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Neuroscience and Biobehavioral Reviews 36 (2012) 1030–1042

Contents lists available at SciVerse ScienceDirect

Neuroscience and Biobehavioral Reviews

journa l h o me pa g e: www.elsev ier .com/ locate /neubiorev

eview

he use of rodent skilled reaching as a translational model for investigatingrain damage and disease

lexander Kleina,∗,1, Lori-Ann R. Sacreyb,1, Ian Q. Whishawb, Stephen B. Dunnetta

Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, Wales, UKCanadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, Alberta, Canada

r t i c l e i n f o

rticle history:eceived 6 July 2011eceived in revised form6 December 2011ccepted 19 December 2011

eywords:arkinson’s diseaseuntington’s disease

a b s t r a c t

Neurological diseases, including Parkinson’s disease, Huntington’s disease, and brain damage caused bystroke, cause severe motor impairments. Deficits in hand use are one of the most debilitating motor symp-toms and include impairments in body posture, forelimb movements, and finger shaping for manipulatingobjects. Hand movements can be formally studied using reaching tasks, including the skilled reachingtask, or reach-to-eat task. For skilled reaching, a subject reaches for a small food item, grasps it withthe fingers, and places it in the mouth for eating. The human movement and its associated deficits canbe modeled by experimental lesions to the same systems in rodents which in turn provide an avenuefor investigating treatments of human impairments. Skilled reaching movements are scored using three

troketaircase testingle pellet reaching testotor impairmentsotor test

methods: (1) end point measures of attempts and success, (2) biometric measures, and (3) movementelement rating scales derived from formal descriptions of movement. The striking similarities betweenhuman and rodent reaching movements allow the analysis of the reach-to-eat movement to serve as apowerful tool to generalize preclinical research to clinical conditions.

Crown Copyright © 2012 Published by Elsevier Ltd. All rights reserved.

ehavioreach-to-eat

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10312. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1031

2.1. Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10312.2. Evaluation of skilled reaching . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1033

3. Skilled reaching in healthy humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10344. Skilled reaching in healthy rodents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10345. Comparison of rodent and human reaching . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10356. Skilled reaching in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1037

6.1. Skilled reaching in Parkinson’s disease subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10376.2. Skilled reaching in rodent models of Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1037

7. Skilled reaching in Huntington’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10387.1. Skilled reaching in Huntington’s disease subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10387.2. Skilled reaching in rodent models of Huntington’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1038

8. Skilled reaching in stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10398.1. Skilled reaching in stroke subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1039

8.2. Skilled reaching in rodent models of stroke . . . . . . . . . . . . . . . . . . . . . . . .

9. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author at: Brain Repair Group, School of Biosciences, Cardiff Universityel.: +44 2920 874112; fax: +44 2920 876749.

E-mail address: kleina@cardiff.ac.uk (A. Klein).1 These authors equally contributed to this project.

149-7634/$ – see front matter. Crown Copyright © 2012 Published by Elsevier Ltd. All rioi:10.1016/j.neubiorev.2011.12.010

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1039. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1040. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1040

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A. Klein et al. / Neuroscience and Bio

. Introduction

Translational research in neuroscience involves generalizingrom preclinical models to human disease. Generalizations fromreclinical behavioral models using rats and mice face the dif-culty that these species display behavioral specializations thatre very different from those of humans. This presents the prob-em that therapies developed in rodents may not generalize toumans. The difficulties in generalization can be reduced by devel-ping therapies using behaviors in the preclinical model that arehylogenetically and structurally similar to the target behavior inumans.

The purpose of the present review is to describe one such behav-or, skilled reaching. In skilled reaching, a subject reaches for aood item that is placed in the mouth for eating. It is a naturalehavior in humans and is the first complex behavior displayed byuman infants (Sacrey and Whishaw, 2010), used daily by adults,nd requires no special training. Both rats and mice can be trainedo display a similar behavior in which they reach for small pelletsf food under a regime of mild food deprivation. For both humansnd rodents, the behavior can be documented using high-speedideo recording and frame-by-frame replay. The behavior can thene measured using end point measures of success and failure, byinematics of the movement, and formal behavioral descriptions ofovement elements. Although there are differences in rodent and

uman reaching, there are many similarities suggesting that theehavior can serve as a powerful model for translational research.

Among the many motor impairments following neurologicalnsult in humans, the loss of manual dexterity, i.e. the skilledse of the hands, is one of the most debilitating. Impairments inkilled hand use are seen in many neurological conditions includ-ng Parkinson’s disease (PD; Whishaw et al., 2002; Sacrey et al.,009b), Huntington’s disease (HD; Klein et al., 2011), and strokeForoud and Whishaw, 2006; Harris-Love et al., 2011). Very sim-lar impairments in reaching movements are observed in rodent

odels of PD (Miklyaeva et al., 1994; Whishaw and Pellis, 1990;ontoya et al., 1990; Whishaw et al., 1986), HD (Dobrossy andunnett, 2001; Fricker-Gates et al., 2003; Whishaw et al., 2007),nd stroke (Gharbawie et al., 2005a, 2008; Whishaw et al., 1991);onsequently, the rodent model of skilled reaching has high facealidity (Cenci et al., 2002; Iwaniuk and Whishaw, 2000; Annettt al., 1995; Brooks and Dunnett, 2009). Additionally, experimen-al and ethical costs limit the use of primates for some preclinicalesearch experiments, hence recommending the use of rodents.

