Interactions between functional networks in Parkinson's disease mild cognitive impairment.

The study of mild cognitive impairment (MCI) is critical to understand the underlying processes of cognitive decline in Parkinson's disease (PD). Functional connectivity (FC) disruptions in PD-MCI patients have been observed in several networks. However, the functional and cognitive changes associated with the disruptions observed in these networks are still unclear. Using a data-driven methodology based on independent component analysis, we examined differences in FC RSNs among PD-MCI, PD cognitively normal patients (PD-CN) and healthy controls (HC) and studied their associations with cognitive and motor variables. A significant difference was found between PD-MCI vs PD-CN and HC in a FC-trait comprising sensorimotor (SMN), dorsal attention (DAN), ventral attention (VAN) and frontoparietal (FPN) networks. This FC-trait was associated with working memory, memory and the UPDRS motor scale. SMN involvement in verbal memory recall may be related with the FC-trait correlation with memory deficits. Meanwhile, working memory impairment may be reflected in the DAN, VAN and FPN interconnectivity disruptions with the SMN. Furthermore, interactions between the SMN and the DAN, VAN and FPN network reflect the intertwined decline of motor and cognitive abilities in PD-MCI. Our findings suggest that the memory impairments observed in PD-MCI are associated with reduced FC within the SMN and between SMN and attention networks.

Neural basis of social attention: common and distinct mechanisms for social and nonsocial orienting stimuli.

Social and nonsocial directional stimuli (such as gaze and arrows, respectively) share their ability to trigger attentional processes, although the issue of whether social stimuli generate other additional (and unique) attentional effects is still under debate. In this study, we used the spatial interference paradigm to explore, using functional magnetic resonance imaging, shared and dissociable brain activations produced by gaze and arrows. Results showed a common set of regions (right parieto-temporo-occipital) similarly involved in conflict resolution for gaze and arrows stimuli, which showed stronger co-activation for incongruent than congruent trials. The frontal eye field showed stronger functional connectivity with occipital regions for congruent as compared with incongruent trials, and this effect was enhanced for gaze as compared with arrow stimuli in the right hemisphere. Moreover, spatial interference produced by incongruent (as compared with congruent) arrows was associated with increased functional coupling between the right frontal eye field and a set of regions in the left hemisphere. This result was not observed for incongruent (as compared with congruent) gaze stimuli. The right frontal eye field also showed greater coupling with left temporo-occipital regions for those conditions in which larger conflict was observed (arrow incongruent vs. gaze incongruent trials, and gaze congruent vs. arrow congruent trials). These findings support the view that social and nonsocial stimuli share some attentional mechanisms, while at the same time highlighting other differential effects. Highlights Attentional orienting triggered by social (gaze) and nonsocial (arrow) cues is comparable. When social and nonsocial stimuli are used as targets, qualitatively different behavioral effects are observed. This study explores the neural bases of shared and dissociable neural mechanisms for social and nonsocial stimuli. Shared mechanisms were found in the functional coupling between right parieto-temporo-occipital regions. Dissociable mechanisms were found in the functional coupling between right frontal eye field and ipsilateral and contralateral occipito-temporal regions.

Word frequency and reading demands modulate brain activation in the inferior frontal gyrus.

Processing efficiency differs between high- and low-frequency words, with less frequent words resulting in longer response latencies in several linguistic behavioral tasks. Nevertheless, studies using functional MRI to investigate the word frequency effect have employed diverse methodologies and produced heterogeneous results. In this study, we examine the effect of word frequency through complementary analytical approaches and functional connectivity analyses. Furthermore, we examine whether reading demands, which have been shown to influence reading-related activation, modulate the effects of word frequency. We conducted MRI scanning on 54 healthy participants who performed two versions of a single-word reading task involving high- and low-frequency words: a low-level perceptual reading task and a high-level semantic reading task. The results indicate that word frequency influenced the activation of the pars orbitalis and pars triangularis of the inferior frontal gyrus, but only in the semantic reading task. Additionally, the ventral occipitotemporal cortex exhibited stronger regional activation during the semantic reading task compared to the perceptual reading task, with no effects of word frequency. Functional connectivity analyses demonstrated significant coupling among regions within both the dorsal and ventral reading networks, without any observable effects of word frequency or task. These findings were consistent across group- and individual-level analytical approaches. Overall, our results provide further support for the involvement of the inferior frontal gyrus in semantic processing during reading, as indicated by the effect of word frequency and the influence of reading demands, highlighting the role of the ventral reading network. These findings are discussed in line with their implications for lexical and pre-lexical reading processing.

