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4 Falls Resulting from Extensive Striatal Dopamine Loss

4 Falls Resulting from Extensive Striatal Dopamine Loss

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more step timing variability, smaller steps, decreased arm swing, forward bended

posture, and frontal plane instability (Bridenbaugh and Kressig 2011; Kurz et al.

2013; Marchese et al. 2003; Mazzoni et al. 2007; Winter et al. 1990). Dopamine loss

is known to slow responding and decrease accuracy in tasks involving habitual/

automatic responding or tasks requiring shifts between behavioral contingencies

(Baunez and Robbins 1999; Darvas and Palmiter 2009; Domenger and Schwarting

2008; Hauber and Schmidt 1994; Lex and Hauber 2010; Rogers et al. 2001). Thus,

in addition to falls that originate from the combined attentional-motoric deficits

described above, falls may result from relatively severe impairments in normally

habitual motor functions caused by striatal dopamine loss, especially when traversing dynamic surfaces (Cole et al. 2011; Wood et al. 2002; Woollacott and ShumwayCook 2002).

To assess the impact of large dopamine losses on fall propensity, more extensive 6-OHDA lesions that extended into the dorsolateral and dorsomedial striatum

were administered to rats. As in the previous experiment, rats performed traversals

with a progressively demanding battery of MCMCT conditions, including inclines

and reversing the direction of the rotating rod. These large dopamine lesions

increased falls and slowed traversal speed (Kucinski et al. 2015). Falls were characterized by frequent freezing episodes, defined as stoppages of forward traversal

movement for more than 1 s. Freezing episodes occurred both spontaneously (with

no obvious trigger) or following stepping errors. Despite these impairments, falls

were less frequent than falls in DL rats tested previously. In addition, large dopamine losses did not impair the ability to perform increasingly complex movements,

such as traversing the rotating rod when the direction of rotation was reversed, as

was the case in DL rats or rats with only BF cholinergic lesions. However, falls that

were triggered by a doorframe distractor, a distractor designed to model doorframeevoked freezing of gait episodes in PD patients (Cowie et al. 2012), were preceded

by longer periods of immobility and occurred earlier in the run compared to DL rats.

Thus, we hypothesized that falls in these two lesion models stemmed from different

cognitive-behavioral mechanisms—large dopamine lesions of the dorsal striatum

caused falling due to propensity of freezing forward movement, while dorsomedial

lesions combined with cortical cholinergic loss models falls resulting from impairments in attentional-motor interactions and complex movement control.

Freezing of gait (FOG), a sudden disturbance of gait, in which patients often feel

stuck with their feet being “glued to the floor,” occurs in 30–60 % of the PD patients.

FOG is common in challenging situations with increased “mental stress” (Giladi

and Hausdorff 2006) and can often be overcome by applying external tricks such as

visual or auditory cues (Nieuwboer et al. 1997). Freezing episodes can be triggered

by disruptions in gait rhythm control and symmetry, postural control, and step scaling as well as attentional shifts (Cowie et al. 2012; Plotnik et al. 2012). It was

hypothesized that subcortical regions may fail to “update” motor sets during ongoing task performance during freezing episodes (Chee et al. 2009), thus shifting

habitual-driven movement to goal-directed movement. Such a shift would necessitate an over-reliance on cortical networks to complete tasks normally handled by

automatic networks and reduce efficiency and delay movement responses (Hallett



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2008; Shine et al. 2011; Spildooren et al. 2010). PD patients exhibit greater activity

in cortical, including prefrontal, regions while performing automatic movements,

suggesting recruitment of complex cognitive networks even for relatively undemanding gait and posture control (Wu and Hallett 2005). With an increased reliance

on cognitive resources to carry out habitual actions, falls may occur primarily due

to the inability to perform intricate, attention-demanding actions when needed. In

these situations, compensatory mechanisms to limit the degree of gait disruption

and limb incoordination or to disengage from the freezing response may be insufficient and/or deployed too late to prevent falls (Fasano et al. 2012).



6.5



Preventing Falls



Severe motor deficits in PD patients such as loss of motor vigor and gait impairments are benefited with levodopa treatment; however, levodopa does not generally improve and can worsen cognitive symptoms (Cools et al. 2001, 2007;

Schneider et al. 2013). Importantly, falls and related complex motor impairments

tend to be unresponsive to levodopa (Koller et al. 1989; McNeely and Earhart

2013; Michalowska et al. 2005; Sethi 2008) and often additional motor impairments such as dyskinesia can occur with levodopa treatment (Huot et al. 2013;

Iravani et al. 2012). However, despite its shortcomings, levodopa is essential for

enhancing basic motor functions in PD. Given that falls in PD and our rodent

model (“DLs”) are associated with reduced cholinergic-attentional control of

movement, specifically, reduced detection and reporting of external and interoperceptive cues related to ongoing motion, co-administration of compounds that

enhance cortical cholinergic activity and improve attention may reduce fall propensity in levodopa-treated patients.