The following sections of this review will describe reaching inuman subjects and the use of rats and mice in modeling and inves-igating reaching deficits in the conditions of PD, HD, and stroke.he method for analyzing skilled reaching of humans and rodentsill be presented first, followed by descriptions of research on

killed reaching in PD, HD and stroke. Throughout the paper theerm hand is used for both rodents and humans following the con-entional practice of labeling to indicate the functional role of thergan (Whishaw et al., 2010).

. Methods

.1. Tests

Human subjects are tested in a quasi-natural testing situationn the laboratory or at home. Subjects are asked to sit comfort-bly in an armless chair with their feet flat on the floor and their

ands palm down on their thigh with their fingers extended (seeigs. 1 and 4). A pedestal is placed in front of the subject with heightnd distance normalized to each subjects’ trunk height and armength. A small food item (we use CheeriosTM) is placed on the

ioral Reviews 36 (2012) 1030–1042 1031

pedestal and the subject is asked to reach for the food item, grasp it,and bring it to the mouth for eating (Melvin et al., 2005; Whishawet al., 2002). CheeriosTM are used as the reaching target for two rea-sons: (1) they are easy to pick up with a pincer grasp, and (2) theywill dissolve when placed in the mouth to avoid potential chokinghazards in neurological subjects. Three to five reaches with eitherhand are sufficient for behavioral analysis and can be performedwithin a few minutes. Skilled reaching is video-recorded using stan-dard consumer or high speed cameras with a shutter speed set to1/1000 frames per second to produce a blur free image and is scoredusing frame-by-frame playback.

Skilled reaching in rodents is assessed using a number of tasks,two of which are the staircase test (Klein and Dunnett, in press;Baird et al., 2001; Montoya et al., 1991; Kloth et al., 2006; Nikkhahet al., 1998) and the single pellet reaching test (Klein and Dunnett,in press; Whishaw et al., 2008a,b, 1991; Farr and Whishaw, 2002;Metz and Whishaw, 2000). In the staircase test, rats are placed ina narrow box for a period of 15 min in which they are required toreach down from a central plinth for food pellets located on a stair-case. Mice require longer test sessions, typically 30 min, becausethey adopt a strategy of collecting one pellet at a time and retireto the back of the box to eat it (Baird et al., 2001), whereas ratstypically collect multiple pellets in a single visit to the staircasecorridor and eat them in situ. Because the food pellets are locatedon the stairs at varying distances, reaching for pellets placed fur-ther down requires a longer reach and a more skillfully coordinatedgrasp (Fig. 2). Normal rats will first attempt to retrieve pellets withtheir tongue, however, only the pellets located on the first (highest)step can be reached using the tongue, all other (lower) steps requireuse of the forearm (Montoya et al., 1991; Whishaw et al., 1997).Pellet collection by the tongue from the first step provides a simplemeasure in a disease model to examine if unilaterally lesioned ratsmaintain their basic motivation to respond in the test.

The staircase test is advantageous because performance mea-sures are objective, the test is easy to administer, and littlehabituation or training are required for the rats or mice to rapidlyacquire and successfully perform this task (Dobrossy and Dunnett,2003; Klein et al., 2007; Fricker-Gates et al., 2003). Moreover, akey feature of the staircase apparatus is that it is configured sothat the right forelimb can reach only for pellets on the right stair-case and the left forelimb for pellets on the left staircase, so thatthe performance of each forelimb can be measured independently,without additional constraint. Consequently, for unilateral modelsof neurodegenerative diseases, the affected limb can be contrastedwith the unaffected limb, and each animal serves as its own con-trol. The quantitative evaluation of reaching performance in thestaircase test can also be supplemented with qualitative analysisusing video recording technique that describes normal retrievalstrategies, compensatory movements following brain injury, andcheating (Whishaw et al., 1997). Furthermore, the sensitivity of thestaircase test can be increased by using color-coded food pellets,which allows the analysis of reaching strategies in addition to thepurely quantitative analysis of reaching success (Kloth et al., 2006).

For the single pellet reaching test (Fig. 3) rodents are filmedin a similar situation as used for humans: cameras with a shutterspeed set to 1/1000 frames per second to produce a blur free imageare used as a single reach can be less than one third of second inlength. Rats and mice are trained to go to the rear of a reachingbox, come back to the front, sniff through the slot to locate thepellet, advance their preferred forelimb through the slot, grasp thepellet, and withdraw their hand to bring the pellet to the mouth foreating. Thus, each reaching act is an individual event comprised of

(i) an approach to the food, (ii) postural adjustments in preparationfor reaching, (iii) the reach, (iv) grasping, and (v) withdrawal andconsumption of the food. Typically, a rat is given 20 trials each dayuntil they achieve success scores of 60–80%, but the procedure can

1032 A. Klein et al. / Neuroscience and Biobehavioral Reviews 36 (2012) 1030–1042

Fig. 1. (A) Lateral view of a subject before reaching for a food item. Please note the high-visibility markers attached to appendicular landmarks for kinematic analysis.Eye-movements are tracked by special goggles. Panel (B) displays a schematic view of the set-up of the reaching task. Panel (C) and (D) show superimposed images of acontrol and HD subject during a reach-to-grasp movement.

Images modified from Sacrey et al. (2009b) and Klein et al. (2011).

Fig. 2. (A) Rat on central plinth in the staircase box. Panel (B) displays typical results of a 15 min testing session of hemiparkinsonian rats with dopamine depletion in theirright hemisphere: the right stairs (ipsilateral to the lesion) have been nearly fully cleared, whereas the left stairs (contralateral to the lesion) have been neglected and only afew pellets from the top stairs have been eaten. The results show a clear bias toward the ipsilateral side and a severe reaching impairment on the contralateral side.

