Compensatory neural mechanisms in cognitively unimpaired Parkinson disease.
Annals of neurology
2016; 79 (3): 448-463
Multivariate dynamical systems-based estimation of causal brain interactions in fMRI: Group-level validation using benchmark data, neurophysiological models and human connectome project data.
Journal of neuroscience methods
Cognitive impairments in Parkinson's disease (PD) are thought to be caused in part by dopamine dysregulation. However, even when nigrostriatal dopamine neuron loss is severe enough to cause motor symptoms, many patients remain cognitively unimpaired. It is unclear what brain mechanisms allow these patients to remain cognitively unimpaired despite substantial dopamine dysregulation.31 cognitively unimpaired PD participants OFF dopaminergic-medications were scanned using fMRI while they performed a working memory task, along with 23 controls. We first compared the PD_OFF medication group with controls to determine whether PD participants engage compensatory frontostriatal mechanisms during working memory. We then studied the same PD participants ON dopaminergic-medications to determine whether these compensatory brain changes are altered with dopamine.Controls and PD showed working memory load-dependent activation in the bilateral putamen, anterior-dorsal insula, supplementary motor area, and anterior cingulate cortex. Compared to controls, PD_OFF showed compensatory hyper-activation of bilateral putamen and posterior insula, and machine learning algorithms identified robust differences in putamen activation patterns. Compared to PD_OFF, PD_ON showed reduced compensatory activation in the putamen. Loss of compensatory hyper-activation ON dopaminergic-medication correlated with slower performance on the working memory task and slower cognitive speed on the Symbol Digit Modality Test.Our results provide novel evidence that PD patients maintain normal cognitive performance through compensatory hyper-activation of the putamen. Dopaminergic-medication down-regulates this hyper-activation and the degree of down-regulation predicts behavior. Identifying cognitive compensatory mechanisms in PD is important for understanding how some patients maintain intact cognitive performance, despite nigrostriatal dopamine loss. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/ana.24585
View details for PubMedID 26696272
Development and validation of consensus clustering-based framework for brain segmentation using resting fMRI
JOURNAL OF NEUROSCIENCE METHODS
2015; 240: 128-140
Causal estimation methods are increasingly being used to investigate functional brain networks in fMRI, but there are continuing concerns about the validity of these methods.Multivariate Dynamical Systems (MDS) is a state-space method for estimating dynamic causal interactions in fMRI data. Here we validate MDS using benchmark simulations as well as simulations from a more realistic stochastic neurophysiological model. Finally, we applied MDS to investigate dynamic casual interactions in a fronto-cingulate-parietal control network using Human Connectome Project (HCP) data acquired during performance of a working memory task. Crucially, since the ground truth in experimental data is unknown, we conducted novel stability analysis to determine robust causal interactions within this network.MDS accurately recovered dynamic causal interactions with an area under receiver operating characteristic (AUC) above 0.7 for benchmark datasets and AUC above 0.9 for datasets generated using the neurophysiological model. In experimental fMRI data, bootstrap procedures revealed a stable pattern of causal influences from the anterior insula to other nodes of the fronto-cingulate-parietal network.MDS is effective in estimating dynamic causal interactions in both the benchmark and neurophysiological model based datasets in terms of AUC, sensitivity and false positive rates.Our findings demonstrate that MDS can accurately estimate causal interactions in fMRI data. Neurophysiological models and stability analysis provide a general framework for validating computational methods designed to estimate causal interactions in fMRI. The right anterior insula functions as a causal hub during working memory.
View details for DOI 10.1016/j.jneumeth.2016.03.010
View details for PubMedID 27015792
Evidence Supports Specific Braking Function for Inferior PFC.
Trends in cognitive sciences
Causal Interactions Within a Frontal-Cingulate-Parietal Network During Cognitive Control: Convergent Evidence from a Multisite-Multitask Investigation.
