James M. Shine

The specific contributions of set-shifting to freezing of gait in Parkinson's disease†

Freezing of gait (FOG) in Parkinsons disease (PD) is common and the pathophysiology of FOG is poorly understood. It has been hypothesized to reflect complementary yet competing frontostriatal pathways that reduce the ability to keep different tasks (motor or cognitive) on‐line. This inability to “set‐shift” has been proposed to trigger a freezing episode. If correct, this hypothesis would predict a differential pattern of executive dysfunction with FOG being most specifically related to attentional set‐shifting. In this study, 31 patients with a range of self‐reported FOG symptom severities were administered tests of executive functioning. The results demonstrate that FOG symptoms were selectively correlated with poorer performance on tasks of set‐shifting, but not with a range of other executive tasks. This was apparent even after controlling for slowed processing speed, disease stage and depressive symptoms. The results support the recently proposed hypothesis for the pathophysiology underlying FOG in PD.

Freezing of gait in Parkinson’s disease is associated with functional decoupling between the cognitive control network and the basal ganglia

Recent neuroimaging evidence has led to the proposal that freezing of gait in Parkinsons disease is due to dysfunctional interactions between frontoparietal cortical regions and subcortical structures, such as the striatum. However, to date, no study has employed task-based functional connectivity analyses to explore this hypothesis. In this study, we used a data-driven multivariate approach to explore the impaired communication between distributed neuronal networks in 10 patients with Parkinsons disease and freezing of gait, and 10 matched patients with no clinical history of freezing behaviour. Patients performed a virtual reality gait task on two separate occasions (once ON and once OFF their regular dopaminergic medication) while functional magnetic resonance imaging data were collected. Group-level independent component analysis was used to extract the subject-specific time courses associated with five well-known neuronal networks: the motor network, the right- and left cognitive control networks, the ventral attention network and the basal ganglia network. We subsequently analysed both the activation and connectivity of these neuronal networks between the two groups with respect to dopaminergic state and cognitive load while performing the virtual reality gait task. During task performance, all patients used the left cognitive control network and the ventral attention network and in addition, showed increased connectivity between the bilateral cognitive control networks. However, patients with freezing demonstrated functional decoupling between the basal ganglia network and the cognitive control network in each hemisphere. This decoupling was also associated with paroxysmal motor arrests. These results support the hypothesis that freezing behaviour in Parkinsons disease is because of impaired communication between complimentary yet competing neural networks.

Long-term neural and physiological phenotyping of a single human

Psychiatric disorders are characterized by major fluctuations in psychological function over the course of weeks and months, but the dynamic characteristics of brain function over this timescale in healthy individuals are unknown. Here, as a proof of concept to address this question, we present the MyConnectome project. An intensive phenome-wide assessment of a single human was performed over a period of 18 months, including functional and structural brain connectivity using magnetic resonance imaging, psychological function and physical health, gene expression and metabolomics. A reproducible analysis workflow is provided, along with open access to the data and an online browser for results. We demonstrate dynamic changes in brain connectivity over the timescales of days to months, and relations between brain connectivity, gene expression and metabolites. This resource can serve as a testbed to study the joint dynamics of human brain and metabolic function over time, an approach that is critical for the development of precision medicine strategies for brain disorders.

The Dynamics of Functional Brain Networks: Integrated Network States during Cognitive Task Performance

Higher brain function relies upon the ability to flexibly integrate information across specialized communities of macroscopic brain regions, but it is unclear how this mechanism manifests over time. Here we characterized patterns of time-resolved functional connectivity using resting state and task fMRI data from a large cohort of unrelated subjects. Our results demonstrate that dynamic fluctuations in network structure during the resting state reflect transitions between states of integrated and segregated network topology. These patterns were altered during task performance, demonstrating a higher level of network integration that tracked with the complexity of the task and correlated with effective behavioral performance. Replication analysis demonstrated that these results were reproducible across sessions, sample populations and datasets. Together these results provide insight into the brains coordination between integration and segregation and highlight key principles underlying the reorganization of the network architecture of the brain during both rest and behavior.

Visual misperceptions and hallucinations in Parkinson's disease: dysfunction of attentional control networks?

Visual misperceptions and hallucinations are a major cause of distress in patients with Parkinsons disease (PD), particularly in the advanced stages of the condition. Recent work has provided a framework for understanding the pathogenesis of these symptoms, implicating impairments from the retina to the integration of external information with preformed internal images. In this article, we propose a novel hypothesis that attempts to explain the presence of visual misperceptions and hallucinations in PD through the aberrant coordination of complimentary yet competing neural networks. We propose that hallucinations in PD reflect the relative inability to recruit activation in the dorsal attention network in the presence of an ambiguous percept, leading to overreliance on default mode network processing and salience arising from the ventral attention network. This inability is proposed to stem from improper function across cortical and subcortical structures secondary to the presence of Lewy body pathology. This hypothesis may be empirically tested by the use of targeted cognitive paradigms. In turn, this may assist our understanding of the pathophysiological mechanisms and cognitive processes contributing to visual misperceptions and hallucinations and ultimately may inform more effective treatment strategies for this troubling symptom.