A. Klein et al. / Neuroscience and Biobehav

Fig. 3. Schematic view of the single pellet reaching test box (A). Panel (B) showsthe olfactory engagement with a food pellet and the body posture of a healthy ratbr

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efore initiating a reach. Panel (C) displays the arpeggio movement with which theat grasps the food.

mage modified from Metz and Whishaw (2000).

e varied to tailor the task to specific research goals (Gharbawiend Whishaw, 2006).

In contrast to human subjects, rodents do not use vision butlfaction to locate the food (Whishaw and Kolb, 2005). In addition,s they advance the hand toward the food, they raise their head, sohat the target is not in the line of vision and to allow passage of theand. For this reason the advance of the hand toward the food is

preprogrammed ballistic movement. This explains in part why aodent can miss the food or knock it away whereas a sighted humans almost always successful. Thus, reaching success in rodents is aseful measure of central motor planning. Many behavioral studiessing humans use a non-visual condition with a similar objectivesee Sacrey and Whishaw, 2011).

Motor deficits may severely impair use of the preferred limb innilateral models, thus the rodent may switch to its non-preferredand healthy) ipsilateral forelimb as a compensatory action. In thetaircase test, this is prevented by an experimental design thatorces use of both hands. For the single pellet task, application of aracelet prevents the use of the ipsilateral paw and reinforces these of the contralateral paw, enabling the measure of lesion out-ome or therapy (Whishaw et al., 1986). Thus, both tasks model theonstraint-induced therapy approach in humans in which the goodimb is restrained in order to force use of an affected limb (Tillersont al., 2001; Taub and Uswatte, 2003).

.2. Evaluation of skilled reaching

Skilled reaching can be evaluated by a number of measuresncluding assessments of reaching success, biometric measures thatescribe the kinematics of the movements, and by formal descrip-ions and ratings of the movement elements used in a reach. Each

f these measures will be briefly described.

. Reach success. For human skilled reaching and rodent skilledreaching in the single pellet reaching test, a reach trial is defined

ioral Reviews 36 (2012) 1030–1042 1033

as an attempt to obtain a food item. Trials are scored to deter-mine the number of attempts (individual approaches of thehand toward the food), successes (the food item is grasped andbrought to the mouth for eating), and misses, (the food itemis knocked off the shelf, dropped, or is not withdrawn to themouth). Results are commonly presented as percent successand compared either to baseline results or to a control group.Humans, even when impaired in making reaching movements,seldom fail to make a successful reach on a trial. Rodents, how-ever, are seldom successful on each trial but can achieve goodperformance of between 60 and 80% success with repetitivetraining. Interestingly, after brain injury, rodents may regainsuccess levels equivalent to normal performance as do humans,indicating that compensatory strategies are similarly success-fully by both rodents and humans. For the staircase test, in whichanimals retrieve food from a staircase, the number of food itemsobtained and eaten with each forelimb is the dependent measureand results are expressed as percent success rate.

2. Biomechanical measures. To track arm trajectory and velocity,human subjects wear biomechanical markers fitted to the reach-ing arm. The sensory control of the movement is examinedthrough the use of eye-tracking glasses to monitor eye move-ments before reach initiation, during the task, and after thefood has been placed in the mouth (de Bruin et al., 2008). Thedata from the biomechanical markers and eye-tracking glassesare time synchronized to determine the temporal relationshipbetween eye and arm movements. Similar biomechanical mea-sures can be made from rodents; their movements can bedigitized from the video record and kinematic results are recon-structed from the digitized X–Y coordinates (Whishaw et al.,2010).

3. Movement element rating. Reaching for both humans and rodentscan be described using conceptual approaches (for reviews seeForoud and Whishaw, 2006; Gharbawie and Whishaw, 2006;Metz and Whishaw, 2000; Whishaw et al., 2002, 2008a,b;Whishaw and Pellis, 1990) derived from Eshkol–WachmanMovement Notation (EWMN; Eshkol and Wachman, 1958) orLaban Movement Notation (LMN; Foroud and Whishaw, 2006).The notations developed for describing human dance have beenadopted to describe the movements of animals. A detaileddescription of the methods is beyond the scope of the presentreview, but briefly, the notations identify regularities in themovement of reaching and thus allow the behavior to be sub-divided into a number of movement elements. The elements inturn can be identified by frame-by-frame inspection of the videorecord. Following brain injury, many movement elements of thearm may be absent and substituted for by rotational movementsof the body (Melvin et al., 2005). Accordingly, a three point scaleis used to evaluate each movement element of each reach withscores of 0 = normal, 0.5 = abnormal, and 1 = absent. A summaryof movement elements and comparisons of the scoring scalesfor rodents and humans is presented in Tables 1 and 2. Scoringresults of the first three successful trials are expressed either asa total score (e.g. a skilled normal rat who performs the move-ment perfectly would score ‘0’, whereas a maximally impairedlesioned rat would score ‘1’). A ‘1’ signifies that a rodent or humanomits all normal elements of the movement and uses only com-pensatory strategies.

Finding landmarks for scoring limb segment locations can bedifficult in rodents as they have a pliable moving skin covered withfur. The analysis of the X-ray footage (Alaverdashvili et al., 2008a),

however, has confirmed that the element rating scale accuratelyestimates limb segment movements. There are strain differences inreaching performance, but such differences are easily incorporatedwithin the scoring systems by adding appropriate control groups

1034 A. Klein et al. / Neuroscience and Biobehavioral Reviews 36 (2012) 1030–1042

Table 1Movement element rating scale for rodents.

