amygdala response in PD that may underlie the emotional deficits accompanying the disease. Furthermore, consistent with findings in experimental animal paradigms, our results provide in vivo evidence of the role of dopamine in modulating the response of the amygdala to sensory information in human subjects.
We investigated the effect of transient dopamine depletion on functional connectivity during performance of the Wisconsin Card Sorting Task. Functional magnetic resonance imaging data were analyzed as a psychophysiological interaction, a statistical method used to identify functional connectivity during experimental manipulations. Nineteen healthy subjects were scanned, double blind, on 2 separate days: once after drinking an amino acid mixture deficient in the dopamine precursors tyrosine and phenylalanine, and once after drinking a nutritionally balanced mixture. In the balanced drink session, statistically significant connectivity between the frontal lobes and striatum was observed during set shifting, and the greater the prefrontostriatal connectivity, the faster the response time after a shift. Neither of these associations were observed after dopamine depletion. Moreover, dopamine depletion also reduced the degree of deactivation in areas normally suppressed during attention-demanding tasks, including the medial prefrontal cortex, posterior cingulate cortex, and hippocampus. Together, these results suggest that functional connectivity between the frontal lobes and basal ganglia during set shifting contributes to more efficient performance and that dopamine modulates this corticostriatal connectivity.
Thirty years of brain imaging research has converged to define the brain's default network-a novel and only recently appreciated brain system that participates in internal modes of cognition. Here we synthesize past observations to provide strong evidence that the default network is a specific, anatomically defined brain system preferentially active when individuals are not focused on the external environment. Analysis of connectional anatomy in the monkey supports the presence of an interconnected brain system. Providing insight into function, the default network is active when individuals are engaged in internally focused tasks including autobiographical memory retrieval, envisioning the future, and conceiving the perspectives of others. Probing the functional anatomy of the network in detail reveals that it is best understood as multiple interacting subsystems. The medial temporal lobe subsystem provides information from prior experiences in the form of memories and associations that are the building blocks of mental simulation. The medial prefrontal subsystem facilitates the flexible use of this information during the construction of self-relevant mental simulations. These two subsystems converge on important nodes of integration including the posterior cingulate cortex. The implications of these functional and anatomical observations are discussed in relation to possible adaptive roles of the default network for using past experiences to plan for the future, navigate social interactions, and maximize the utility of moments when we are not otherwise engaged by the external world. We conclude by discussing the relevance of the default network for understanding mental disorders including autism, schizophrenia, and Alzheimer's disease.
Functional imaging studies using working memory tasks have documented both prefrontal cortex (PFC) hypo- and hyperactivation in schizophrenia. However, these studies have often failed to consider the potential role of task-related deactivation.
Thirty-two patients with chronic schizophrenia and 32 age- and sex-matched normal controls underwent functional magnetic resonance imaging (fMRI) scanning while performing baseline, 1-back and 2-back versions of the n-back task. Linear models were used to obtain maps of activations and deactivations in the groups.
The controls showed activation in the expected frontal regions. There were also clusters of deactivation, particularly in the anterior cingulate/ventromedial PFC and the posterior cingulate cortex/precuneus. Compared to the controls, the schizophrenic patients showed reduced activation in the right dorsolateral prefrontal cortex (DLPFC) and other frontal areas. There was also an area in the anterior cingulate/ventromedial PFC where the patients showed apparently greater activation than the controls. This represented a failure of deactivation in the schizophrenic patients. Failure to activate was a function of the patients' impaired performance on the n-back task, whereas the failure to deactivate was less performance dependent.
Patients with schizophrenia show both failure to activate and failure to deactivate during performance of a working memory task. The area of failure of deactivation is in the anterior prefrontal/anterior cingulate cortex and corresponds to one of the two midline components of the 'default mode network' implicated in functions related to maintaining one's sense of self.