High-Resolution Tractography Protocol to Investigate the Pathways between Human Mediodorsal Thalamic Nucleus and Prefrontal Cortex.

Animal studies have established that the mediodorsal nucleus (MD) of the thalamus is heavily and reciprocally connected with all areas of the prefrontal cortex (PFC). In humans, however, these connections are difficult to investigate. High-resolution imaging protocols capable of reliably tracing the axonal tracts linking the human MD with each of the PFC areas may thus be key to advance our understanding of the variation, development, and plastic changes of these important circuits, in health and disease. Here, we tested in adult female and male humans the reliability of a new reconstruction protocol based on in vivo diffusion MRI to trace, measure, and characterize the fiber tracts interconnecting the MD with 39 human PFC areas per hemisphere. Our protocol comprised the following three components: (1) defining regions of interest; (2) preprocessing diffusion data; and, (3) modeling white matter tracts and tractometry. This analysis revealed largely separate PFC territories of reciprocal MD-PFC tracts bearing striking resemblance with the topographic layout observed in macaque connection-tracing studies. We then examined whether our protocol could reliably reconstruct each of these MD-PFC tracts and their profiles across test and retest sessions. Results revealed that this protocol was able to trace and measure, in both left and right hemispheres, the trajectories of these 39 area-specific axon bundles with good-to-excellent test-retest reproducibility. This protocol, which has been made publicly available, may be relevant for cognitive neuroscience and clinical studies of normal and abnormal PFC function, development, and plasticity.SIGNIFICANCE STATEMENT Reciprocal MD-PFC interactions are critical for complex human cognition and learning. Reliably tracing, measuring and characterizing MD-PFC white matter tracts using high-resolution noninvasive methods is key to assess individual variation of these systems in humans. Here, we propose a high-resolution tractography protocol that reliably reconstructs 39 area-specific MD-PFC white matter tracts per hemisphere and quantifies structural information from diffusion MRI data. This protocol revealed a detailed mapping of thalamocortical and corticothalamic MD-PFC tracts in four different PFC territories (dorsal, medial, orbital/frontal pole, inferior frontal) showing structural connections resembling those observed in tracing studies with macaques. Furthermore, our automated protocol revealed high test-retest reproducibility and is made publicly available, constituting a step forward in mapping human MD-PFC circuits in clinical and academic research.

Performance feedback enhances test-potentiated encoding.

Introduction: Long-term memory retention is enhanced after testing compared to restudying (testing effect). Notably, memory retrieval further improves when correct-answer feedback is provided after the retrieval attempt (test-potentiated encoding-TPE). Methods: To evaluate whether explicit positive or negative feedback further enhances memory performance beyond the effect of TPE, in two experiments additional explicit positive or negative performance-contingent feedback was presented before providing correct-answer feedback. After an initial exposure to the full material, 40 participants learned 210 weakly associated cue-target word pairs by either restudying or testing (Experiment 1). Depending on the accuracy of the retrieval attempt, the tested word pairs were followed by positive or negative performance feedback (50%) or no feedback (50%). Irrespective of the type of repetition, trials were followed by a restudy opportunity. Participants returned to perform a final cued-recall test (Day 2). Results: Final test results replicated the testing effect (better memory performance for tested compared to restudied items). Explicit performance feedback in addition to correct-answer feedback increased retrieval performance, but only on Day 2. This pattern of results was replicated in Experiment 2 in an independent sample of 25 participants. To assess the specific effects of learning history, we also examined retrieval accuracy and reaction times during repetition cycles: Explicit feedback improved retrieval for material successfully encoded in the initial study phase (consistent positive feedback) as well as for material learned during the repetition phase (mixed positive and negative feedback). Discussion: Performance feedback improves learning beyond the effects of retrieval practice and correct-answer feedback, suggesting that it strengthens memory representations and promotes re-encoding of the material.