Rodent movement elements

Element Sub-element Description

1. Orient A. Head Head is raised until snout ispoking through the slot

B. Nose Nose locates the food target viasniffing

2. Lift A. Flex elbow Initial paw lift due to flexion ofelbow

B. Digits semi-flex Digits semi-flexC. Wrist supination Wrist supinates so palm is

aligned almost verticallyD. Digits to midline Tips of digits are aligned to the

midline of the body

3. Aim A. Elbow adduction Elbow adducts to perfect 90◦ atmidline; digits remain atmidline

4. Advance A. Limb advance Limb is advanced directlythrough the slot; digitspartially open

B. Snout Snout is raised to allowforearm passage through slot

5. Pronation A. Digits open/extend Digits open and extend directlyover food target

B. Full paw turn Digits perform arpeggiomovement as digits 5 throughdigit 2 touches the surface insuccession

C. Elbow extend Elbow open to full arm lengthas rat reaches

6. Grasp A. Power grasp Digits flex over food item andclose around it

B. Wrist extension Paw remains in place and wristextends slightly to lift the food

7. Supination A. Supination I As paw is withdrawn, itsupinates by almost 90◦

B. Supination II Once clear of slot, pawsupinates another 45◦ to bringfood to mouth

8. Release A. Paw contacts mouth Mouth contacts the pawB. Digits open Digits open to release the food

item into mouthC. Paw to floor Paw is placed on floor with

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Table 2Movement element rating scale for humans.

Human movement elements

Element Sub-element Description

1. Orient A. Head Head is moving freely thenfixes on target at beginning oftrial

B. Eye Eyes locate target prior tomovement of head/reach

2. Lift A. Flex elbow Initial hand lift is due to flexionof the elbow

B. Digits semi-flex Digits semi-flexC. Wrist supination Wrist supinates approximately

30◦

D. Digits to midline Tips of digits are broughttoward the midline of the body

3. Advance A. Limb advance Hand takes shortest path totarget

B. Hand ends at target Hand stops directly abovetarget

C. Trunk Trunk leans to the sideopposite reach as handapproaches the target

4. Pronation A. Digits open/extend Digits open and extend overthe food target

B. Full hand turn Knuckle on reaching handforms horizontal line

C. Elbow extend Elbow opens to full arm lengthas subject reaches

5. Grasp A. Pincer grasp Thumb and index finger graspfood item

B. Digits 3–5 independent Digits 3–5 remain still as graspis executed

C. Wrist extension Wrist extends to lift food itemfrom platform

6. Supination A. Supination I Reaching hand supinates 45◦

immediately after vertical liftB. Supination II Hand supinates another 45◦

when in close proximity tomouth

7. Release A. Hand contacts mouth Fingertips contact lips forplacement of food item inmouth

B. Digits open Digits open to release fooditem into mouth

C. Hand on lap Hand is placed on lap withfingers extended and palm

fingers extended OR onto wallof box

Klein and Dunnett, in press; Whishaw et al., 2003, 2008a,b; Kleint al., 2007).

. Skilled reaching in healthy humans

Healthy adults initiate a reaching movement by flexing thelbow to lift their hand from the lap (Figs. 1 and 4). The fingers begino close and semi-flex into a “collected” position as the forearmupinates approximately 30◦. The hand is transported toward theood item through movement of the upper arm and shifting of therunk in opposition to the reaching arm. As the hand approaches theood item, the elbow and fingers extend, and, as the wrist pronatesver the food item in preparation for grasping, the fingers open andreshape to grasp the food item. The grasp is made by the thumbnd forefinger in a pincer grip. The thumb and one of the other fin-ers or a combination of fingers may also be used. Fingers threehrough five may also close and flex as the pincer grasp is achieved.

he wrist then extends to lift the food item from the platform. Theand is supinated approximately 45◦ and the hand is withdrawn

rom the pedestal and then supinates an additional 45◦ as the handears the mouth. The thumb and forefinger touch the lips and open

downD. Trunk Trunk leans back toward

midline

to release the food item into the mouth, after which the hand isreplaced back at the start position on the lap.

Visual monitoring is tightly coupled to the transport phase ofthe reach. Healthy adults only visually engage the target food itemimmediately prior to, or concurrent with, the initiation of the trans-port movement. The eyes remain fixated on the target withoutblinking during hand transport. The target is visually disengagedby an upward deviation of the eye, or with an accompanying eyeblink, as the fingers contact the target food item. The eyes remainvisually disengaged from the food item and hand through the graspand return of the reaching hand on the lap (de Bruin et al., 2008).

4. Skilled reaching in healthy rodents

Rodent skilled reaching (Figs. 3 and 4) is similar to human

skilled reaching (Sacrey et al., 2009a; Whishaw et al., 1992). Nev-ertheless, as noted above, unlike human subjects who alwayspurchase the food item, rodents frequently miss the food item,additional performance measures of attempts, hits, and misses are

A. Klein et al. / Neuroscience and Biobehav

Fig. 4. (A) Frontal view of the skilled reaching task comparing a rat and a humansubject ready to initiate a reach-to-eat movement. The rat uses olfaction to orientits head toward the food pellet whereas the human subject uses vision to connectwa

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ith the food item. (B) Comparison of hand movements and digits shaping during reach-to-grasp movement (see text for further description).

mages modified from Sacrey et al. (2009a).

ecorded. The movement elements of a reach are scored using theame movement element scale used for humans (Gharbawie and

hishaw, 2006; Metz and Whishaw, 2000; Whishaw and Pellis,990). Reaching is also video-recorded and biometric measures ofhe movement are generated using digitizing systems with slow

otion playback.