The notion of a “default mode of brain function” has taken on certain relevance in human neuroimaging studies and in relation to a network of lateral parietal and midline cortical regions that show prominent activity fluctuations during passive imaging states, such as rest. In this study, we perform three fMRI experiments that demonstrate consistency and specialization in the default mode network. Correlated activity fluctuations of default mode network regions are identified during (i) eyes-closed spontaneous rest, (ii) activation by moral dilemma, and (iii) deactivation by Stroop task performance. Across these imaging states, striking uniformity is shown in the basic anatomy of the default mode network, but with both tasks clearly and differentially modulating this activity compared with spontaneous fluctuations of the network at rest. Against rest, moral dilemma is further shown to evoke regionally specific activity increases of hypothesized functional relevance. Mapping spontaneous and task-related brain activity will help to constrain the meaning of the default mode network. These findings are discussed in relation to recent debate on the topic of default modes of brain function.
• activation
• deactivation
• default mode
• functional MRI
• spontaneous activity
Objective: To examine the integrity of the default mode network in patients with Parkinson disease (PD). Previous functional neuroimaging experiments have studied executive deficits in patients with PD with regard to task-related brain activation. However, recent studies suggest that executive performance also relies on the integrity of the default mode network (ie, medial prefrontal cortex, posterior cingulate cortex, precuneus, and lateral parietal and medial temporal cortices), characterized by a deactivation of these cortical areas during the performance of executive tasks. Design: We used functional magnetic resonance imaging to investigate cortical deactivations during a card-sorting task (retrieval and manipulation of short-term memory contents) compared with a simple sensory-motor matching task. In addition, a functional connectivity analysis was performed. Setting: Tertiary outpatient clinic. Participants: Seven patients with mild to moderate PD (not taking medication) and 7 healthy controls. Main Outcome Measure: Cortical deactivations. Results: Both groups showed comparable deactivation of the medial prefrontal cortex but different deactivation in the posterior cingulate cortex and the precuneus. Compared with controls, patients with PD not only showed less deactivation of the posterior cingulate cortex and the precuneus, they even demonstrated a reversed pattern of activation and deactivation. Connectivity analysis yielded that in contrast to healthy individuals, medial prefrontal cortex and the rostral ventromedial caudate nucleus were functionally disconnected in PD. Conclusions: We describe specific malfunctioning of the default mode network during an executive task in PD. This finding is plausibly linked to dopamine depletion and may critically contribute to the understanding of executive deficits in PD.
Background: There are doubts wether generic medications have the same bioavailability and efficacy compared with the original drugs developed by pharmaceutical companies with research capabilities. Aim: To compare the pharmacokinetics and clinical (motor) responses of Sinemet((R)) and Grifoparkin((R)) (generic carbidopa/levodopa 250/25 mg) in patients with advanced Parkinson's disease. Patients and methods. Patients were randomly assigned to Sinemet((R)) (15 patients 62 12 years old; mean disease duration 11 7 years) or Grifoparkin((R)) (15 Patients, 64 +/- 11 years old; mean disease duration 12 4 years) groups. Medication and food were withheld 12 b before the study. Fifteen blood samples were collected (starting 9 AM) immediately before (sample 1, t=0 min) and after (samples 2-15, t=20-360 min) oral administration of a single dose of Sinemet((R)) or Grifoparkin((R)) and plasmatic L-DOPA was quantified using HPLC with electrochemical detection. Additionally, each patient was clinically evaluated every 20 minutes, using the tapping test and the unified Parkinson's disease scale Hoehn & Yarb. Results: T-max (time at which the maximal L-DOPA concentration was reached) were 69 +/- 12 min and 64 +/- 11 min for Sinemet((R)) and Grifoparkin((R)) respectively (NS). C-max (maximal L-DOPA concentration reached) was 3161+/-345 ng/ml for Sinemet((R)) and 3274+/-520 ng/ml for Grifoparkin((R)) (NS). The(t1/2) (half life time), CL (clearance) and volume of distribution (VI) values calculated were 159+/-32 min, 51.7+/-5.1 1/h and 3.6+/-1.2 l/kg for Sinemet((R)) and 161 48 min, 58.7+/-8 l/h and 3.0+/-0.7 l/kg for Grifoparkin((R)) (NS). UPDRS-III value for the best "on state" and for the worst "off state" were 23+/-11 and 50+/-19 for Sinemet((R)) and 20 and 46+/-13 for Grifoparkin((R)) respectively (NS). Conclusion: the results obtained showed that both drugs arc, bioequivalent in patients with advanced Parkinson's disease.