Cerebral cortex (New York, N.Y. : 1991)
Clustering methods are increasingly employed to segment brain regions into functional subdivisions using resting-state functional magnetic resonance imaging (rs-fMRI). However, these methods are highly sensitive to the (i) precise algorithms employed, (ii) their initializations, and (iii) metrics used for uncovering the optimal number of clusters from the data.To address these issues, we develop a novel consensus clustering evidence accumulation (CC-EAC) framework, which effectively combines multiple clustering methods for segmenting brain regions using rs-fMRI data. Using extensive computer simulations, we examine the performance of widely used clustering algorithms including K-means, hierarchical, and spectral clustering as well as their combinations. We also examine the accuracy and validity of five objective criteria for determining the optimal number of clusters: mutual information, variation of information, modified silhouette, Rand index, and probabilistic Rand index.A CC-EAC framework with a combination of base K-means clustering (KC) and hierarchical clustering (HC) with probabilistic Rand index as the criterion for choosing the optimal number of clusters, accurately uncovered the correct number of clusters from simulated datasets. In experimental rs-fMRI data, these methods reliably detected functional subdivisions of the supplementary motor area, insula, intraparietal sulcus, angular gyrus, and striatum.Unlike conventional approaches, CC-EAC can accurately determine the optimal number of stable clusters in rs-fMRI data, and is robust to initialization and choice of free parameters.A novel CC-EAC framework is proposed for segmenting brain regions, by effectively combining multiple clustering methods and identifying optimal stable functional clusters in rs-fMRI data.
View details for DOI 10.1016/j.jneumeth.2014.11.014
View details for Web of Science ID 000347867500014
View details for PubMedID 25450335
Dissociable Roles of Right Inferior Frontal Cortex and Anterior Insula in Inhibitory Control: Evidence from Intrinsic and Task-Related Functional Parcellation, Connectivity, and Response Profile Analyses across Multiple Datasets
JOURNAL OF NEUROSCIENCE
2014; 34 (44): 14652-14667
Sensorimotor-independent prefrontal activity during response inhibition
HUMAN BRAIN MAPPING
2014; 35 (5): 2119-2136
Cognitive control plays an important role in goal-directed behavior, but dynamic brain mechanisms underlying it are poorly understood. Here, using multisite fMRI data from over 100 participants, we investigate causal interactions in three cognitive control tasks within a core Frontal-Cingulate-Parietal network. We found significant causal influences from anterior insula (AI) to dorsal anterior cingulate cortex (dACC) in all three tasks. The AI exhibited greater net causal outflow than any other node in the network. Importantly, a similar pattern of causal interactions was uncovered by two different computational methods for causal analysis. Furthermore, the strength of causal interaction from AI to dACC was greater on high, compared with low, cognitive control trials and was significantly correlated with individual differences in cognitive control abilities. These results emphasize the importance of the AI in cognitive control and highlight its role as a causal hub in the Frontal-Cingulate-Parietal network. Our results further suggest that causal signaling between the AI and dACC plays a fundamental role in implementing cognitive control and are consistent with a two-stage cognitive control model in which the AI first detects events requiring greater access to cognitive control resources and then signals the dACC to execute load-specific cognitive control processes.
View details for DOI 10.1093/cercor/bhv046
View details for PubMedID 25778346
Proactive Selective Response Suppression Is Implemented via the Basal Ganglia
JOURNAL OF NEUROSCIENCE
2013; 33 (33): 13259-13269
A network of brain regions involving the ventral inferior frontal gyrus/anterior insula (vIFG/AI), presupplementary motor area (pre-SMA) and basal ganglia has been implicated in stopping impulsive, unwanted responses. However, whether this network plays an equal role in response inhibition under different sensorimotor contexts has not been tested systematically. Here, we conducted an fMRI experiment using the stop signal task, a sensorimotor task requiring occasional withholding of the planned response upon the presentation of a stop signal. We manipulated both the sensory modality of the stop signal (visual versus auditory) and the motor response modality (hand versus eye). Results showed that the vIFG/AI and the preSMA along with the right middle frontal gyrus were commonly activated in response inhibition across the various sensorimotor conditions. Our findings provide direct evidence for a common role of these frontal areas, but not striatal areas in response inhibition independent of the sensorimotor contexts. Nevertheless, these three frontal regions exhibited different activation patterns during successful and unsuccessful stopping. Together with the existing evidence, we suggest that the vIFG/AI is involved in the early stages of stopping such as triggering the stop process while the preSMA may play a role in regulating other cortical and subcortical regions involved in stopping.
