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Udall Center Theme

Degeneration of brain cholinergic pathways produces cognitive deficits which disrupt integration of cognitive, sensory, and motor functions critical for normal gait and balance.

The central theme of the University of Michigan Udall Center is the role of cholinergic deficits in treatment-refractory aspects of Parkinson disease (PD), particularly gait and balance disorders, and cognitive decline. Through an interrelated and complementary set of neuroimaging and behavioral studies in patients with PD and unique animal model experiments, Center investigators examine the contribution of distinct cholinergic projection system deficits to abnormalities of gait, balance, and cognition in PD.  A major aspect of this central theme is the role of cholinergic systems in integrating afferent sensory, attentional, and cognitive information with motor functions.
Diagram of attentional motor interface

Attentional-Motor Interface

Multiple neurochemical systems degenerate in Parkinson’s Disease (PD). Progressive gait and balance difficulties, with associated falls, are among the most common levodopa resistant symptoms, eventually occurring in nearly all patients. The consequences of these levodopa resistant symptoms are devastating, and include bone fractures, hospitalizations, self-imposed isolation because of fear of falling, wheelchair confinement, and eventual nursing home placement.  Similarly, cognitive decline is a prominent, common, and disabling feature of advancing PD, overlapping significantly with gait and balance disorders.

Data collected by Center investigators indicates that gait and postural control are not purely “motor” functions but require complex integration of motor, sensory, and cognitive functions. Defining the relationship between cholinergic dysfunction, gait abnormalities, and cognitive decline requires a multidisciplinary approach in which investigators view the relationship between cholinergic function, gait, and cognition through different lenses, share insights and challenge each other in ways that yield progress far beyond that achievable were each project pursued separately. The research team at the Center developed data that led to the development of a conceptual model of cognitive-motor integration (the Attentional-Motor Interface above) in which cholinergic systems’ interactions with basal ganglia and cortical circuits are critical for normal function. This model provides a systems-level framework for understanding the interactive nature of gait, balance, and cognitive dysfunctions in PD and focuses experimental attention on critical nodes of this system.

The lack of effective therapies for gait, balance, and cognitive abnormalities in advancing PD stems in large part from a limited understanding of the role of non-dopaminergic systems in the pathophysiology of these symptoms. It is increasingly clear that normal gait and balance depends upon complex interplay of motor, sensory and cognitive functions, indicating that the full spectrum of PD neuropathology must be considered to identify the responsible neural substrates. The molecular imaging work of Udall Center investigators demonstrated that PD subjects with a history of falls and/or gait freezing have differing deficits of specific cholinergic systems.  Parallel work with a unique animal model demonstrated the critical role of cholinergic systems subserving attentional functions in normal gait and balance functions.  In recent preliminary work, Udall Center molecular imaging data shows that other cholinergic deficits are related to other important aspects of motor and cognitive functions.  Complementary experimental animal model work is illuminating the specific cellular mechanisms by which the cholinergic systems and nodes identified as abnormal by Udall Center clinical research integrate diverse circuits to produce normal cognitive and motor functions. All of this work is a necessary prelude to developing interventions for these treatment refractory aspects of PD.

Udall Projects

Project Lead: Nicolaas Bohnen, MD, PhD

Postural instability and gait difficulty (PIGD) motor features are common in Parkinson disease (PD), and a significant cause of treatment-refractory disability. Accumulating evidence implicates cholinergic systems dysfunctions as significant contributors to gait and balance impairment. During the initial funding period, we established the vesicular acetylcholine transporter (VAChT) ligand [18F]FEOBV, which uniquely assesses cholinergic terminal density in high density regions such as the striatum. Our recent cross-sectional findings suggest that PwP participants with isolated falls and those with freezing of gait (FoG) status share common cholinergic deficits in the thalamus (lateral geniculate nucleus [LGN]) and striatum (caudate) with more extensive striatal, limbic, and prefrontal VAChT reductions in PwP with FoG. Consistent with Project II preclinical data indicating a critical role for striatal cholinergic interneurons (SChI) in integration of attentional and motor functions, these data suggest that SChI deficits are a common denominator in the etiology of falls and FoG. These results emphasize the need to understand PIGD, falls, and FoG as products of cholinergic projection dysfunctions within the framework of failing Attentional-Motor Integration (AMI) combined with failures of additional multisensory and cognitive integration.