Accurate Bayesian segmentation of thalamic nuclei using diffusion MRI and an improved histological atlas.

The human thalamus is a highly connected brain structure, which is key for the control of numerous functions and is involved in several neurological disorders. Recently, neuroimaging studies have increasingly focused on the volume and connectivity of the specific nuclei comprising this structure, rather than looking at the thalamus as a whole. However, accurate identification of cytoarchitectonically designed histological nuclei on standard in vivo structural MRI is hampered by the lack of image contrast that can be used to distinguish nuclei from each other and from surrounding white matter tracts. While diffusion MRI may offer such contrast, it has lower resolution and lacks some boundaries visible in structural imaging. In this work, we present a Bayesian segmentation algorithm for the thalamus. This algorithm combines prior information from a probabilistic atlas with likelihood models for both structural and diffusion MRI, allowing segmentation of 25 thalamic labels per hemisphere informed by both modalities. We present an improved probabilistic atlas, incorporating thalamic nuclei identified from histology and 45 white matter tracts surrounding the thalamus identified in ultra-high gradient strength diffusion imaging. We present a family of likelihood models for diffusion tensor imaging, ensuring compatibility with the vast majority of neuroimaging datasets that include diffusion MRI data. The use of these diffusion likelihood models greatly improves identification of nuclear groups versus segmentation based solely on structural MRI. Dice comparison of 5 manually identifiable groups of nuclei to ground truth segmentations show improvements of up to 10 percentage points. Additionally, our chosen model shows a high degree of reliability, with median test-retest Dice scores above 0.85 for four out of five nuclei groups, whilst also offering improved detection of differential thalamic involvement in Alzheimer's disease (AUROC 81.98%). The probabilistic atlas and segmentation tool will be made publicly available as part of the neuroimaging package FreeSurfer (https://freesurfer.net/fswiki/ThalamicNucleiDTI).

Brain structure, phenotypic and genetic correlates of reading performance.

Reading is an evolutionarily recent development that recruits and tunes brain circuitry connecting primary- and language-processing regions. We investigated whether metrics of the brain's physical structure correlate with reading performance and whether genetic variants affect this relationship. To this aim, we used the Adolescent Brain Cognitive Development dataset (n = 9,013) of 9-10-year-olds and focused on 150 measures of cortical surface area (CSA) and thickness. Our results reveal that reading performance is associated with nine measures of brain structure including relevant regions of the reading network. Furthermore, we show that this relationship is partially mediated by genetic factors for two of these measures: the CSA of the entire left hemisphere and, specifically, of the left superior temporal gyrus CSA. These effects emphasize the complex and subtle interplay between genes, brain and reading, which is a partly heritable polygenic skill that relies on a distributed network.

Reproducible Tract Profiles 2 (RTP2) suite, from diffusion MRI acquisition to clinical practice and research.

Diffusion MRI is a complex technique, where new discoveries and implementations occur at a fast pace. The expertise needed for data analyses and accurate and reproducible results is increasingly demanding and requires multidisciplinary collaborations. In the present work we introduce Reproducible Tract Profiles 2 (RTP2), a set of flexible and automated methods to analyze anatomical MRI and diffusion weighted imaging (DWI) data for reproducible tractography. RTP2 reads structural MRI data and processes them through a succession of serialized containerized analyses. We describe the DWI algorithms used to identify white-matter tracts and their summary metrics, the flexible architecture of the platform, and the tools to programmatically access and control the computations. The combination of these three components provides an easy-to-use automatized tool developed and tested over 20 years, to obtain usable and reliable state-of-the-art diffusion metrics at the individual and group levels for basic research and clinical practice.

Functional underpinnings of feedback-enhanced test-potentiated encoding.