View details for DOI 10.1002/hbm.22315
View details for Web of Science ID 000334012100023
View details for PubMedID 23798325
The role of the right presupplementary motor area in stopping action: two studies with event-related transcranial magnetic stimulation
JOURNAL OF NEUROPHYSIOLOGY
2012; 108 (2): 380-389
In the welter of everyday life, people can stop particular response tendencies without affecting others. A key requirement for such selective suppression is that subjects know in advance which responses need stopping. We hypothesized that proactively setting up and implementing selective suppression relies on the basal ganglia and, specifically, regions consistent with the inhibitory indirect pathway for which there is scant functional evidence in humans. Consistent with this hypothesis, we show, first, that the degree of proactive motor suppression when preparing to stop selectively (indexed by transcranial magnetic stimulation) corresponds to striatal, pallidal, and frontal activation (indexed by functional MRI). Second, we demonstrate that greater striatal activation at the time of selective stopping correlates with greater behavioral selectivity. Third, we show that people with striatal and pallidal volume reductions (those with premanifest Huntington's disease) have both absent proactive motor suppression and impaired behavioral selectivity when stopping. Thus, stopping goals are used to proactively set up specific basal ganglia channels that may then be triggered to implement selective suppression. By linking this suppression to the striatum and pallidum, these results provide compelling functional evidence in humans of the basal ganglia's inhibitory indirect pathway.
View details for DOI 10.1523/JNEUROSCI.5651-12.2013
View details for Web of Science ID 000323155700002
View details for PubMedID 23946385
Stimulating deep cortical structures with the batwing coil: How to determine the intensity for transcranial magnetic stimulation using coil-cortex distance
JOURNAL OF NEUROSCIENCE METHODS
2012; 204 (2): 238-241
Rapidly stopping action engages a network in the brain including the right presupplementary motor area (preSMA), the right inferior frontal gyrus, and the basal ganglia. Yet the functional role of these different regions within the overall network still remains unclear. Here we focused on the role of the right preSMA in behavioral stopping. We hypothesized that the underlying neurocognitive function of this region is one or more of setting up a stopping rule in advance, modulating response tendencies (e.g., slowing down in anticipation of stopping), and implementing stopping when the stop signal occurs. We performed two experiments with magnetic resonance imaging (MRI)-guided, event-related, transcranial magnetic stimulation(TMS), during the performance of variants of the stop signal task. In experiment 1 we show that stimulation of the right preSMA versus vertex (control site) slowed the implementation of stopping (measured via stop signal reaction time) but had no influence on modulation of response tendencies. In experiment 2, we showed that stimulation of the right preSMA slowed implementation of stopping in a mechanistically selective form of stopping but had no influence on setting up stopping rules. The results go beyond the replication of prior findings by showing that TMS of the right preSMA impairs stopping behavior (including a behaviorally selective form of stopping) through a specific disruption of the implementation of stopping. Future studies are required to establish whether this was due to stimulation of the right preSMA itself or because of remote effects on the wider stopping network.
View details for DOI 10.1152/jn.00132.2012
View details for Web of Science ID 000306416400002
View details for PubMedID 22514296
Stopping speech suppresses the task-irrelevant hand
BRAIN AND LANGUAGE
2012; 120 (3): 412-415
Transcranial magnetic stimulation (TMS) is increasingly used in cognitive neuroscience to probe non-motor cortical regions. A key question for such studies is the choice of stimulation intensity. Early studies used a simple metric such as 115% of motor threshold (MT) for non-motor regions; where MT is the stimulation intensity required to elicit a particular amplitude of motor evoked potential or visible muscle twitch when the coil is placed over primary motor cortex. Recently, however, it was demonstrated that this simple metric for stimulation of non-motor regions is inadequate - it could lead to over or under-stimulation depending on the distance between the coil and the cortex. Instead, a method was developed to scale the motor threshold based on coil-cortex distance, at least for standard figure-of-eight stimulating coils. Here we validate the same method for a 'batwing coil', which is designed to stimulate deeper cortical structures such as the medial frontal cortex. We modulated coil-cortex distance within-participant by inserting spacers of different thickness between coil and scalp. We then measured MT at each spacer. We show that for every millimeter between coil and scalp an additional 1.4% of TMS output is required to induce an equivalent level of brain stimulation at the motor cortex. Using this parameter we describe a linear function to adjust MT for future studies of non-motor regions-of-interest using the batwing coil. This is the first study to demonstrate the effects of coil-cortical distance on stimulation efficiency via a monophasic system using a batwing coil.