The postsynaptic targets of cortically projecting BF neurons include nicotinic

acetylcholine receptors (nAChRs) on the terminals of thalamic glutamatergic projections. The neuromodulatory effects of ACh influence the generation of cholinergic transients via this target (Aracri et al. 2013; Guillem et al. 2011; Howe et al.

2010; Parikh et al. 2008, 2010). Our previous studies indicated nAChR agonist

α4β2* reliably enhanced attentional performance in non-lesioned rats (Howe et al.

2010). Also, stimulation of α4β2* nAChRs in the cortex mimics and amplifies the

cholinergic neuromodulatory effects on cortical cue detection circuitry and

thus enhances top-down control of attention (Howe et al. 2010; Parikh et al. 2010).

As predicted by the beneficial effects on attention in animals, α4β2* nAChR agonists improve symptoms of adult ADHD (Apostol et al. 2012; Bain et al. 2013).

Cholinergic agents that do not specifically target nAChRs, such as acetylcholinesterase inhibitors (McCall et al. 2013; Possin et al. 2013) or muscarinic (m) AChR

agonists (Hasselmo and Sarter 2011), have thus far yielded inconclusive effects on

falls and PD-related attentional deficits.

Recent evidence has supported the hypothesis that stimulation of α4β2* nAChRs

in combination with levodopa can benefit cognitive symptoms (Decamp and



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Schneider 2009; Schneider et al. 1999, 2003) as well as motor symptoms that are

not addressed by levodopa, such as dyskinesias (Huang et al. 2011; Quik et al.

2008). In our DL rat model (Kucinski et al. 2013), co-administration of the α4β2*

nAChR agonist ABT-089 (Arneric et al. 2007) with levodopa and benserazide

reduced falls from the rotating rods on the MCMCT by approximately 50 %. Also,

nonspecific nAChR agonist varenicline and other nAChR agonists, such as agonists

of the α6β2* subtype, have been effective at reducing levodopa-induced dyskinisia

in non-human primates (Zhang et al. 2013) and in a rat lesion model (Huang et al.

2011). Thus, nAChRs appear to be a viable therapeutic target for improving

cholinergic-mediated attentional deficits as well as falls in PD.



6.6



Conclusions and Future Directions



Complex movement relies on networks of cortical-BG-cortical loops that integrate

sensorimotor and cognitive operations to achieve goal-directed objectives

(Alexander et al. 1990; Haber et al. 2000). The basal ganglia and its connections

with the cortex compartmentalize motor control into habitual and goal-directed

components, mediated by distinct but overlapping pathways (Balleine and

O’Doherty 2010; Redgrave et al. 2010). This parallel organization is essential for

performing complex motor operations such as responding to cues, action selection,

and motor feedback (Balleine et al. 2009).

Attention is a particularly important cognitive operation that is essential for guiding complex movement. Detection and reporting of external and interoceptive cues

to the striatum is an example of cognitive-motor communication that underlies complex and flexible goal-directed behaviors (Amboni et al. 2013; Yogev-Seligmann

et al. 2008). Our lesion studies have demonstrated that loss of cholinergic-driven

attentional control over damaged striatal circuitry reveals robust impairments in

complex movements, particularly increased falls (Kucinski et al. 2013). This finding

is corroborated by observations in PD patients with attentional impairments and

cortical cholinergic losses that are prone to falls (Allcock et al. 2009; LaPointe et al.

2010; Nagamatsu et al. 2013). In addition, large dopamine lesions resulted in FOGassociated falls (Kucinski et al. 2015) which may involve the loss of motor automation and the shifting of cognitive resources to attend to basic motor operations, thus

taxing the ability to perform essential cognitive functions such as detecting cues,

processing distractors, and rapidly correcting movement errors (Fasano et al. 2012;

Hallett 2008). These models of complex movement deficits and falls, together with

evidence from PD fallers, help to elucidate mechanisms that underscore cognitivemotor interactions in mediating movement and behavior.

