Structural connections between the noradrenergic and cholinergic system shape the dynamics of functional brain networks.

Complex cognitive abilities are thought to arise from the ability of the brain to adaptively reconfigure its internal network structure as a function of task demands. Recent work has suggested that this inherent flexibility may in part be conferred by the widespread projections of the ascending arousal systems. While the different components of the ascending arousal system are often studied in isolation, there are anatomical connections between neuromodulatory hubs that we hypothesise are crucial for mediating key features of adaptive network dynamics, such as the balance between integration and segregation. To test this hypothesis, we estimated the strength of structural connectivity between key hubs of the noradrenergic and cholinergic arousal systems (the locus coeruleus [LC] and nucleus basalis of Meynert [nbM], respectively). We then asked whether the strength of structural LC and nbM inter-connectivity was related to individual differences in the emergent, dynamical signatures of functional integration measured from resting state fMRI data, such as network and attractor topography. We observed a significant positive relationship between the strength of white-matter connections between the LC and nbM and the extent of network-level integration following BOLD signal peaks in LC relative to nbM activity. In addition, individuals with denser white-matter streamlines interconnecting neuromodulatory hubs also demonstrated a heightened ability to shift to novel brain states. These results suggest that individuals with stronger structural connectivity between the noradrenergic and cholinergic systems have a greater capacity to mediate the flexible network dynamics required to support complex, adaptive behaviour. Furthermore, our results highlight the underlying static features of the neuromodulatory hubs can impose some constraints on the dynamic features of the brain.

A data resource from concurrent intracranial stimulation and functional MRI of the human brain.

Mapping the causal effects of one brain region on another is a challenging problem in neuroscience that we approached through invasive direct manipulation of brain function together with concurrent whole-brain measurement of the effects produced. Here we establish a unique resource and present data from 26 human patients who underwent electrical stimulation during functional magnetic resonance imaging (es-fMRI). The patients had medically refractory epilepsy requiring surgically implanted intracranial electrodes in cortical and subcortical locations. One or multiple contacts on these electrodes were stimulated while simultaneously recording BOLD-fMRI activity in a block design. Multiple runs exist for patients with different stimulation sites. We describe the resource, data collection process, preprocessing using the fMRIPrep analysis pipeline and management of artifacts, and provide end-user analyses to visualize distal brain activation produced by site-specific electrical stimulation. The data are organized according to the brain imaging data structure (BIDS) specification, and are available for analysis or future dataset contributions on openneuro.org including both raw and preprocessed data.

Virtual reality walking and dopamine: opening new doorways to understanding freezing of gait in Parkinson's disease.

Freezing of gait (FOG) is a disabling form of gait disturbance that is common in the advanced stages of Parkinson's disease (PD). Despite its prevalence, methods of studying and assessing FOG are limited. We have previously shown that a virtual reality paradigm was able to distinguish between those who report FOG ("freezers") and those who do not report FOG ("non-freezers"). In this paradigm, 'freezers' were found to have prolonged footstep latency in response to known triggers of FOG including doorways, sliding doors and dual-tasking. In this study, we employed the same paradigm to assess performance of 27 freezers and 14 non-freezers in their clinical 'on' and 'off' medication states. In this study, only participants in the freezing group demonstrated statistically significant increases in latencies experienced in the 'off' state compared to the 'on' state in response to wide and narrow doorways and the opening of a sliding door. By contrast, these behavioral differences were not apparent in non-freezers. Furthermore the delay was specific to environmental cues and was not due to generalized slowing in the 'off' state. The findings suggest that this motor delay when processing environmentally salient cues is specific to freezers and is partially mediated by dopamine-dependent neurocircuitry.

Neuropsychiatric symptoms in Parkinson's disease: fronto-striatal atrophy contributions.