The testing effect describes the finding that retrieval practice enhances memory performance compared to restudy practice. Prior evidence demonstrates that this effect can be boosted by providing feedback after retrieval attempts (i.e. test-potentiated encoding [TPE]). The present fMRI study investigated the neural processes during successful memory retrieval underlying this beneficial effect of correct answer feedback compared with restudy and whether additional performance feedback leads to further benefits. Twenty-seven participants learned cue-target pairs by (i) restudying, (ii) standard TPE including a restudy opportunity, or (iii) TPE including a restudy opportunity immediately after a positive or negative performance feedback. One day later, a cued retrieval recognition test was performed inside the MRI scanner. Behavioral results confirmed the testing effect and that adding explicit performance feedback-enhanced memory relative to restudy and standard TPE. Stronger functional engagement while retrieving items previously restudied was found in lateral prefrontal cortex and superior parietal lobe. By contrast, lateral temporo-parietal areas were more strongly recruited while retrieving items previously tested. Performance feedback increased the hippocampal activation and resulted in stronger functional coupling between hippocampus, supramarginal gyrus, and ventral striatum with lateral temporo-parietal cortex. Our results unveil the main functional dynamics and connectivity nodes underlying memory benefits from additional performance feedback.

Verbal production dynamics and plasticity: functional contributions of language and executive control systems.

Bilingual language production requires both language knowledge and language control in order to communicate in a target language. Learning or improving a language in adulthood is an increasingly common undertaking, and this has complex effects on the cognitive and neural processes underlying language production. The current functional magnetic resonance imaging (fMRI) experiment investigated the functional plasticity of verbal production in adult language learners, and examined the dynamics of word retrieval in order to dissociate the contributions of language knowledge and executive control. Thirty four adults who were either intermediate or advanced language learners, underwent MRI scanning while performing verbal fluency tasks in their native and new languages. A multipronged analytical approach revealed (i) time-varying contributions of language knowledge and executive control to verbal fluency performance, (ii) learning-related changes in the functional correlates of verbal fluency in both the native and new languages, (iii) no effect of learning on lateralization, and (iv) greater functional coupling between language and language control regions with greater second language experience. Collectively, our results point to significant functional plasticity in adult language learners that impacts the neural correlates of production in both the native and new languages, and provide new insight into the widely used verbal fluency task.

Functional characterization of correct and incorrect feature integration.

Our sensory system constantly receives information from the environment and our own body. Despite our impression to the contrary, we remain largely unaware of this information and often cannot report it correctly. Although perceptual processing does not require conscious effort on the part of the observer, it is often complex, giving rise to errors such as incorrect integration of features (illusory conjunctions). In the present study, we use functional magnetic resonance imaging to study the neural bases of feature integration in a dual task that produced ~30% illusions. A distributed set of regions demonstrated increased activity for correct compared to incorrect (illusory) feature integration, with increased functional coupling between occipital and parietal regions. In contrast, incorrect feature integration (illusions) was associated with increased occipital (V1-V2) responses at early stages, reduced functional connectivity between right occipital regions and the frontal eye field at later stages, and an overall decrease in coactivation between occipital and parietal regions. These results underscore the role of parietal regions in feature integration and highlight the relevance of functional occipito-frontal interactions in perceptual processing.

Reproducible protocol to obtain and measure first-order relay human thalamic white-matter tracts.

The "primary" or "first-order relay" nuclei of the thalamus feed the cerebral cortex with information about ongoing activity in the environment or the subcortical motor systems. Because of the small size of these nuclei and the high specificity of their input and output pathways, new imaging protocols are required to investigate thalamocortical interactions in human perception, cognition and language. The goal of the present study was twofold: I) to develop a reconstruction protocol based on in vivo diffusion MRI to extract and measure the axonal fiber tracts that originate or terminate specifically in individual first-order relay nuclei; and, II) to test the reliability of this reconstruction protocol. In left and right hemispheres, we investigated the thalamocortical/corticothalamic axon bundles linking each of the first-order relay nuclei and their main cortical target areas, namely, the lateral geniculate nucleus (optic radiation), the medial geniculate nucleus (acoustic radiation), the ventral posterior nucleus (somatosensory radiation) and the ventral lateral nucleus (motor radiation). In addition, we examined the main subcortical input pathway to the ventral lateral posterior nucleus, which originates in the dentate nucleus of the cerebellum. Our protocol comprised three components: defining regions-of-interest; preprocessing diffusion data; and modeling white-matter tracts and tractometry. We then used computation and test-retest methods to check whether our protocol could reliably reconstruct these tracts of interest and their profiles. Our results demonstrated that the protocol had nearly perfect computational reproducibility and good-to-excellent test-retest reproducibility. This new protocol may be of interest for both basic human brain neuroscience and clinical studies and has been made publicly available to the scientific community.