View details for DOI 10.1016/j.jneumeth.2011.11.020
View details for Web of Science ID 000301612700005
View details for PubMedID 22138632
Roles for the pre-supplementary motor area and the right inferior frontal gyrus in stopping action: Electrophysiological responses and functional and structural connectivity
2012; 59 (3): 2860-2870
Some situations require one to quickly stop an initiated response. Recent evidence suggests that rapid stopping engages a mechanism that has diffuse effects on the motor system. For example, stopping the hand dampens the excitability of the task-irrelevant leg. However, it is unclear whether this 'global suppression' could apply across wider motor modalities. Here we tested whether stopping speech leads to suppression of the task-irrelevant hand. We used Transcranial Magnetic Stimulation over the primary motor cortex with concurrent electromyography from the hand. We found that when speech was successfully stopped the motor evoked potential from the task-irrelevant hand was significantly reduced compared to when the participant failed to stop speaking, or responded on non stop signal trials, or compared to baseline. This shows that when speech is quickly stopped, there is a broad suppression across the motor system. This has implications for the neural basis of speech control and stuttering.
View details for DOI 10.1016/j.bandl.2011.11.006
View details for Web of Science ID 000301759100022
View details for PubMedID 22206872
Transcranial Magnetic Stimulation Reveals Dissociable Mechanisms for Global Versus Selective Corticomotor Suppression Underlying the Stopping of Action
2012; 22 (2): 363-371
Both the pre-supplementary motor area (preSMA) and the right inferior frontal gyrus (rIFG) are important for stopping action outright. These regions are also engaged when preparing to stop. We aimed to elucidate the roles of these regions by harnessing the high spatio-temporal resolution of electrocorticography (ECoG), and by using a task that engages both preparing to stop and stopping outright. First, we validated the task using fMRI in 16 healthy control participants to confirm that both the preSMA and the rIFG were active. Next, we studied a rare patient with intracranial grid coverage of both these regions, using macrostimulation, diffusion tractography, cortico-cortical evoked potentials (CCEPs) and task-based ECoG. Macrostimulation of the preSMA induced behavioral motor arrest. Diffusion tractography revealed a structural connection between the preSMA and rIFG. CCEP analysis showed that stimulation of the preSMA evoked strong local field potentials within 30 ms in rIFG. During the task, when preparing to stop, there was increased high gamma amplitude (~70-250 Hz) in both regions, with preSMA preceding rIFG by ~750 ms. For outright stopping there was also a high gamma amplitude increase in both regions, again with preSMA preceding rIFG. Further, at the time of stopping, there was an increase in beta band activity (~16 Hz) in both regions, with significantly stronger inter-regional coherence for successful vs. unsuccessful stop trials. The results complement earlier reports of a structural/functional action control network between the preSMA and rIFG. They go further by revealing between-region timing differences in the high gamma band when preparing to stop and stopping outright. They also reveal strong between-region coherence in the beta band when stopping is successful. Implications for theories of action control are discussed.