BACKGROUND: Neuropsychiatric symptoms (NPS) in Parkinson's disease (PD) have been mostly attributed to neurotransmitter imbalances. However, recent findings suggest that gray matter atrophy also contributes to NPS in PD. We contrast PD patients with different levels of NPS, who are well-matched for dopaminergic medication levels and disease stage, to identify the fronto-striatal gray matter atrophy areas associated with NPS in PD. METHODS: Fifty mild, non-demented PD patients were included. We median-split the group via a neuropsychiatric screening tool (Cambridge Behavioural Inventory-Revised), which resulted in higher vs. lower NPS groups (n = 25 in each group). Using T1 brain scans acquired on a 3 Tesla MRI scanner, voxel-based morphometry analysis was applied to characterize the pattern of fronto-striatal gray matter atrophy associated with elevated NPS. RESULTS: We found that the higher NPS group was characterized by greater atrophy in the prefrontal cortex, but not striatal areas. This was further corroborated by a post-hoc analysis cross-correlating the severity of NPS with gray matter loss across the whole PD group, which revealed that atrophy in the orbitofrontal cortex and frontal pole was specifically associated with elevated NPS. CONCLUSIONS: Prefrontal cortex atrophy in PD has an additional effect to dopamine replacement therapy on the generation of NPS in these patients. These findings are an important step towards the delineation of atrophy vs. neurochemical imbalance in PD, and the results emphasize the importance of considering interactions between prefrontal atrophy and neurochemical dysfunction in the genesis of neuropsychiatric symptoms in PD.

Delegation to automaticity: the driving force for cognitive evolution?

The ability to delegate control over repetitive tasks from higher to lower neural centers may be a fundamental innovation in human cognition. Plausibly, the massive neurocomputational challenges associated with the mastery of balance during the evolution of bipedality in proto-humans provided a strong selective advantage to individuals with brains capable of efficiently transferring tasks in this way. Thus, the shift from quadrupedal to bipedal locomotion may have driven the rapid evolution of distinctive features of human neuronal functioning. We review recent studies of functional neuroanatomy that bear upon this hypothesis, and identify ways to test our ideas.

Early phenotypic differences between Parkinson's disease patients with and without freezing of gait.

BACKGROUND: Previous studies have associated freezing of gait in Parkinson's disease with the presence of specific phenotypic features such as mood disturbances, REM sleep behavior disorder and selective cognitive impairments. However, it is not clear whether these features are present in the earlier stages of disease or simply represent a more general pattern of progression. To investigate this issue, the current study evaluated motor, cognitive, affective and autonomic features as well as REM sleep behavior disorder in Parkinson's disease patients in the early stages of the condition. METHODS: Thirty-eight freezers and fifty-three non-freezers with disease duration of less than five years and a Hoehn and Yahr stage of less than three were included in this study. The groups were matched on a number of key disease features including age, disease duration, motor severity and dopamine dose equivalence. Furthermore, patients were assessed on measures of motor, cognitive, affective and autonomic features, as well as REM sleep behavior disorder. RESULTS: Compared to non-freezers, patients with freezing of gait had significantly more non-tremor symptoms and a selective impairment on executive functions, such as set-shifting ability and working memory. Freezers and non-freezers did not differ on measures of tremor, autonomic function, REM sleep behavior disorder, mood or more general cognition. CONCLUSION: These results suggest the pathophysiological mechanisms underlying freezing of gait in the early clinical stages of Parkinson's disease are likely to be related to specific changes in the frontostriatal pathways rather than being due to brainstem or more diffuse neuropathology.

Freezing beyond gait in Parkinson's disease: a review of current neurobehavioral evidence.

Besides the continuous motor impairments that characterize Parkinson's disease (PD), patients are frequently troubled by sudden paroxysmal arrests or brief episodes of movement breakdown, referred to as 'freezing'. Freezing of gait (FOG) is common in advanced PD and typically occurs in walking conditions that challenge dynamic motor-cognitive control. Mounting evidence suggests that episodic motor phenomena during repetitive upper limb (e.g. writing), lower limb (e.g. foot tapping) and speech sequences resemble FOG and may share some underlying neural mechanisms. However, the precise association between gait and non-gait freezing phenomena remains controversial. This review aimed to clarify this association based on literature on non-gait freezing published between 2000 and 2013. We focused on clinical and epidemiological features of the episodes and their relevance to current influential models of FOG, including recent neuroimaging studies that used a non-gait freezing paradigm as a proxy for FOG. Although not capturing the full complexity of FOG, the neurobehavioral insights obtained with non-gait freezing paradigms will contribute to an increased understanding of disturbed brain-behavior output in PD.

Abnormal patterns of theta frequency oscillations during the temporal evolution of freezing of gait in Parkinson's disease.