Administered 16 visual analog scales to 8 normal Ss to test the validity of the scales in measuring drug effects; Ss received 150 mg of butobarbitone sodium, 15 and 30 mg of flurazepam, and a placebo. Results indicate that (a) there were no significant effects on Factor 1 (Alertness), but there was a tendency for Ss to rate themselves as more alert after placebo; (b) there was a significant Drug * Times interaction effect on Factor 2 (Contentedness); and (c) Factor 3 (Calmness) also showed a significant Drug * Times interaction effect which was caused by the anti-anxiety effect of flurazepam. (15 ref) (PsycINFO Database Record (c) 2004 APA, all rights reserved)
Variable findings have been reported for emotional processing in patients with Parkinson disease (PD). These contradictions could be due to differences in the progression of dopamine (DA) depletion. Levodopa treatment could have either beneficial or detrimental effects on brain functions modulated by DA according to disease progression. In healthy subjects, levodopa administration leads to a decreased amygdala activation in response to emotional tasks. Because it is known that there is a link between DA loss in mesolimbic system and depression, we hypothesized that PD patients without depression would have spared limbic DA projections. Consequently, levodopa medication could overdose limbic regions relative to severe dorsal striatal denervation. To evaluate the effect of levodopa on amygdala activation, we conducted a functional magnetic resonance imaging study in nondemented, nondepressed PD patients compared with healthy volunteers. Patients with PD and healthy subjects received either levodopa or placebo in 2 functional magnetic resonance imaging sessions. Amygdala activation was evaluated during a facial emotion recognition task. A similar right-amygdala activity was seen in both healthy subjects and PD patients in the placebo session. After levodopa administration, activity was reduced in both groups. In the patients, the levodopa dose used significantly improved motor dysfunction. Nondemented, nondepressed PD patients thus seem to have relatively preserved DA mesolimbic projections, and consequently, the same dose of levodopa needed to correct the lack of DA in the severely depleted putamen (motor part of striatum) would incidentally overdose the mesolimbic projections toward the amygdala.
The Default Mode Network (DMN) is a constellation of brain areas that decrease their activity during a wide number of different goal-oriented tasks as compared to passive “rest” tasks. DMN can be modulated by different factors such as emotional states, cognitive load of the task and psychopathology, including anxiety. Moreover, DMN seems to play a pivotal role in social cognition. For example, the ability to predict another person's behaviour taking his or her perspective modulates the activity of the DMN. Recent data from autistic patients support a role of DMN in social cognition as well. Social Phobia (SP) is an anxiety disorder characterized by an abnormal distress in situations that require social interaction. To date, no study has assessed DMN in Social Phobia. To determine potential differences in DMN activity between Social Phobia patients (SPP) and healthy control (HC) subjects we examined functional magnetic resonance imaging (fMRI) data obtained during a face perception study with emotional and neutral stimuli. As compared to HC, SPP showed a lower deactivation in the precuneus and posterior cingulate regions (PCun/PCC) during task conditions. These regions are part of the so-called “Theory of Mind” circuit and in particular they are involved in the evaluation of one's own emotional state.
Task-induced deactivation is frequently reported in the ventro-medial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC), regions considered to belong to the default mode network. To investigate the effect of dopamine on task-induced deactivation, we used positron emission tomography to measure cerebral blood flow during performance of the Tower of London task before and after administration of the dopamine receptor agonist apomorphine in six healthy volunteers (49-66 years old) and six Parkinson disease patients (52-69 years old). Although task-induced deactivation was observed in the vmPFC and PCC in both groups and in both conditions, an inverse correlation between activation and problem complexity was observed in the vmPFC only in the apomorphine condition.