View details for DOI 10.1016/j.neuroimage.2011.09.049
View details for Web of Science ID 000299494000085
View details for PubMedID 21979383
Rule-Guided Executive Control of Response Inhibition: Functional Topography of the Inferior Frontal Cortex
2011; 6 (6)
Stopping an initiated response is an essential function, investigated in many studies with go/no-go and stop-signal paradigms. These standard tests require rapid action cancellation. This appears to be achieved by a suppression mechanism that has "global" effects on corticomotor excitability (i.e., affecting task-irrelevant muscles). By contrast, stopping action in everyday life may require selectivity (i.e., targeting a specific response tendency without affecting concurrent action). We hypothesized that while standard stopping engages global suppression, behaviorally selective stopping engages a selective suppression mechanism. Accordingly, we measured corticomotor excitability of the task-irrelevant leg using transcranial magnetic stimulation while subjects stopped the hand. Experiment 1 showed that for standard (i.e., nonselective) stopping, the task-irrelevant leg was suppressed. Experiment 2 showed that for behaviorally selective stopping, there was no mean leg suppression. Experiment 3 directly compared behaviorally nonselective and selective stopping. Leg suppression occurred only in the behaviorally nonselective condition. These results argue that global and selective suppression mechanisms are dissociable. Participants may use a global suppression mechanism when speed is stressed; however, they may recruit a more selective suppression mechanism when selective stopping is behaviorally necessary and preparatory information is available. We predict that different fronto-basal-ganglia pathways underpin these different suppression mechanisms.
View details for DOI 10.1093/cercor/bhr112
View details for Web of Science ID 000299124400011
View details for PubMedID 21666129
A Proactive Mechanism for Selective Suppression of Response Tendencies
JOURNAL OF NEUROSCIENCE
2011; 31 (16): 5965-5969
The human inferior frontal cortex (IFC) is a large heterogeneous structure with distinct cytoarchitectonic subdivisions and fiber connections. It has been found involved in a wide range of executive control processes from target detection, rule retrieval to response control. Since these processes are often being studied separately, the functional organization of executive control processes within the IFC remains unclear.We conducted an fMRI study to examine the activities of the subdivisions of IFC during the presentation of a task cue (rule retrieval) and during the performance of a stop-signal task (requiring response generation and inhibition) in comparison to a not-stop task (requiring response generation but not inhibition). We utilized a mixed event-related and block design to separate brain activity in correspondence to transient control processes from rule-related and sustained control processes. We found differentiation in control processes within the IFC. Our findings reveal that the bilateral ventral-posterior IFC/anterior insula are more active on both successful and unsuccessful stop trials relative to not-stop trials, suggesting their potential role in the early stage of stopping such as triggering the stop process. Direct countermanding seems to be outside of the IFC. In contrast, the dorsal-posterior IFC/inferior frontal junction (IFJ) showed transient activity in correspondence to the infrequent presentation of the stop signal in both tasks and the left anterior IFC showed differential activity in response to the task cues. The IFC subdivisions also exhibited similar but distinct patterns of functional connectivity during response control.Our findings suggest that executive control processes are distributed across the IFC and that the different subdivisions of IFC may support different control operations through parallel cortico-cortical and cortico-striatal circuits.
View details for DOI 10.1371/journal.pone.0020840
View details for Web of Science ID 000291356400032
View details for PubMedID 21673969
Deep Brain Stimulation of the Subthalamic Nucleus Alters the Cortical Profile of Response Inhibition in the Beta Frequency Band: A Scalp EEG Study in Parkinson's Disease
JOURNAL OF NEUROSCIENCE
2011; 31 (15): 5721-5729
While most research on stopping action examines how an initiated response is stopped when a signal occurs (i.e., reactively), everyday life also calls for a mechanism to prepare to stop a particular response tendency (i.e., proactively and selectively). We hypothesized that human subjects can prepare to stop a particular response by proactively suppressing that response representation in the brain. We tested this by using single-pulse transcranial magnetic stimulation and concurrent electromyography. This allowed us to interrogate the corticomotor excitability of specific response representations even before action ensued. We found that the motor evoked potential of the effector that might need to be stopped in the future was significantly reduced compared with when that effector was at rest. Further, this neural index of proactive and selective suppression predicted the subsequent selectivity with which the behavioral response was stopped. These results go further than earlier reports of reduced motor excitability when responses are stopped. They show that the control can be applied in advance (proactively) and also targeted at a particular response channel (selectively). This provides novel evidence for an active mechanism of suppression in the brain that is setup according to the subject's goals and even before action ensues.