Episodic mobility disturbances (falls, FoG) are typically preceded by insidiously developing non-episodic PIGD features. We have novel preliminary data that cholinergic deficits of the medial geniculate nucleus (MGN) and the entorhinal cortex (ERC) are robustly associated with non-episodic PIGD deficits, These results imply a significant role of impaired sensorimotor integration underlying non-episodic PIGD motor features in PwP. The overarching goal of this project is to investigate the evolution of cholinergic deficits within multisensory, cognitive and motor integration brain regions and development of PIGD features in PwP. We hypothesize that this progresses from the MGN and ERC, then LGN and caudate nucleus, and then more diffuse striatal, limbic and cortical (prefrontal followed by anterior cingulum and insula) cholinergic deficits. To assess our hypotheses, we propose to perform a prospective cohort study with [18F]FEOBV brain PET at baseline and 2-year follow-up in PD subjects at risk of conversion to non-episodic and episodic (falls and FoG) PIGD motor features. Novel insights in cholinergic changes underlying incident development of PIGD may inform new therapeutic interventions to treat these debilitating motor complications. Project I is highly integrated thematically with Project II and the Catalyst Research Project, complementary to Project III, and will interact extensively with all Cores. Our work is based on a unique, deeply phenotyped cohort of PD participants developed in the prior funding cycle allowing us to recruit an enriched sample of patients likely to convert to fall and FoG status, allowing longitudinal within-subject assessments.

Udall Project I Figure

[18F]FEOBV PET delineates specific cortical regions and deep brain structures, including striatum and thalamic subnuclei. PD subjects with falls vs those with falls and gait freezing exhibit distinct abnormal patterns, highlighted by reduced striatal [18F]FEOBV as a shared dysfunctional node. Dr. Bohnen and his team will prospectively test the hypothesis that the cholinergic AMI network dysfunctions they describe are core features of PD gait and balance dysfunction, and that distinct patterns of cholinergic pathology predict specific features of PD gait dysfunction. The serial assessments proposed will allow unique within-subject analysis for the temporal dissection of distinct and converging elements of mobility control deficits of gait-balance motor features in PD. Unlike the prior grant cycle where longitudinal assessment was limited, esp. for PwP converting from non-fallers/freezers to fallers/freezers, the current cycle will allow clinically meaningful follow-up assessments of up to 5-6 years of PwP who completed baseline [18F]FEOBV PET. Hypotheses to test: 1) whether incident fallers exhibit [18F]FEOBV defects in the caudate, visual thalamus, and prefrontal cortex (compared to non-converters), and 2) whether the subsequent emergence of gait freezing involves additional and more widespread cholinergic vulnerability of the striatum, limbic archicortex, including the cingulo-opercular and insular cortices. The existence of the unique PD subject cohort developed in the currently funded cycle, together with newly recruited subjects, will allow study of an enriched sample of those converting to falls and/or to gait freezing. The focus on visual thalamus, based on the repeated association of falls with cholinergic dysfunction (found with both [11C]PMP and [18F]FEOBV), is another important and novel element. Many thalamic nuclei are primarily interconnected with association cortices with these thalamic nuclei are increasingly viewed as partners and/or modulators of cortical functions. Emerging evidence supports critical roles of visual thalamus in mediating visual attention. LGN function is modulated by attention, indicating a key role for this relay structure in bottom-up attention. Dr. Bohnen has new data implicating cholinergic denervation of additional regions driving non-episodic PIGD deficits preceding falls and FoG. This data indicates that cholinergic deficits within the MGN and entorhinal cortex (EC) are robustly associated with non-episodic PIGD, independent of nigrostriatal dopaminergic deficits. MGN is involved in processing multi-sensory (auditory, vestibular and proprioceptive) inputs, implying a significant role of impaired sensorimotor integration underlying early PIGD features in PwP. EC is associated with visuospatial maps, suggesting deficient attention-visuomotor integration.  Complementary work will be performed in the Catalyst Research Project. The analysis of cholinergic system changes of the evolution of balance and gait disturbances will be complemented by exploratory mechanistic multisensory and attentional-motor integration studies.  These studies will identify the key patterns of cholinergic systems dysfunction underlying treatment-refractory gait and balance disorders in PwP.