Anhedonia, as a deficit symptom, may be associated with default-mode hypofrontality in schizophrenia. To explore whether trait anhedonia in schizophrenia pertains to altered hypofrontal resting state brain function, resting state metabolic activities were compared and correlated with the Physical and Social Anhedonia Scale scores in 29 patients with schizophrenia and 21 healthy controls using (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET). In patients with schizophrenia, Physical Anhedonia Scale scores showed a trend-level negative correlation with the hypoactive dorsomedial prefrontal metabolism while Positive and Negative Symptom Scale (PANSS) negative subscale scores positively correlated with hyperactive cerebellar metabolism. Voxelwise correlation analysis showed physical anhedonia correlates in resting state activities of the supplementary motor area, ventromedial and dorsolateral prefrontal cortex, insular gyrus, and the precuneus in patients with schizophrenia while no frontal metabolic correlates were found in healthy controls. The hypoactive dorsomedial prefrontal metabolism correlated with physical anhedonia-correlated resting state regional activities. These findings provide further evidence for the relation of functional hypofrontality to the deficit syndrome and possible involvement of the functional imbalance in the cortico-cerebellar-thalamic-cortical circuit in the resting state brain function of schizophrenia.
In this review we are concerned specifically with the putative role of the default-mode network (DMN) in the pathophysiology of mental disorders. First, we define the DMN concept with regard to its neuro-anatomy, its functional organisation through low frequency neuronal oscillations, its relation to other recently discovered low frequency resting state networks, and the cognitive functions it is thought to serve. Second, we introduce methodological and analytical issues and challenges. Third, we describe putative mechanisms proposed to link DMN abnormalities and mental disorders. These include interference by network activity during task performance, altered patterns of antagonism between task specific and non-specific elements, altered connectively and integrity of the DMN, and altered psychological functions served by the network DMN. Fourth, we review the empirical literature systematically. We relate DMN dysfunction to dementia, schizophrenia, epilepsy, anxiety and depression, autism and attention deficit/hyperactivity disorder drawing out common and unique elements of the disorders. Finally, we provide an integrative overview and highlight important challenges and tasks for future research.
The default mode network (DMN) is a set of functionally connected brain regions which shows deactivation (task-induced deactivation, TID) during a cognitive task. Evidence shows an age-related decline in task-load-related modulation of the activity within the DMN during cognitive tasks. However, the effect of age on the functional coupling within the DMN and their relation to cognitive performance has hitherto been unexplored. Using functional magnetic resonance imaging, we investigated functional connectivity within the DMN in older and younger subjects during a working memory task with increasing task load. Older adults showed decreased connectivity and ability to suppress low frequency oscillations of the DMN. Additionally, the strength of the functional coupling of posterior cingulate (pCC) with medial prefrontal cortex (PFC) correlated positively with performance and was lower in older adults. pCC was also negatively coupled with task-related regions, namely the dorsolateral PFC and cingulate regions. Our results show that in addition to changes in canonical task-related brain regions, normal aging is also associated with alterations in the activity and connectivity of brain regions within the DMN. These changes may be a reflection of a deficit in cognitive control associated with advancing age that results in deficient resource allocation to the task at hand.
Basal ganglia contribute to a wide variety of behavioral functions, including skeletomotor, oculomotor, cognitive, and limbic processes. This chapter focuses on the basal ganglia-thalamocortical circuits. Basal ganglia-thalamocortical circuits are organized in a parallel manner and remain largely segregated from one another, both structurally and functionally. The central theme of the segregated circuits hypothesis is that structural convergence and functional integration occurs within each of the identified circuits. In primates, the basal ganglia motor pathways are focused principally on the putamen and its connections. This part of the neostriatum receives topographic projections from primary motor cortex (MC). The focus of the terminals originating in the putamen appears to lie somewhat dorsal to that of the terminals arising from the body of the caudate. The basal ganglia-thalamocortical circuits might be seen as having a unified role in modulating the operations of the entire frontal lobe, and thereby influencing—by common mechanisms, such as diverse frontal lobe processes—the maintenance and switching of behavioral sets and the planning and execution of limb and eye movements.