In future work, we will continue to explore brain–behavior relationships associated with cognitive control of movement and fall behavior. First, given that

cholinergic-attentional processes guide complex motor control, we expect higher

levels of neuromodulatory ACh activity in the prefrontal cortex during attentionally

demanding MCMCT conditions, specifically during traversals of rotating rods, rela-



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tive to nondemanding trials with a wider and stationary plank surface. Brain analytes from the cortex will be collected by in vivo microdialysis using a modified

MCMCT apparatus with dialysis lines attached to an overhead sliding rig that

moves along with the animals as they traverse the plank and rods. Following each

traversal, rats receive water rewards in boxed chambers on both ends of the beam,

which are surrounded by motorized retractable walls that are brought down to signify the start of the next traversal, thus minimizing experimenter interference during

the task. ACh and other brain neurotransmitters in the prefrontal cortex will be

assessed using HPLC-mass spectrometry. Furthermore, given our hypothesis that

cholinergic-attentional control compensates for striatal-mediated motor deficits following partial loss of striatal dopamine, we expect cholinergic release on the rotating rod to be further amplified in rats with striatal dopamine lesions, consistent with

an increased reliance on cognitive control over habitual movement.

In addition, brief cholinergic release events (“transients”) may be assessed using

enzyme-sensitive microelectrodes/amperometry (Howe et al. 2010; Parikh et al.

2008, 2010) during MCMCT traversals. Cholinergic transients in the medial prefrontal cortex are required for detection and selection of appropriate cues, as well as

the sequencing and execution of cue-associated responses (Parikh et al. 2008). We

expect that cholinergic transients, measured on the timescale of seconds, are

required to perform attention-demanding movements such as postural and balance

adjustments during recovery from slips or movements needed to maintain balance

on the rotating rods or while processing distractors. Also, recent advances in wireless optogenetic technology (Kim et al. 2013; McCall et al. 2013; Stark et al. 2012)

may allow for the activation of cholinergic-attentional circuitry during performance

of MCMCT traversals. We have previously determined that BF cholinergic stimulation enhances the detection of signals in an attention task and, conversely, evokes

“false alarms” in non-signal trials (reporting the presence of signals when they were

not presented) (submitted for publication). A major goal will be to stimulate cortical

cholinergic circuits in rats with extensive loss of striatal dopamine in order to

enhance cholinergic-attentional supervision over movement during beam traversals

and thus prevent falls.

Acknowledgements Supported by NINDS Grant P50NS091856 (Morris K. Udall Center for

Excellence in Parkinson’s Disease Research).



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Chapter 7



Interactions Between the Basal Ganglia

and the Cerebellum and Role in Neurological

Disorders

Christopher H. Chen, Diany Paola Calderon, and Kamran Khodakhah



7.1



The Cerebellum



Many functions have been attributed to the cerebellum—especially in more recent

years—but the most consistently and historically agreed upon function of the cerebellum is that it coordinates movements (Fine et al. 2002; Ito 1984; Medina 2011;

Rolando 1828). The cerebellum can be grossly subdivided into three divisions. The

most medial is the vermis. The lateral regions are known as the lateral hemispheres,

and the region between the hemispheres and the vermis is the paravermis. The cerebellum also has some somatotopy, similar to that of other brain regions (Ghez and

Thach 2000; Ito 1984; Manni and Petrosini 2004).

The circuitry of cerebellar pathways is illustrated in Fig. 7.1. The primary input

to the cerebellum is the mossy fibers. This system originates from the brain stem

and spinal cord and relays information from throughout the brain to the cerebellar

cortex (Eccles et al. 1966b). Mossy fibers form excitatory synapses on an extensive

array of granule cells, the most abundant cell type in the brain. Granule cell axons

extend and bifurcate in the cerebellar cortex, forming the parallel fibers, and en passant synapses formed by these axons make excitatory connections with a set of

interneurons in the cerebellar cortex (Palay and Chan-Palay 1974; y Cajal 1889).

The parallel fibers themselves are the primary input to the computational unit of the

cerebellum: the Purkinje cell (Ito 1984).



C.H. Chen • K. Khodakhah, Ph.D.

Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine,

Bronx, NY 10461, USA

e-mail: christopher.chen@phd.einstein.yu.edu; k.khodakhah@einstein.yu.edu

D.P. Calderon, M.D., Ph.D. (*)

Laboratory for Neurobiology and Behavior, The Rockefeller University,

1230 York Ave, New York, NY 10065, USA

e-mail: dcalderon@rockefeller.edu; dcalderon@mail.rockefeller.edu

© Springer International Publishing Switzerland 2016

J.-J. Soghomonian (ed.), The Basal Ganglia, Innovations in Cognitive

Neuroscience, DOI 10.1007/978-3-319-42743-0_7



135



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