Differential Neural Activation Patterns in Patients with Parkinson's Disease and Freezing of Gait in Response to Concurrent Cognitive and Motor Load

Freezing of gait is a devastating symptom of Parkinsons disease (PD) that is exacerbated by the processing of cognitive information whilst walking. To date, no studies have explored the neural correlates associated with increases in cognitive load whilst performing a motor task in patients with freezing. In this experiment, 14 PD patients with and 15 PD patients without freezing of gait underwent 3T fMRI while performing a virtual reality gait task. Directions to walk and stop were presented on the viewing screen as either direct cues or as more cognitively indirect pre-learned cues. Both groups showed a consistent pattern of BOLD response within the Cognitive Control Network during performance of the paradigm. However, a between group comparison revealed that those PD patients with freezing of gait were less able to recruit the bilateral anterior insula, ventral striatum and the pre-supplementary motor area, as well as the left subthalamic nucleus when responding to indirect cognitive cues whilst maintaining a motor output. These results suggest that PD patients with freezing of gait are unable to properly recruit specific cortical and subcortical regions within the Cognitive Control Network during the performance of simultaneous motor and cognitive functions.

The role of dysfunctional attentional control networks in visual misperceptions in Parkinson's disease

Visual misperceptions and hallucinations represent a problematic symptom of Parkinsons disease. The pathophysiological mechanisms underlying these symptoms remain poorly understood, however, a recent hypothesis has suggested that visual misperceptions and hallucinations may arise from disrupted processing across attentional networks. To test the specific predictions of this hypothesis, 22 patients with Parkinsons disease underwent 3T fMRI while performing the Bistable Percept Paradigm, a task that has previously been shown to identify patients with hallucinations. Subjects are required to study a battery of randomly assigned “monostable” and “bistable” monochromatic images for the presence or absence of a bistable percept. Those patients who scored a high percentage of misperceptions and missed images on the task were less able to activate frontal and parietal hubs of the putative Dorsal Attention Network. Furthermore, poor performance on the task was significantly correlated with the degree of decreased activation in a number of these hubs. At the group level, the difference between processing a bistable versus a monostable cue was associated with increased recruitment of the anterior insula. In addition, those patients with impaired performance on the paradigm displayed decreased resting state functional connectivity between hubs of the Ventral and Dorsal Attention Networks. These same patients had significantly decreased gray matter in the insula bilaterally. In addition, a combined analysis of the separate neuroimaging approaches revealed significant relationships across the impaired networks. These findings are consistent with specific predictions from a recently proposed hypothesis that implicates dysfunction within attentional networks in Parkinsonian hallucinations. Hum Brain Mapp 35:2206–2219, 2014.

The role of frontostriatal impairment in freezing of gait in Parkinson's disease

Freezing of gait (FOG) is a disabling symptom of advanced Parkinsons disease (PD) that leads to an increased risk of falls and nursing home placement. Interestingly, multiple lines of evidence suggest that the manifestation of FOG is related to specific deficits in cognition, such as set shifting and the ability to process conflict-related signals. These findings are consistent with the specific patterns of abnormal cortical processing seen during functional neuroimaging experiments of FOG, implicating increased neural activation within cortical structures underlying cognition, such as the Cognitive Control Network. In addition, these studies show that freezing episodes are associated with abnormalities in the BOLD response within key structures of the basal ganglia, such as the striatum and the subthalamic nucleus. In this article, we discuss the implications of these findings on current models of freezing behavior and propose an updated model of basal ganglia impairment during FOG episodes that integrates the neural substrates of freezing from the cortex and the basal ganglia to the cognitive dysfunctions inherent in the condition.

The pathophysiological mechanisms underlying freezing of gait in Parkinson’s Disease

Freezing of gait is a paroxysmal phenomenon most commonly found in patients with advanced Parkinsons Disease. The pathophysiological mechanisms underlying this behaviour remain uncertain despite a well-characterised phenotype. Freezing behaviour extends beyond gait to affecting speech and upper limb function, suggesting that there is likely to be a universal mechanism underlying the phenomenon. This paper identifies the essential features required for a comprehensive model of freezing and evaluates a number of hypotheses that seek to explain the phenomenon. It appears likely that the pathophysiology of freezing involves context-dependant dysfunction across multiple levels of the neurological system, including cortical, subcortical and brainstem regions.

Temporal metastates are associated with differential patterns of time-resolved connectivity, network topology, and attention

Significance The brain is an inherently dynamic organ; however, the manner in which the brain changes over longitudinal time remains poorly understood. An understanding of these dynamic mechanisms is critical for understanding normal childhood development and aging as well as neurological and psychiatric disease states. Here, we leverage data collected in a single individual over the course of 2 y to investigate changes in brain organization over time. In doing so, we show intermittent fluctuations in brain network configuration that were associated with separable patterns of time-resolved interactions between neural regions. The states also directly relate to alterations in whole-brain information processing and self-reported attention. In addition, the patterns that we observed were replicated in a separate longitudinal dataset. Little is currently known about the coordination of neural activity over longitudinal timescales and how these changes relate to behavior. To investigate this issue, we used resting-state fMRI data from a single individual to identify the presence of two distinct temporal states that fluctuated over the course of 18 mo. These temporal states were associated with distinct patterns of time-resolved blood oxygen level dependent (BOLD) connectivity within individual scanning sessions and also related to significant alterations in global efficiency of brain connectivity as well as differences in self-reported attention. These patterns were replicated in a separate longitudinal dataset, providing additional supportive evidence for the presence of fluctuations in functional network topology over time. Together, our results underscore the importance of longitudinal phenotyping in cognitive neuroscience.