OBJECTIVE: We sought to characterize the electrophysiological signature of Freezing of gait in Parkinson's disease. METHODS: We examined 24 patients with idiopathic Parkinson's disease and significant freezing of gait as they performed a series of timed up-and-go tasks in their 'off' state while electroencephalographic data was collected from four scalp leads. Fast Fourier Transformation was utilized to explore the power spectral density between periods of normal walking and periods of freezing, as well as during the transition between the two states. In addition, Cross Spectrum and Cross Frequency analyses were used to explore the role of impaired temporal and spatial connectivity. RESULTS: When compared to walking, episodes of freezing were associated with a significant increase in theta band power within the central and frontal leads. The transition from normal walking to freezing of gait was also associated with increased theta frequency coupling between the central and frontal leads, along with an increase in cross-frequency coupling in the central lead. CONCLUSIONS: Episodes of freezing of gait in Parkinson's disease are associated with abnormal oscillatory activity in the brain. SIGNIFICANCE: These results provide novel insights into the pattern of spatiotemporal dynamics underlying freezing of gait and may provide a potential means for therapeutic prediction and alleviation of freezing episodes in susceptible patients.

A novel bedside task to tap inhibitory dysfunction and fronto-striatal atrophy in Parkinson's disease.

BACKGROUND: Given the heterogeneity of mild cognitive deficits in non-demented Parkinson's disease (PD), sensitive and anatomically specific behavioural measures are crucial when evaluating cognition in this patient group. Inhibitory dysfunction is one such deficit increasingly being recognised in non-demented PD; however, few clinical measures exist to detect it and its associated fronto-striatal pathology. METHODS: In 50 non-demented PD patients and 27 controls we employ a novel measure, the Excluded Letter Fluency (ELF) test, to objectively assess inhibitory dysfunction. ELF results were also contrasted with an established inhibitory measure (Hayling Test) and covaried against grey matter atrophy via voxel-based morphometry analysis in a subset of patients. RESULTS: The findings show that patients made significantly more rule-break errors than controls on the ELF and this measure was more sensitive than the Hayling in detecting inhibitory dysfunction, classifying over 76% of patients in logistic regression analysis. Importantly, ELF rule-break errors correlated with grey matter atrophy in known inhibitory-control regions (orbitofrontal cortex, inferior frontal gyrus and ventral striatum). CONCLUSIONS: The ELF is a brief bedside task that efficiently detects inhibitory dysfunction in non-demented PD. The utility of this novel behavioural measure is further substantiated by its anatomical specificity for fronto-striatal inhibitory control regions.

The differential yet concurrent contributions of motor, cognitive and affective disturbance to freezing of gait in Parkinson's disease.

OBJECTIVES: We sought to concurrently examine the specific motor, cognitive and affective contributions to self-reported FOG symptoms. PATIENTS AND METHODS: Ninety-six patients with Parkinson's disease completed the validated freezing of gait questionnaire and had their motor function scored on section three of the Unified Parkinson's Disease Rating Scale questionnaire. A 5-choice reaction time task was administered in order to measure cognitive processing speed and the Beck Depression Inventory was utilised to assess affective disturbance. RESULTS: The results showed that after controlling disease duration and dopaminergic medication dose, the triad of motor disability, cognitive processing speed and affective symptoms were all significant independent predictors of scores on the freezing of gait questionnaire. CONCLUSIONS: These findings suggest the need to consider the interplay between distinct motor, cognitive and affective domains in aetiological studies of freezing and the development of future therapies.

Modeling freezing of gait in Parkinson's disease with a virtual reality paradigm.

Freezing of gait is a paroxysmal and disabling symptom that commonly affects patients in the latter stages of Parkinson's disease, however the intermittent nature of this symptom makes it difficult to study in the clinical setting. Our research group has previously reported a correlation between self-reported freezing of gait symptoms and performance on a seated virtual reality gait task. In this study, we sought to determine whether behavioral measures recorded on this task were correlated with actual clinical measures of freezing of gait recorded in a cohort of 38 Parkinson's disease patients whilst in their clinically defined 'off' state. Firstly, patients with freezing of gait had a significantly larger frequency of spontaneous motor arrests recorded on the virtual reality gait task than 'non-freezers'. In addition, in those 24 patients with clinically proven freezing of gait, the number and percentage of time spent with freezing on the virtual reality task were both moderately correlated with the duration of freezing of gait recorded on the timed up-and-go tasks. These findings suggest that the freezing behavior observed during a virtual reality gait task may share similar neural substrates to freezing of gait. Such a relationship could offer a potential avenue for modeling the phenomenon of freezing of gait in Parkinson's disease, allowing for the exploration of the neural correlates of freezing.