Simulating the situated-self drives hippocampo-cortical engagement during inner narration of events.

We often use inner narration when thinking about past and future events. The present paradigm explicitly addresses the influence of the language used in inner narration on the hippocampus-dependent event construction process. We assessed the language context effect during the inner narration of different event types: past, future, daydream, and self-unrelated fictitious events. The language context was assessed via a fluent bilingual population who used inner narration, either in their first language (L1) or second language (L2). Not all inner narration of events elicited hippocampo-cortical activity. In fact, only the angular gyrus and precuneus-retrosplenial cortex were activated by inner narration across all event types. More precisely, only inner narration of events which entailed the simulation of bodily self-location in space (whether or not they were time-marked: past, future, daydream) depended on the hippocampo-cortical system, while inner narration of events that did not entail bodily self-location (self-unrelated fictitious) did not. The language context of the narration influenced the bilinguals' hippocampo-cortical system by enhancing the co-activation of semantic areas with the hippocampus for inner narration of events in the L2. Overall, this study highlights 2 important characteristics of hippocampo-cortical-dependent inner narration of events: The core episodic hippocampal system is activated for inner narration of events simulating self-location in space (regardless of time-marking), and the inner language used for narration (L1 or L2) mediates hippocampal functional connectivity.

Encoding and inhibition of arbitrary episodic context with abstract concepts.

Context is critical for conceptual processing, but the mechanism underpinning its encoding and reinstantiation during abstract concept processing is unclear. Context may be especially important for abstract concepts-we investigated whether episodic context is recruited differently when processing abstract compared with concrete concepts. Experiments 1 and 2 presented abstract and concrete words in arbitrary contexts at encoding (Experiment 1: red/green colored frames; Experiment 2: male/female voices). Recognition memory for these contexts was worse for abstract concepts. Again using frame color and voice as arbitrary contexts, respectively, Experiments 3 and 4 presented words from encoding in the same or different context at test to determine whether there was a greater recognition memory benefit for abstract versus concrete concepts when the context was unchanged between encoding and test. Instead, abstract concepts were less likely to be remembered when context was retained. This suggests that at least some types of episodic context-when arbitrary-are attended less, and may even be inhibited, when processing abstract concepts. In Experiment 5, we utilized a context-spatial location-which (as we show) tends to be relevant during real-world processing of abstract concepts. We presented words in different locations, preserving or changing location at test. Location retention conferred a recognition memory advantage for abstract concepts. Thus, episodic context may be encoded with abstract concepts when context is relevant to real-world processing. The systematic contexts necessary for understanding abstract concepts may lead to arbitrary context inhibition, but greater attention to contexts that tend to be more relevant during real-world processing.

Task-Relevant Representations and Cognitive Control Demands Modulate Functional Connectivity from Ventral Occipito-Temporal Cortex During Object Recognition Tasks.

The left ventral occipito-temporal cortex (vOTC) supports extraction and processing of visual features. However, it has remained unclear whether left vOTC-based functional connectivity (FC) differs according to task-relevant representations (e.g., lexical, visual) and control demands imposed by the task, even when similar visual-semantic processing is required for object identification. Here, neural responses to the same set of pictures of meaningful objects were measured, while the type of task that participants had to perform (picture naming versus size-judgment task), and the level of cognitive control required by the picture naming task (high versus low interference contexts) were manipulated. Explicit retrieval of lexical representations in the picture naming task facilitated activation of lexical/phonological representations, modulating FC between left vOTC and dorsal anterior-cingulate-cortex/pre-supplementary-motor-area. This effect was not observed in the size-judgment task, which did not require explicit word-retrieval of object names. Furthermore, retrieving the very same lexical/phonological representation in the high versus low interference contexts during picture naming increased FC between left vOTC and left caudate. These findings support the proposal that vOTC functional specialization emerges from interactions with task-relevant brain regions.