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Rats initiate a reaching movement by approaching the slot atthe front of the box and by sniffing to locate the food pellet (ratsuse olfaction to detect food in contrast to humans who use vision).The movements of lifting, aiming, and advancing the limb are car-ried out mainly by the upper arm, with assistance from the elbow.In order to grasp the food, the limb is pronated by adduction ofthe upper arm and movement at the wrist, and the hand is placedinto grasping position with an arpeggio movement, in which fin-gers 5 through 2 are placed on the shelf. During the advance, thefingers are extended and during arpeggio they are opened. Grasp-ing is a discrete movement in which the fingers are flexed andclosed, and the target is grasped and lifted while the hand remainsin place. As the hand is withdrawn, it supinates by about 45◦, andas it approaches the mouth, it supinates a further 30◦ to place thefood proximal to the mouth. The fingers extend to release the foodto the mouth and the food is lapped up with the tongue or graspedwith the incisors. The limb is then replaced on the floor or on thefront wall of the box, and the rat walks to the back of the reachingbox to initiate a new trial.

5. Comparison of rodent and human reaching

As described above, the reaching movements of humans and ratsare similar. This is not surprising as they share similarities in bones,muscles, and neural control of limb movements (Cenci et al., 2002;Iwaniuk and Whishaw, 2000; Sacrey et al., 2009a). As rodents andprimates are sister clades (Iwaniuk and Whishaw, 2000; Whishawet al., 2008a,b; Whishaw and Kolb, 2005), their behavior, muscula-ture and skeletal structure, neuronal pathways, and cortical motororganization likely derive from a relatively recent common ances-tor (Sacrey et al., 2009a; Whishaw et al., 1992).

Nevertheless, there are differences between rodents and pri-mates (Whishaw et al., 2008a,b). First, corticospinal neurons makedirect connections with spinal motor neurons in humans, whereasthey connect mainly with interneurons in rodents. Second, themotor and somatosensory cortices are distinct brain regions in pri-mates, but overlap in rodents. Third, in primates, the basal gangliaare separated into distinctive caudate and putamen nuclei by theinternal capsule fibers, whereas there is a single ‘caudate–putamen’nucleus (also known as the ‘neostriatum’) in rodents. Fourth,rodents do not have a ball–socket joint in their shoulders as doprimates, and achieve shoulder movement via a scapula tetheredto muscles. Fifth, rodents have a fused radius and ulna, and somust pronate and supinate the hand using movements at the upperarm and wrist. Finally, humans and primates have opposed fin-gers and thumb allowing them to perform a pincer grasp, whereasrodents clasp objects between all fingers using an arpeggio move-ment or power grasp. These differences must be recognized whenconsidering rats as experimental surrogates for primates (includ-ing humans) for the purposes of basic research (Cenci et al., 2002;Whishaw et al., 2008a,b). Nevertheless, the similarities in the move-ments speak for the utility of using rodents as analogs to primatesin the study of skilled movement.

In Fig. 4B, a direct comparison of a rat and a human reach-to-grasp movement is presented, focusing on hand shaping, i.e. theposition of wrist and digits during (i) start, (ii) lift, (iii) advance, (iv)pronation and (v) grasp (Sacrey et al., 2009a). Wrist movements anddigit shaping appear to be very similar, although there were somedifferences, such as rats supinate their wrist further, bring theirhand to the center of the body, and use an arpeggio movement tograsp (whole hand) compared to the pincer grasp in humans. Atthe start of the reach, both humans and rats, have their digits open

and the hand rests on the lap or floor, respectively. Then, during lift,digits close and flex and the hand is lifted by upper-arm movements(not seen in the image). Furthermore, the hand supinates and thedigits point toward the center of the body. Next, during advance,

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Table 3Comparison of reaching deficits in humans and rodents and differences between human disease and rodent model.

Parkinson’s Huntington’s Stroke

Human Rodent Human Rodent Human Rodent

Cause idiopathicgenetic

toxictransgenic

genetic toxic(transgenic)

MCAOcortical/striatal

MCAO(+other surgicalmodels)cortical/striatal

Striatal (MSN) cell death − − +++ +++ +++/++/+ +++/++/+

Interneuron loss − − + + +++ ++

Nigral DA cell death +++ +++ + − +? +

Cortical cell death +/− − ++ +/− +++/++/+ +++/++/+

Progressive +++ +/− +++ + − −Orient impaired

prolonged visualengagement withtarget

normalolfactory

normal/impairedmajority of subjectsshows prolongedengagement withtarget

normalolfactory

visual* normalolfactory

Transport impairedslowed mov.; hand toolateral; shoulderdriven; no postural anddistaladjustments/rotation

impairedcompensatory posturaladjustments; abnormalelbow rotation anddistal limb mov.

impairedjerky; hand too lateral;shoulder/elbow driven;abnormal posturaladjustments androtatory mov.

impairedelbow too lateral,abnormal posturaladjustments and distalrotatory mov.

impairedtorso aids mov.initiation and limbadvance; no elbowextension; shoulderraises to supinate andlift hand

impairedfull body mov. to liftand advance hand;abnormal posture andbody weight shift

Grasp impairedabnormal pincer grasp;no pronation; fingersnot open

impairedabnormal power grasp;no or little pronation

impairedabnormal pincer grasp;hand shaping too early;abnormal pronation

mildly impairedpower grasp but handmoves too quickly

impairedabnormal pincer graspand pronation

impairedpower grasp; abnormalrotatory mov.