View details for DOI 10.1523/JNEUROSCI.6292-10.2011
View details for Web of Science ID 000289769400010
View details for PubMedID 21508221
Cortical activity during manual response inhibition guided by color and orientation cues
2009; 1261: 20-28
Stopping an initiated response could be implemented by a fronto-basal-ganglia circuit, including the right inferior frontal cortex (rIFC) and the subthalamic nucleus (STN). Intracranial recording studies in humans reveal an increase in beta-band power (approximately 16-20 Hz) within the rIFC and STN when a response is stopped. This suggests that the beta-band could be important for communication in this network. If this is the case, then altering one region should affect the electrophysiological response at the other. We addressed this hypothesis by recording scalp EEG during a stop task while modulating STN activity with deep brain stimulation. We studied 15 human patients with Parkinson's disease and 15 matched healthy control subjects. Behaviorally, patients OFF stimulation were slower than controls to stop their response. Moreover, stopping speed was improved for ON compared to OFF stimulation. For scalp EEG, there was greater beta power, around the time of stopping, for patients ON compared to OFF stimulation. This effect was stronger over the right compared to left frontal cortex, consistent with the putative right lateralization of the stopping network. Thus, deep brain stimulation of the STN improved behavioral stopping performance and increased the beta-band response over the right frontal cortex. These results complement other evidence for a structurally connected functional circuit between right frontal cortex and the basal ganglia. The results also suggest that deep brain stimulation of the STN may improve task performance by increasing the fidelity of information transfer within a fronto-basal-ganglia circuit.
View details for DOI 10.1523/JNEUROSCI.6135-10.2011
View details for Web of Science ID 000289472400021
View details for PubMedID 21490213
Common and differential ventrolateral prefrontal activity during inhibition of hand and eye movements
JOURNAL OF NEUROSCIENCE
2007; 27 (37): 9893-9900
It has been suggested that the right inferior frontal gyrus (IFG) plays a critical role in manual response inhibition, although neuroimaging studies of healthy adults have also reported widespread activations in other cortical regions during a variety of response inhibition tasks. We conducted a functional magnetic resonance imaging (fMRI) experiment to examine whether the activation of the IFG is dependent on the type of visuo-motor associations during response inhibition by varying the feature of the stop signal (color vs. orientation) in the stop-signal task. Results from 12 subjects showed that the bilateral ventral posterior IFG, anterior insula, inferior frontal junction (IFJ), middle temporal gyrus (MTG) and fusiform gyrus (FG) are active during response inhibition cued by both color and orientation stop signals. While only the MTG showed differential activity to the two stop signals, both MTG and FG showed significantly stronger activity during successful than unsuccessful stopping of unwanted responses cued by orientation and color, respectively. Our findings suggest that the right ventral posterior IFG may play a more general role in response inhibition regardless of the feature of the visual signal, while successful inhibition may depend on efficient processing of the signal.
View details for DOI 10.1016/j.brainres.2008.12.073
View details for Web of Science ID 000264693300003
View details for PubMedID 19401178
The inferior frontal cortex, particularly the ventrolateral prefrontal cortex (VLPFC) in the right hemisphere, has been implicated to serve as a general inhibitory mechanism in the cognitive control of behavior. Because this notion was primarily based on studies of response inhibition in manual tasks, it has yet to be validated in other response modalities. We conducted a functional magnetic resonance imaging study to examine whether the VLPFC is commonly activated during inhibition of responses by hand and by eye within the same subjects. We used the stop-signal task, a relatively pure measure of response inhibition, as the behavioral paradigm. Results from 12 subjects showed that both the right and the left caudal VLPFC and anterior insula, rostral to the premotor area, are activated during inhibition of both manual and saccadic responses. Within the posterior VLPFC, activations overlapped to a significant extent across the two response modalities, although a weaker functionally differentiation was also found along the dorsoventral axis. Other areas such as medial superior frontal gyrus (pre-supplementary motor area/supplementary eye field), dorsolateral prefrontal cortex, and inferior parietal cortex were also activated during canceling both hand and eye movements. Our findings suggest that a common VLPFC network is involved in response inhibition, although the specific control of the different response modalities may be partially segregated within the lateral prefrontal cortex.
View details for DOI 10.1523/JNEUROSCI.2837-07.2007
View details for Web of Science ID 000249415000010
View details for PubMedID 17855604