The Montgomery and Asberg Depression Rating Scale (MADRS) is a 10 item severity scale constructed to be sensitive to change with treatment. It was designed to be sensitive for individual items and is therefore useful for measuring differential profiles of action. The MADRS profiles of activity were examined in a six-week double-blind comparative group study of depressed patients treated with mianserin or zimeldine. Three of the ten items on the MADRS showed individual significant advantages for mianserin, reduced sleep (weeks 1 and 3), concentration difficulties (week 1), and reduced appetite (week 3). These findings are in agreement with earlier reports of poor sleep and gastrointestinal upset associated with the 5-HT uptake inhibitor zimeldine. The selective improvement in concentration difficulties and in the other items support the view that mianserin is particularly useful in alleviating the anxiety associated with depression. The sedative effect of mianserin did not appear to interfere with concentration. There were significant improvements in the mianserin-treated group at 1, 2, 3, and 4 weeks for the MADRS, Hamilton Depression Rating Scale and Clinicians Global Impression scale. There was no significant advantage for mianserin at 5 and 6 weeks. The differential clinical effects were apparent early in the study but any selectivity of action appeared to be overwhelmed by the general antidepressant effect later in treatment.
The recent resurgent interest in functional surgery for the treatment of Parkinson's disease (PD) has focused on the effects on akinesia and levodopa-induced dyskinesia. Stimulation of the subthalamic nucleus (STN) improves akinesia and rigidity but its effects on tremor have not been studied. The objective of this study was to assess the efficacy of STN stimulation on tremor in patients with the complete parkinsonian triad with motor fluctuations. Of 27 consecutive patients with STN stimulation (26 bilateral), 15 exhibited tremor rated at least 2/4 according to item 20 (rest tremor) of the Unified Parkinson's Disease Rating Scale (UPDRS) in at least one limb. The mean preoperative tremor score was 11.3+/-5.6 in off-drug and 1.2+/-2.4 in on-drug conditions. The postoperative tremor scores at the last follow up (from 1-12 months) were 2.2+/-2.2 off-drug/on-stimulation and 0.2+/-0.4 on-drug/on-stimulation. Both rest and action tremors were improved in all patients. The UPDRS tremor score was reduced by 80%, rigidity score by 65%, and akinesia score by 51% on average. For the three symptoms, the stimulation effect was close to that induced before surgery by a suprathreshold dose of levodopa given in the morning. STN stimulation can be considered an interesting alternative to thalamic or internal pallidal surgery even in PD patients with severe high-amplitude tremor. In keeping with electrophysiological data in monkeys rendered parkinsonian by MPTP injections, our results emphasize the importance of the oscillation of a neuronal loop involving the STN in the pathophysiology of parkinsonian tremor.
Functional brain imaging in humans has revealed task-specific increases in brain activity that are associated with various mental activities. In the same studies, mysterious, task-independent decreases have also frequently been encountered, especially when the tasks of interest have been compared with a passive state, such as simple fixation or eyes closed. These decreases have raised the possibility that there might be a baseline or resting state of brain function involving a specific set of mental operations. We explore this possibility, including the manner in which we might define a baseline and the implications of such a baseline for our understanding of brain function.
The perception of pain due to an acute injury or in clinical pain states undergoes substantial processing at supraspinal levels. Supraspinal, brain mechanisms are increasingly recognized as playing a major role in the representation and modulation of pain experience. These neural mechanisms may then contribute to interindividual variations and disabilities associated with chronic pain conditions.
To systematically review the literature regarding how activity in diverse brain regions creates and modulates the experience of acute and chronic pain states, emphasizing the contribution of various imaging techniques to emerging concepts.
MEDLINE and PRE-MEDLINE searches were performed to identify all English-language articles that examine human brain activity during pain, using hemodynamic (PET, fMRI), neuroelectrical (EEG, MEG) and neurochemical methods (MRS, receptor binding and neurotransmitter modulation), from January 1, 1988 to March 1, 2003. Additional studies were identified through bibliographies.
Studies were selected based on consensus across all four authors. The criteria included well-designed experimental procedures, as well as landmark studies that have significantly advanced the field.