Withdrawal/release impairedno distal limb mov.;elbow aids to supinatehand

impairedabnormal distal limbmov.; exaggeratedshoulder/body mov.

impairedno distal limb mov.;elbow aids to supinatehand; head mov.supports release

impairedno distal limb mov.;elbow/snout aid tosupinate hand andrelease pellet

impairedtorso, shoulder andhead aid withdrawaland release; no distalmov. and rotation

impairedabnormal body weightshift; no supination;digits closed;difficulties to opendigits

(*) There is currently no data about visual impairments of stroke subjects during reaching available; (?) under debate; MSN: medium spiny neurons; DA: dopamine; MCAO: middle cerebral artery occlusion; mov.: movement.

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he digits flex and the hand is lifted in an aiming position toward theood item. Then, during pronation, the digits open and pronate overhe food. Finally, during grasp, digits flex and close around the foodtem. Human subjects, however, use digits 1 and 2 for grasping theood item (pincer grasp), whereas rats use the whole hand (powerrasp). A comprehensive description of the major reaching deficitsn humans and rodents and differences between human diseasend rodent models are presented in Table 3.

In conclusion, it is important to note that for scoring reaching inoth rodents and humans, the movement can be parsed in a numberf different ways (see Gharbawie and Whishaw, 2006). The skilledeaching movement can be viewed as learned act that combines aumber of submovements such as hand advance and hand with-rawal, and so behavioral measures may be tailored to the analysisf motor learning. The movement depends upon both sensory andotor control and so possible impairments following brain injuryay measure sensorimotor integration. Finally, the movement may

e viewed in terms of elementary movements of joint segmentsllowing a refined measure of motor control.

. Skilled reaching in Parkinson’s disease

.1. Skilled reaching in Parkinson’s disease subjects

PD symptoms are mainly caused by the degeneration ofopamine producing neurons in the substantia nigra (Albin et al.,989). This reduction of nigrostriatal dopamine (DA) results inevere motor symptoms, such as akinesia, tremor, postural imbal-nce, and deficits in skilled forelimb use, as well as impairmentso the sensory systems (Marsden, 1990; Rodter et al., 2000; Sacreyt al., 2009b). These pathological changes can be partially replicatedn rodents using different neurotoxins and routes of applicationCenci et al., 2002; Dunnett and Lelos, 2010).

PD subjects initiate a reaching movement by flexing the wristo lift the hand from the lap. Following lift, the fingers seldom closer semi-flex and the hand does not supinate but rather is passivelyifted from the lap. The hand is transported toward the food item in aegmented manner (i.e., x then y planes rather than one smooth tra-ectory) and the approach is typically from the side, in part from theircumduction of the shoulder and the absence of postural adjust-ent to bring the hand to the correct location above the target. As

he hand approaches the food item, the elbow extends to open therm. The fingers do not open and extend, nor pronate over the foodtem, but rather the fingers semi-flex to provide ample room forhe thumb and forefinger to purchase the food item. The food items grasped using a pincer grasp; however, the thumb and forefingero not close around the item independently as fingers 3 through 5lso close.

For withdrawal of the food to the mouth, the elbow extends toift the food item from the platform and the hand is withdrawnoward the mouth with little to no supination of the hand. Thelbow rotates out to bring the hand to the mouth, and for someubjects, the hand is dropped to the lap before the food item isransported to the mouth. As the hand approaches the mouth, theres again little or no supination, and the food item is released intohe mouth with the hand oriented in such a way that the fingers aret the side of the mouth rather than directly in front of it. Followingelease of the food item into the mouth, the hand is returned backo the lap. Through the course of the movement, the hand does notupinate and the fingers do not open and extend, but rather theand rests on the lap in a loose fist (Sacrey et al., 2011; Whishawt al., 2002). The elements of the movement are exaggerated with

isease progression, as movement becomes more rigid and moreradykinetic (Sacrey et al., 2009b).

Visual engagement with the target is exaggerated in PD. PD sub-ects engage the target food item prior to the initiation of forelimb

ioral Reviews 36 (2012) 1030–1042 1037

movement. Advanced PD is associated with staring at the platformboth before the food item has been placed there and after it has beenplaced on the pedestal. For both mild and advanced PD subjects,the eyes remain fixated on the target as the hand is transportedtoward the target and as it is grasped by the fingers. The eyes visu-ally disengage from the food item with an upward deviation of theeyes or with an accompanying eye blink as the target is withdrawnapproximately half way to the mouth (Sacrey and Whishaw, 2010).The effect of PD on visual attention of the skilled reaching task isexaggerated with disease progression, as more advanced patientsshow an increased visual fixation on the target both before theyinitiate a reaching movement toward the food item and after it hasbeen grasped (Sacrey et al., 2009a).

Skilled reaching in PD subjects has been assessed under differingtherapeutic regimens to determine the benefits of each treatmenton skilled reaching. Medication (Melvin et al., 2005; Sacrey et al.,2011), pallidal deep brain stimulation (Melvin et al., 2005), andaccompanying preferred music (Sacrey et al., 2009b, 2011) do notimprove execution of the skilled reach-to-eat task. By contrast, sub-thalamic stimulation does have a slight positive effect on reaching,although the effects are small (Doan et al., 2008). Interestingly,medications and accompanying preferred musical pieces affectvisual attention in that both treatments normalize visual attentionto the same level as healthy adult controls (Sacrey et al., 2009b,2011).