Project Lead: Kent Berridge, PhD  (replacing Martin Sarter, PhD)

This project builds on Dr. Martin Sarter’s published and preliminary work dissecting the mechanisms of the detection of relevant cues, transfer of this information to striatum, and its integration with ongoing motor processing. Based on the Sarter team’s demonstration of a role for basal forebrain cholinergic projections in the DL (dual lesion) rodent model of PD falling, this project uses optogenetic techniques to test the hypothesis that an enhanced fall propensity can be caused specifically by the loss of fast cholinergic signaling (i.e., “transients”) known to mediate attention. Additional experiments define how cholinergic-mediated cortical attentional information is integrated with motor selection processes. Frontostriatal circuitry (glutamatergic corticostriatal projections) is essential for action planning, particularly when habit-guided action is disrupted and task shifts are needed. Such adjustment depends critically on corticostriatal information transfer to guide adaptive movement selection and sequencing. Deficient cortical cholinergic activity impairs attentional shifts toward alternative actions, uncoupling striatal action selection from goals, causing ill-timed or absent responses. Guided by this framework, intrinsic to the AMI model, Dr. Sarter’s team acquired compelling preliminary data detecting the signals encoding attentional information transferred to the striatum (via corticostriatal terminals), where it is hypothesized to be integrated with vigor and kinematic signals supplied by nigrostriatal dopaminergic terminals. Utilizing a novel behavioral paradigm, they demonstrate that a cue instructing the animal to turn evokes a time-locked increase of striatal glutamate (that will be shown to originate from corticostriatal afferents), and a similarly timed burst of acetylcholine from cholinergic neurons. Dr. Sarter’s former team, now under the direction of Dr. Berridge, is specifically testing the hypothesis that this integrative function is essential for complex motor control, including PD gait dysfunction. Preliminary findings strongly support a role for cholinergic signals in integrating the attentional and motor signals during gait; chemogenetic activation of these neurons reduces fall propensity in DL rats (often preceded by freezing-like motor behaviors in the animals), whereas their inhibition in intact animals mimics DL-type falls. These data support key aspects of the AMI model by implicating cholinergic neurotransmission at two successive nodes along the cortico-striatal pathway critical to support the attentional-motor interface – in cortex for signal detection, and in striatum for signal integration. These studies will identify key substrates of attentional-motor integration in the AMI.

Udall Project II Figure

 

Project Lead: Roger Albin, MD

Cognitive deficits are a morbid dopamine replacement therapy-refractory feature of Parkinson disease (PD). The pathophysiology of PD-related cognitive deficits is complex, likely involving interacting and variable impairments of several brain systems, particularly in early to moderate disease. Incidence and natural history of PD cognitive deficits is heterogeneous. Understanding the pathophysiologies of PD cognitive impairments is essential for development of personalized therapies. PD heterogeneity is a major obstacle to effective clinical research. Identifying PD subgroups will enhance discovery of useful interventions through subgroup specific or stratified clinical trials, identify biomarkers, improve prognosis assessment in clinical care, and assist etiopathogenic research. Some of the “highest priority recommendations” of the NINDS PD 2014 Research Report call for research to understand the pathophysiology of cognitive impairments and for PD subgroup identification. The U-M Udall Center established a deeply phenotyped PD cohort imaged with the vesicular acetylcholine transporter PET ligand [18F]FEOBV, revealing heterogeneous cholinergic deficits. Cholinergic terminal deficits in Cingulo-Opercular Task Control network (COTC) nodes – Anterior Cingulate and Insular Cortices (AC-I) – correlate with both domain specific and global cognitive deficits. An important component of the Attentional-Motor Interface, the COTC subserves tonic attention, coordinating network activities across different cognitive domains. Preliminary analysis suggests that early COTC node (AC-I) cholinergic deficits are a subgroup defining-feature in PD, predicting more rapid cognitive decline. The central hypothesis of Project III is that early COTC node (AC-I) cholinergic denervation contributes significantly to cognitive impairment in early to moderate PD and identifies a D subgroup with accelerated cognitive decline In addition to our established Udall subject cohort, we have access to a separate cohort of incident PD subjects through collaboration with the University of Groningen, deeply phenotyped and imaged with [18F]FEOBV PET, for rigorous experimental replication and validation of our primary hypothesis. We will correlate early COTC node (AC-I) cholinergic denervation with domain-specific and general measures of cognitive function. In a prospective analyses, we will determine if early COTC node (AC-I) cholinergic denervation predicts more rapid cognitive decline. In an integrated analysis with Project I, we will determine if COTC node (AC-I) cholinergic denervation is associated with Freezing of Gait (FoG). In exploratory analyses, we will assess if more accessible MRI or other measures correlate with COTC node (AC-I) cholinergic denervation, identifying potential, accessible biomarkers of COTC node (AC-I) cholinergic denervation. Project III will identify an important substrate of PD cognitive impairment and identify a PD subgroup with a more aggressive natural history – a “malignant hypocholinergic disease phenotype.” These results will identify potential targets for therapeutic interventions and biomarker development.