Sixty-eight hemodynamic studies of experimental pain in normal subjects, 30 in clinical pain conditions, and 30 using neuroelectrical methods met selection criteria and were used in a meta-analysis. Another 24 articles were identified where brain neurochemistry of pain was examined. Technical issues that may explain differences between studies across laboratories are expounded. The evidence for and the respective incidences of brain areas constituting the brain network for acute pain are presented. The main components of this network are: primary and secondary somatosensory, insular, anterior cingulate, and prefrontal cortices (S1, S2, IC, ACC, PFC) and thalamus (Th). Evidence for somatotopic organization, based on 10 studies, and psychological modulation, based on 20 studies, is discussed, as well as the temporal sequence of the afferent volley to the cortex, based on neuroelectrical studies. A meta-analysis highlights important methodological differences in identifying the brain network underlying acute pain perception. It also shows that the brain network for acute pain perception in normal subjects is at least partially distinct from that seen in chronic clinical pain conditions and that chronic pain engages brain regions critical for cognitive/emotional assessments, implying that this component of pain may be a distinctive feature between chronic and acute pain. The neurochemical studies highlight the role of opiate and catecholamine transmitters and receptors in pain states, and in the modulation of pain with environmental and genetic influences.
The nociceptive system is now recognized as a sensory system in its own right, from primary afferents to multiple brain areas. Pain experience is strongly modulated by interactions of ascending and descending pathways. Understanding these modulatory mechanisms in health and in disease is critical for developing fully effective therapies for the treatment of clinical pain conditions.
Schizophrenia is characterized by positive symptoms, negative symptoms and cognitive impairment. The dopamine hypothesis of schizophrenia postulates that an excess of dopamine subcortically is associated with the positive symptoms. At the same time, the negative and cognitive symptoms of schizophrenia are thought to arise from a deficit of dopamine in the cortex. Evidence for the co-existence of subcortical dopamine excess and cortical dopamine deficit in the schizophrenic brain is presented. Neuroreceptor-imaging techniques, such as SPECT and PET, have been used to provide that evidence. After amphetamine challenge (to stimulate dopamine release), dopamine transmission was substantially increased in the brains of schizophrenic subjects compared with healthy controls. In addition, amphetamine challenge was associated with an increase in positive symptoms of schizophrenia. Furthermore, acute dopamine depletion studies indicated that there was an increased occupancy of D2 receptors by dopamine at baseline in schizophrenia in comparison with healthy controls. This is consistent with the notion of hyperstimulation of D2 receptors in schizophrenia. In the cortex, dopamine type-1 (D1) receptors were found to be up-regulated in patients with schizophrenia compared to controls; in the dorsolateral prefrontal cortex, a brain region involved in working memory, this increase correlated with a poor performance on the n-back task. The up-regulation of D1 receptors may represent a compensatory effect of the dopamine deficit in the cortex. These findings provide evidence for a corticalsubcortical imbalance in the schizophrenic brain.
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.
The network of regions shown by functional imaging studies to be deactivated by experimental tasks relative to nominally more passive baselines (task < baseline) may reflect processes engaged during the resting state or "default mode." Deactivation may result when attention and resources are diverted from default-mode processes toward task processes. Aging is associated with altered patterns of deactivation which may be related to declining resources, difficulties with resource allocation, or both. These possibilities predict that greater task demand, which increases deactivation levels in younger adults, should exacerbate age-related declines in allocating resources away from the default mode. The present study investigated the magnitude and temporal properties of deactivations in young and older adults during tasks that varied in their demand for cognitive control. Two versions of a verb generation task that varied in their demand for selection among competing alternatives were compared to word reading and a fixation baseline condition. Consistent with our hypothesis, greater deactivations were found with increasing demand. Young and older adults showed equivalent deactivations in the minimal selection condition. By contrast, age differences in both the magnitude and time course of deactivation increased with selection demand: Compared to young adults', older adults' deactivation response showed less sensitivity to demand. Demand-related changes in deactivation magnitude correlated with performance changes, suggesting that individual and group differences in deactivation have functional significance.