Assessing the utility of Freezing of Gait Questionnaires in Parkinson's Disease.

There are currently two validated questionnaires, the Freezing of Gait Questionnaire and the New Freezing of Gait Questionnaire, that are intended to assess the degree of freezing of gait in patients with Parkinson's disease. However, to date no study has attempted to determine whether ratings on these questionnaires accurately reflect the severity (frequency and duration) of actual freezing episodes experienced by patients. We studied twenty-four patients with Parkinson's disease who self-reported significant freezing while in their practically-defined 'off' state. Prior to clinical assessment they completed both freezing of gait questionnaires before being video-recorded while performing a series of timed up-and-go tasks, which incorporated turning, rotating and passing through narrow gaps. The rating of video recordings by two independent observers identified a total of 530 freezing events. The frequency and duration of freezing episodes for each patient were calculated and correlated with questionnaire ratings. Scores on either questionnaire did not correlate with either the frequency or duration of freezing episodes experienced by patients during objective assessment. These results suggest the need to re-evaluate the utility of questionnaires in the assessment of freezing of gait. Furthermore, these results highlight the need for accurate objective methods of identifying freezing events when assessing future clinical interventions aimed at reducing this potentially disabling symptom of Parkinson's disease.

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 Parkinson's 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.

First Report of Puccinia kuehnii, Causal Agent of Orange Rust of Sugarcane, in the United States and Western Hemisphere.

In June 2007, approximately 8 km east of Belle Glade, FL, a rust disease was observed on a sugarcane (a complex hybrid of Saccharum L. species) cultivar (CP 80-1743) considered resistant to brown rust caused by Puccinia melanocephala Syd. & P. Syd. Approximately 10 km south of Canal Point, FL, another cultivar (CP 72-2086), also considered resistant to P. melanocephala, was found to be infected with a rust. Samples were sent to the USDA-APHIS National Mycologist and the USDA-ARS Systematic Mycology and Microbiology Laboratory in Beltsville, MD for identification. Observed morphological features were consistent with P. kuehnii E.J. Butler. Uredinial lesions were orange and variable in size, measuring 650 to 850 × 26 to 32 µm, hypophyllous, ellipsoidal to fusiform in shape, and distinctly lighter than pustules of P. melanocephala that were present in the area along with P. kuehnii. Urediniospores were mostly obovoid to pyriform or broadly ellipsoidal, variable in size, 32 to 45 × 25 to 30 µm, and moderately echinulate with mostly evenly distributed spines 2 to 4.5 µm apart. Walls were orange-to-light cinnamon brown, 1 to 2.5 µm thick with a pronounced apical wall thickening as much as 7 µm, and 4 to 5 equatorial pores. Similar orange uredinial lesions were subsequently observed on the same two cultivars and several other cultivars, including CPCL99-1777 and CPCL01-1055, at different locations in South Florida. Telia and teliospores were not observed. The nuclear large subunit rDNA region of the rust infecting cv. CP 80-1743 (BPI 878243, GenBank Accession No. EU164549) and the ITS1, 5.8S, and ITS2 rDNA regions of the rust infecting CP 80-1743 (GenBank Accession No. EU176009) and CP 72-2086 (GenBank Accession No. EU176008) were sequenced (1,4). All sequences were identical to sequences of P. kuehnii and distinct from known sequences of P. melanocephala (4). To our knowledge, this is the first confirmed record of P. kuehnii infecting sugarcane in the Western Hemisphere, and the disease appears to be distributed widely in the South Florida sugarcane-growing area. Although listed by P. Holliday (3) as occurring in Cuba, the Dominican Republic, and Mexico, CMI map no. 215 ed. 4 (2) does not include these three countries in the known distribution of P. kuehnii. P. kuehnii has also been reported in the literature as present in Hawaii (4). However, examination of the specimen label found that the specimen cited in those papers (BPI 079624) was actually collected in Tahiti. Therefore, the report from Hawaii is erroneous. References: (1) M. C. Aime. Mycoscience 47:112, 2006. (2) CMI. Distribution Maps of Plant Diseases. No. 215, ed. 4. CAB International, Wallingford, UK, 1981. (3) P. Holliday. Fungus Diseases of Tropical Crops. Cambridge University Press, Cambridge, 1980. (4) E. V. Virtudazo et al. Mycoscience 42:447, 2001.