Udall Project III Figure

Our preliminary results indicate a global effect of key AMI node AC-I cholinergic denervation on cognitive functions. These cortical regions are key nodes of the COTC network and participate in higher level aspects of attentional function. We will confirm that AC-I denervation is associated with widespread cognitive deficits. Our established PD cohort, extensively characterized with dopaminergic and cholinergic PET, and with motor and cognitive assays, uniquely positions us to define the distinctive natural history of a PD subgroup based on a pathologic marker. Continued follow-up of this valuable cohort will assess if AC-I cholinergic denervation predicts significantly greater global cognitive decline. Quantification of cholinergic changes in the COTC subcortical and cortical (AC-I) network in this cohort will also allow the assessment that progressive cognitive changes coincide with more severe motor changes (aggressive or ‘malignant’ PD subtype). PET studies are costly and [18F]FEOBV is only operational in a handful of centers. A convenient, reliable predictor of AC-I cholinergic denervation is required to employ this phenotype as subgroup marker or stratifying method. We will capitalize on the thorough phenotyping of our cohort and apply more convenient MRI methods, complementing Project I analyses, to explore an accessible biomarker. Through collaboration with investigators at the University of Groningen (Netherlands), we have access to a similarly characterized and prospectively followed cohort of incident PD subjects who also undergo [18F]FEOBV PET. These subjects are part of the Dutch Parkinson and Cognition Study (DUPARC). This collaboration will enable us to rigorously test our hypotheses regarding the impacts and prognostic potential of AC-I cholinergic denervation and identification of a useful predictor in an independent replication cohort. Our Groningen colleagues agreed to share all phenotypic, MRI, and [18F]FEOBV imaging data to address, in parallel, the hypotheses driving Project III.  These studies will identify a key substrate of cognitive impairments and predictor of more rapid cognitive decline in PwP.

Project Lead: Omar Ahmed, PhD

Many patients with Parkinson’s disease (PD) suffer from spatial disorientation – inability to link external landmark cues to internal estimates of self-orientation. These deficits are not improved by dopamine replacement therapy (DRT). The same spatial disorientation features are found in patients with specific lesions, due to a stroke or hemorrhage, of the retrosplenial cortex (RSC), a brain region critical for encoding the combination of allocentric and egocentric navigational information. Attentional and emotional processing impairments in PD patients are accompanied by altered BOLD responses in the retrosplenial cortex. The retrosplenial cortex is densely interconnected with the secondary motor cortex, hippocampus, visual cortex, cingulate cortex and anterior thalamus (containing head orientation cells), and is therefore part of the Attentional-Motor Interface (AMI) and ideally positioned to help transform attentional and spatial information into planned actions. Furthermore, multiple basal forebrain structures send cholinergic projections to the RSC. There are pronounced increases in acetylcholine (ACh) release in the retrosplenial cortex during attentive spatial navigation. Cholinergic deficits, such as those seen in PD, are likely to severely impair the spatial orientation functions of the retrosplenial cortex. Little is known about 1) how cholinergic inputs influence the synapses, cells and circuits of the retrosplenial circuits, and 2) the impact of cholinergic dysfunction on retrosplenial-dependent spatial orientation and navigation. Our central hypothesis is that dysfunctional cholinergic systems projecting to the retrosplenial cortex will manifest in altered navigational encoding by retrosplenial circuits and spatially disoriented behaviors. We will decipher the mechanisms of cholinergic control of retrosplenial cells and synapses, with preliminary data suggesting both cell-type- and synapse-specific cholinergic controls. We will investigate how the loss of cholinergic inputs impairs retrosplenial encoding of space and how it impacts orientation-guided movement. These investigations will elucidate the contributions of the retrosplenial orientation coding circuit to the Attentional-Motor Interface, and lay the groundwork for understanding how altered perception of spatial orientation in Parkinson’s disease can directly impact motor control.