Functional correlates of response inhibition in impulse control disorders in Parkinson's disease.

Impulse control disorder is a prevalent side-effect of Parkinson's disease (PD) medication, with a strong negative impact on the quality of life of those affected. Although impulsivity has classically been associated with response inhibition deficits, previous evidence from PD patients with impulse control disorder (ICD) has not revealed behavioral dysfunction in response inhibition. In this study, 18 PD patients with ICD, 17 PD patients without this complication, and 15 healthy controls performed a version of the conditional Stop Signal Task during functional magnetic resonance imaging. Whole-brain contrasts, regions of interest, and functional connectivity analyses were conducted. Our aim was to investigate the neural underpinnings of two aspects of response inhibition: proactive inhibition, inhibition that has been prepared beforehand, and restrained inhibition, inhibition of an invalid inhibitory tendency. We observed that, in respect to the other two groups, PD patients with ICD exhibited hyperactivation of the stopping network bilaterally while performing proactive inhibition. When engaged in restrained inhibition, they showed hyperactivation of the left inferior frontal gyrus, an area linked to action monitoring. Restrained inhibition also resulted in changes to the functional co-activation between inhibitory regions and left inferior parietal cortex and right supramarginal gyrus. Our findings indicate that PD patients with ICD completed the inhibition task correctly, showing altered engagement of inhibitory and attentional areas. During proactive inhibition they showed bilateral hyperactivation of two inhibitory regions, while during restrained inhibition they showed additional involvement of attentional areas responsible for alerting and orienting.

Converging Evidence for Differential Specialization and Plasticity of Language Systems.

Functional specialization and plasticity are fundamental organizing principles of the brain. Since the mid-1800s, certain cognitive functions have been known to be lateralized, but the provenance and flexibility of hemispheric specialization remain open questions. Language is a uniquely human phenomenon that requires a delicate balance between neural specialization and plasticity, and language learning offers the perfect window to study these principles in the human brain. In the current study, we conducted two separate functional MRI experiments with language learners (male and female), one cross-sectional and one longitudinal, involving distinct populations and languages, and examined hemispheric lateralization and learning-dependent plasticity of the following three language systems: reading, speech comprehension, and verbal production. A multipronged analytic approach revealed a highly consistent pattern of results across the two experiments, showing (1) that in both native and non-native languages, while language production was left lateralized, lateralization for language comprehension was highly variable across individuals; and (2) that with increasing non-native language proficiency, reading and speech comprehension displayed substantial changes in hemispheric dominance, with languages tending to lateralize to opposite hemispheres, while production showed negligible change and remained left lateralized. These convergent results shed light on the long-standing debate of neural organization of language by establishing robust principles of lateralization and plasticity of the main language systems. Findings further suggest involvement of the sensorimotor systems in language lateralization and its plasticity.SIGNIFICANCE STATEMENT The human brain exhibits a remarkable ability to support a vast variety of languages that may be acquired at different points in the life span. Language is a complex construct involving linguistic as well as visual, auditory, and motor processes. Using functional MRI, we examined hemispheric specialization and learning-dependent plasticity of three language systems-reading, speech comprehension, and verbal production-in cross-sectional and longitudinal experiments in language learners. A multipronged analytic approach revealed converging evidence for striking differences in hemispheric specialization and plasticity among the language systems. The results have major theoretical and practical implications for our understanding of fundamental principles of neural organization of language, language testing and recovery in patients, and language learning in healthy populations.

Functional connectivity reveals dissociable ventrolateral prefrontal mechanisms for the control of multilingual word retrieval.