6.2. Skilled reaching in rodent models of Parkinson’s disease

Parkinson’s disease can be modeled in the rat using unilateral orbilateral intrastriatal stereotactic injections of 6-hydroxydopamine(6-OHDA) into the medial forebrain bundle. PD-like symptoms inthe lesioned rat include postural instability (Wolfarth et al., 1996),shuffling gait (Klein et al., 2009), sensorimotor impairments (Rodteret al., 2000) and skilled reaching deficits (Miklyaeva et al., 1994;Whishaw et al., 1986; Faraji and Metz, 2007; Klein et al., 2007).The drawback of the bilateral model is that rats exhibit profoundaphagia and adipsia as a result of bilateral forebrain dopaminedepletion, requiring prolonged intensive nursing care to keep italive (Zigmond and Stricker, 1972). Therefore, the unilateral injec-tion of 6-OHDA into the medial forebrain bundle, producing an‘hemiparkinsonian’ rat, is most commonly used; such unilaterallesions induce sensory and motor impairments on the side of thebody contralateral to the site of injection in the brain, althoughthe ipsilateral side can also show impairment. The unilateral lesionleaves sensorimotor function largely intact on the ipsilateral sideof the body, so that the animal can maintain normal health. Theunaffected side of the body also serves as a partial control forthe impairments of the contralateral side (Miklyaeva et al., 1994;Vergara-Aragon et al., 2003; Klein et al., 2007; Dunnett and Lelos,2010).

In order to match animals to groups, animals may be pre-trainedand tested prior to surgery, and then the 6-OHDA injection orsham treatment is applied to the hemisphere contralateral to eachrats’ preferred paw, reducing variance and maximizing experimen-tal power (Miklyaeva et al., 1994; Nikkhah et al., 2001). Animalswith a unilateral DA depletion develop a rotatory bias towardthe ipsilateral side and a nearly complete sensorimotor neglectof the contralateral side. Spontaneous behavior and gait are alsoimpaired (Klein et al., 2009; Olsson et al., 1995; Schallert and Hall,1988; Vergara-Aragon et al., 2003). Reaching trajectories and suc-cess of both paws are impaired in the unilateral model, althoughthe deficit is much more pronounced on the contralateral side

(Vergara-Aragon et al., 2003; Abrous et al., 1992).

The qualitative analysis of reaching performance of hemiparkin-sonian rats as assessed by the movement element reaching scaleshows that there are many impairments in the precise execution of

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killed movement, even when animals are successful in retrievinghe pellets. The most severe impairments are in the rotatory move-

ents of the hand, in pronating the hand over the food for grasping,nd in supinating the hand in order to bring the food to the mouthnd release it for eating. Independent pronation and supinationf the hand are nearly absent, but success is achieved by com-ensatory body and head rotation. Grasping is also impaired andrequently abnormal as the reaching hand is inaccurate in place-

ent on the food. These deficits in movement patterns show a highegree of similarities with PD subjects (Sacrey et al., 2009b, 2011;hishaw et al., 2002).Reaching behavior has also been investigated in other rodent

odels of PD. The peripheral injection of 1-methyl-4-phenyl-,2,3,6-tetrahydropyridine (MPTP) in the mouse results in loss ofAergic cells in both hemispheres and causes PD-like symptomsnd similar deficits as described above. By contrast, the MPTP modelf PD is not commonly used for rat studies of PD, as this species iselatively insensitive to the toxin, in comparison with mice (Cencit al., 2002).

. Skilled reaching in Huntington’s disease

.1. Skilled reaching in Huntington’s disease subjects

HD is an autosomal dominant genetic disorder in which frag-ents of the mutated huntingtin protein misfold and accumulate

s proteinaceous deposits, primarily in the medium spiny neuronsMSNs) of the striatum and associated areas of neocortex. Thesetriatal MSNs are part of the basal ganglia network that is crucialor executing skilled limb movements (Graybiel, 1990, 2000; Albint al., 1990). HD causes severe motor impairments affecting thehole body including disruption of skilled forelimb use. HD is also

haracterized by jerky and choreic movements. The primary causeor these involuntary movements is a loss of GABAergic MSNs inhe striatum, although early cortical dysfunction has been reporteds well (Hobbs et al., 2010). During the course of the disease, thentire brain becomes affected, causing significant brain tissue atro-hy and generalized cell loss. These neurodegenerative processesesult in severe cognitive and psychiatric impairments, in additiono the motor deficits.

Huntington’s disease (Fig. 1D) subjects initiate a reaching move-ent by passively lifting their hand from their lap through flexing

nd abducting the elbow and rotation of the shoulder (Klein et al.,011). Lifting of the hand from the lap is not associated with semi-exion of the fingers or supination of the hand, but rather theand is passively supinated as it is lifted off of the lap. The hand

s transported toward the target food item through compensatoryontraversive movement of the trunk and shoulder, and theseovements of the arm and shoulder tended to be exaggerated so

hat the reaching hand approached the target platform from a moreateral position than healthy adults. HD subjects do preshape theirngers for grasping, but finger shaping occurs at an incorrect tem-oral location during the reach. The majority of subjects shape theirngers too early in the reaching movement, often just as the hand

s reaching toward the platform, while a small minority shape thengers for grasping as they reach the food item. Additionally, theon-grasping fingers (fingers 3–5) are not semi-flexed and closeds seen in healthy adults, but are open and extended or closed andexed to an exaggerated extent. During the grasp, however, HDubjects do grasp the target food item with the thumb and indexnger and close the other fingers. Nevertheless, for a majority ofD subjects the fingers display abnormal postures and fingers 3–5

erve as leverage on the pedestal to assist with grasp.To withdraw the food to the mouth, the food item is lifted from

he platform through adduction of the elbow and the hand showsittle to no supination immediately following lift of the food item

ioral Reviews 36 (2012) 1030–1042

off the target pedestal. The hand is brought to the mouth throughadduction of the elbow and shows little supination to bring the fooditem to meet the mouth. Instead, the head moves to compensateand meets the food item for release of the food item into the mouth.Reaching in more severe (choreatic) HD subjects is associated witha break in the withdrawal movement, in that the hand is often low-ered to the lap following lift of the food item off the pedestal beforeit is brought to the lips for release of the food item into the mouth.Release of the food item into the mouth is also impaired in HD.The majority of HD subjects place their fingers into the mouth andclose their lips around the fingers to assist the release of the foodinto the mouth. Following release of the food piece, these subjectsalso lower their hand to the lap but the trajectory the hand takes tothe lap can be quite variable. Thus, the fingers might first contactthe lap, and then body posture and the hand is adjusted to takea start position on the lap; the HD subjects may push their handsagainst the lap in an apparent strategy to support the upright trunk;or they may wrap their hands around their midsection and flex thetrunk forward.