Udall Project Catalyst Research Project Figure

Many PwP experience DRT-refractory spatial disorientation with inability to integrate external landmark cues with internal estimates of orientation.  The retrosplenial cortex (RSC) is critical for this function with fMRI studies indicating abnormal attentional information processing in PwP.  RSC, an integral AMI component, is densely interconnected with other AMI nodes, the cingulate cortex and anterior thalamus (locus of head position neurons), and receives dense BF cholinergic afferents.  These cholinergic inputs are critical for attentive spatial navigation. In work funded by a U-M Udall Center Pilot Project, Dr. Ahmed uncovered a unique pattern of local inhibition in the RSC. In this Catalyst Research Project, Dr. Ahmed will evaluate the hypotheses that thalamic input mediated spatial information is modulated by BF cholinergic afferents and that cholinergic receptor mediated responses in RSC neurons are critical for maintaining attentive navigation.  RSC inter-hemispheric communication is necessary to maintain attentive navigation.  Dr. Ahmed specifically hypotheses that cholinergic signaling is necessary for normal inter-hemispheric RSC function.  Dr. Ahmed will evaluate these hypotheses in both normal animals and in the dual lesion (DL) model of combined striatal dopaminergic denervation and cortical cholinergic denervation developed by Dr. Sarter.  This study will identify mechanisms of information transfer within a key AMI node. These experiments provide a cellular level examination of cholinergic functions within an AMI node, complementing the systems and circuit level approaches of the other projects.  The focus on attentive spatial navigation also complements Project I studies assessing the roles of deficient sensorimotor and visuomotor integration in PwP.
Publications
Research Updates

Mac Shine – Updating our models of the basal ganglia using advances in neuroanatomy and computational modelling

Bernardo Sabatini - Basal ganglia circuits for action selection and evaluation

Shelly Flagel - Exploiting individual differences in motivated behavior to identify the neural processes underlying neuropsychiatric disorders

Honglei Chen - Research on environmental risk factors of Parkinson’s disease – challenges and strategies

Christian Burgess - Striatal dopamine dynamics during skilled motor learning

Michael Vesia - Measuring and manipulating brain circuits for goal-directed movements with multi-focal transcranial magnetic stimulation

Prabesh Kanel - Voxel-based principal component analysis of brain PET images

Megha Ghosh - Rhythms of the retrosplenial cortex during movement and REM sleep

Sam Crowley, Alex Johnson, James Brissenden - The basal forebrain, acetylcholine, and cognition in Parkinson's disease; Electrophysiological signatures of a basal forebrain-retrosplenial system; Restoration of vigor-motivation coupling in Parkinson's disease requires both the short and long duration response to L-Dopa 

Per Borghammer - Brain-first vs body-first Parkinson’s disease- the idea, validation studies, and implications

Hong-Yuan Chu - Cortical cellular and synaptic dysfunction in Parkinsonism

Simon Lewis - Parkinson’s and Phrenology for the 21st Century

Yoland Smith - Pathophysiology of Thalamocortical and Corticofugal Systems in Parkinsonism

Benjamin Hampstead - Non-invasive brain stimulation in Parkinson’s and Lewy Body dementia

Kumar Narayanan - Cognition and 4 Hz Rhythms in Parkinson’s Disease

Cassandra Avila - The role of corticostriatal interactions in complex movement
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