This functional magnetic resonance imaging study established that different portions of the ventrolateral prefrontal cortex (vlPFC) support reactive and proactive language control processes during multilingual word retrieval. The study also examined whether proactive language control consists in the suppression of the nontarget lexicon. Healthy multilingual volunteers participated in a task that required them to name pictures alternately in their dominant and less-dominant languages. Two crucial variables were manipulated: the cue-target interval (CTI) to either engage (long CTI) or prevent (short CTI) proactive control processes, and the cognate status of the to-be-named pictures (noncognates vs. cognates) to capture selective pre-activation of the target language. The results of the functional connectivity analysis showed a clear segregation between functional networks related to mid-vlPFC and anterior vlPFC during multilingual language production. Furthermore, the results revealed that multilinguals engage in proactive control to prepare the target language. This proactive modulation, enacted by anterior vlPFC, is achieved by boosting the activation of lexical representations in the target language. Finally, control processes supported by both mid-vlPFC and the left inferior parietal lobe, were similarly engaged by reactive and proactive control, possibly exerted on phonological representations to reduce cross-language interference.

Functional inhibitory control dynamics in impulse control disorders in Parkinson's disease.

BACKGROUND: Impulse control disorders related to alterations in the mesocorticolimbic dopamine network occur in Parkinson's disease (PD). Our objective was to investigate the functional neural substrates of reward processing and inhibitory control in these patients. METHODS: Eighteen PD patients with impulse control disorders, 17 without this complication, and 18 healthy controls performed a version of the Iowa Gambling Task during functional magnetic resonance scanning under 3 conditions: positive, negative, and mixed feedback. Whole-brain contrasts, regions of interest, time courses, functional connectivity analyses, and brain-behavior associations were examined. RESULTS: PD patients with impulse control disorders exhibited hyperactivation in subcortical and cortical regions typically associated with reward processing and inhibitory control compared with their PD and healthy control counterparts. Time-course analyses revealed that only PD patients with impulse control disorders exhibited stronger signal intensity during the initial versus final periods of the negative-feedback condition in bilateral insula, and right ventral striatum. Interestingly, hyperactivation of all the examined right-lateralized frontostriatal areas during negative feedback was positively associated with impulse control disorder severity. Importantly, positive associations between impulse control disorder severity and regional activations in the right insula and right inferior frontal gyrus, but not the right subthalamic nucleus, were mediated by functional connectivity with the right ventral striatum. CONCLUSIONS: During a reward-based task, PD patients with impulse control disorders showed hyperactivation in a right-lateralized network of regions including the subthalamic nucleus that was strongly associated with impulse control disorder severity. In these patients, the right ventral striatum in particular played a critical role in modulating the functional dynamics of right-lateralized inhibitory-control frontal regions when facing penalties. © 2019 International Parkinson and Movement Disorder Society.

Disrupted salience network dynamics in Parkinson's disease patients with impulse control disorders.

BACKGROUND: Dynamic functional network analysis may add relevant information about the temporal nature of the neurocognitive alterations in PD patients with impulse control disorders (PD-ICD). Our aim was to investigate changes in dynamic functional network connectivity (dFNC) in PD-ICD patients, and topological properties of such networks. METHODS: Resting state fMRI was performed on 16 PD PD-ICD patients, 20 PD patients without ICD and 17 healthy controls, whose demographic, clinical and behavioral scores were assessed. We conducted a group spatial independent component analysis, sliding window and graph-theory analyses. RESULTS: PD-ICD patients, in contrast to PD-noICD and HC subjects, were engaged across time in a brain configuration pattern characterized by a lack of between-network connections at the expense of strong within-network connections (State III) in temporal, frontoinsular and cingulate cortices, all key nodes of the salience network. Moreover, this increased maintenance of State III in PD-ICD patients was positively correlated with the severity of impulsivity and novelty seeking as measured by specific scales. While in State III, these patients also exhibited increased local efficiency in all the aforementioned areas. CONCLUSIONS: Our findings show for the first time that PD-ICD patients have a dynamic functional engagement of local connectivity involving the limbic circuit, leading to the inefficient modulation in emotional processing and reward-related decision-making. These results provide new insights into the pathophysiology of ICD in PD patients and indicate that the dFC study of fMRI could be a useful biomarker to identify patients at risk to develop ICD.