The concept of a default mode of brain function arose out of a focused need to explain the appearance of activity decreases in functional neuroimaging data when the control state was passive visual fixation or eyes closed resting. The problem was particularly compelling because these activity decreases were remarkably consistent across a wide variety of task conditions. Using PET, we determined that these activity decreases did not arise from activations in the resting state. Hence, their presence implied the existence of a default mode. While the unique constellation of brain areas provoking this analysis has come to be known as the default system, all areas of the brain have a high level of organized default functional activity. Most critically, this work has called attention to the importance of intrinsic functional activity in assessing brain behavior relationships.
The default mode network (DMN), based in ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC), exhibits higher metabolic activity at rest than during performance of externally oriented cognitive tasks. Recent studies have suggested that competitive relationships between the DMN and various task-positive networks involved in task performance are intrinsically represented in the brain in the form of strong negative correlations (anticorrelations) between spontaneous fluctuations in these networks. Most neuroimaging studies characterize the DMN as a homogenous network, thus few have examined the differential contributions of DMN components to such competitive relationships. Here, we examined functional differentiation within the DMN, with an emphasis on understanding competitive relationships between this and other networks. We used a seed correlation approach on resting-state data to assess differences in functional connectivity between these two regions and their anticorrelated networks. While the positively correlated networks for the vmPFC and PCC seeds largely overlapped, the anticorrelated networks for each showed striking differences. Activity in vmPFC negatively predicted activity in parietal visual spatial and temporal attention networks, whereas activity in PCC negatively predicted activity in prefrontal-based motor control circuits. Granger causality analyses suggest that vmPFC and PCC exert greater influence on their anticorrelated networks than the other way around, suggesting that these two default mode nodes may directly modulate activity in task-positive networks. Thus, the two major nodes comprising the DMN are differentiated with respect to the specific brain systems with which they interact, suggesting greater heterogeneity within this network than is commonly appreciated.
The 'default mode network' is a set of brain regions showing correlated, low-frequency activity during rest. It includes the posterior cingulate/precuneus, medial prefrontal cortex, and bilateral inferior parietal cortex. Earlier studies have characterized this network using either region of interest-based correlation analyses or data-driven techniques; however, there is some disagreement over which method is superior. We conducted both types of analysis on a large (N=40) data set and also investigated age and sex differences in the network. Both region of interest-based analyses and independent component analysis identified the default mode network. Age and sex differences were small and there was less agreement between analytic techniques regarding age and sex effects than regarding default mode network structure.
A core brain network has been proposed to underlie a number of different processes, including remembering, prospection, navigation, and theory of mind [Buckner, R. L., & Carroll, D. C. Self-projection and the brain. Trends in Cognitive Sciences, 11, 49-57, 2007]. This purported network-medial prefrontal, medial-temporal, and medial and lateral parietal regions-is similar to that observed during default-mode processing and has been argued to represent self-projection [Buckner, R. L., & Carroll, D. C. Self-projection and the brain. Trends in Cognitive Sciences, 11, 49-57, 2007] or scene-construction [Hassabis, D., & Maguire, E. A. Deconstructing episodic memory with construction. Trends in Cognitive Sciences, 11, 299-306, 2007]. To date, no systematic and quantitative demonstration of evidence for this common network has been presented. Using the activation likelihood estimation (ALE) approach, we conducted four separate quantitative meta-analyses of neuroimaging studies on: (a) autobiographical memory, (b) navigation, (c) theory of mind, and (d) default mode. A conjunction analysis between these domains demonstrated a high degree of correspondence. We compared these findings to a separate ALE analysis of prospection studies and found additional correspondence. Across all domains, and consistent with the proposed network, correspondence was found within the medial-temporal lobe, precuneus, posterior cingulate, retrosplenial cortex, and the temporo-parietal junction. Additionally, this study revealed that the core network extends to lateral prefrontal and occipital cortices. Autobiographical memory, prospection, theory of mind, and default mode demonstrated further reliable involvement of the medial prefrontal cortex and lateral temporal cortices. Autobiographical memory and theory of mind, previously studied as distinct, exhibited extensive functional overlap. These findings represent quantitative evidence for a core network underlying a variety of cognitive domains.
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