Visual engagement with the target food item is variable for HDsubjects. A minority of HD subjects orient toward the target in thesame way as healthy adults, in that they look at the food itemjust prior to movement onset. The majority of HD subjects, how-ever, show prolonged visual engagement with the target food itemprior to movement onset. Visual fixation during transport of thehand to the target food item is also variable. A minority of HD sub-jects disengage from the target during transport, but reengage thetarget before the fingers contact it. Visual engagement with thetarget food item continues to vary at the grasp. A minority of HDsubjects visually disengage from the target food item in the sameway as do healthy adults, that is they look away as the target fooditem is contacted by the tips of the fingers. The majority of HDsubjects continue to look at the target food item as it is graspedand withdrawn for placement into the mouth. The impairmentsin visual engagement displayed by HD subjects are not obviouslyrelated to their standardized Unified Huntington’s Disease Rat-ing Scale scores or the severity of their movement impairments(Klein et al., 2011).

7.2. Skilled reaching in rodent models of Huntington’s disease

As for many other genetic disorders, genetically modified mousestrains have been developed and have contributed to considerableprogress in understanding pathogenic mechanisms in HD. In par-ticular, HD transgenic mice exhibit marked deficits in cognition,motor learning, and basic motor behavior (Brooks and Dunnett,2009). Skilled limb use has not yet been fully analyzed in trans-genic mouse models, but only in the more established excitotoxiclesioned rat on which the following section will focus.

The majority of studies have modeled HD through the use ofunilateral stereotaxic injections of excitotoxic amino acids (EAA,e.g. kainic, ibotenic or quinolinic acids) into the striatum, resultingin a selective degeneration of MSNs. As a result, EAA-lesioned ratsshow motor deficits, such as a rotational bias, a mild increase ingrip strength (Jeyasingham et al., 2001), impaired spatial orien-tation (Block et al., 1993), impaired skilled reaching (Whishawet al., 1986, 2007; Dobrossy and Dunnett, 2005b), and cognitivedeficits in maze operant and operant delayed response tasksdependent upon frontostriatal function (Dunnett et al., 1999;Divac et al., 1978). Although there are transgenic rat models ofHD (von Horsten et al., 2003), the motor deficits in these ratstrains are rather variable and slow to develop. The analysis of

skilled reaching failed to reveal stable impairments (Fielding et al.,2011) making the transgenic rat model less suitable for detailedevaluation of impairments in skilled limb use and potentialtherapies.

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Quantitative analysis of reaching deficits in the staircase test forhe unilateral excitotoxic lesion model reveals impaired reachinguccess for EAA-lesioned rats compared to control rats (Montoyat al., 1990; Dobrossy and Dunnett, 2005b). Interestingly, in con-rast to the hemiparkinsonian rat model, the unilateral EAA lesionlso induces an obvious deficit in skilled reaching on the (healthy)psilateral side (Whishaw et al., 1986; Jeyasingham et al., 2001).he authors speculate that the EAA lesion has greater destabiliz-ng effects on postural imbalance, which, in turn, reduces reachinguccess. Furthermore, it seems that the degree of reaching deficitsepends on the placement of the EAA injection within the striatum.hishaw et al. (2007) report slightly improved reaching success

n the single pellet reaching test after medial EAA injections andecreased reaching success after lateral EAA injection. The authorsuggest that a focal lesion, such as the medial EAA lesion, can disruptompeting neuronal pathways that are activated to process infor-ation during skilled reaching. If one of the pathways is disrupted,

thers may take over, resulting in better motor performance and aorresponding increase in reaching success (Whishaw et al., 2007).nterestingly, the qualitative assessment by the movement elementating scale was not affected by the placement of the lesion imme-iately after the lesion, but only animals with lateral lesions werehronically impaired.

Reaching performance in HD rats benefits from motor training,ousing conditions, as well as from neurorestorative approaches.ontinuous training and enriched environment result in improvedeaching success rate (in both lesion and graft rats), and intrastri-tal whole ganglionic eminence-derived grafts are able to increaseeaching success in a transplantation paradigm (Dobrossy andunnett, 2001, 2005a). Fricker-Gates et al. (2003) investigated theffect of pre-training of EAA-lesioned rats in the staircase test andhowed that there is no difference in end-point measurementsreaching performance was equally impaired with or without pre-raining after 28 days of testing), but suggest that pre-training isecommended because it reduces performance variability. This ismportant in behavioral studies, as a high variance in performance

ill mask beneficial or detrimental effects in any experimentalaradigm.

The qualitative analysis of reaching performance in rats with anilateral EAA lesion reveals impairment in transport of the handWhishaw et al., 2007). Chronic impairments are also reported forotatory movement during aiming, pronating, and supinating of theorelimb, with supination most affected. Some of these deficits inhe rat are transient, and of the transient deficits, neglect of theood once grasped suggests either a sensory deficit in hapsis or annability to link the advance and withdrawal movements into a suc-essful reach. These impairments are similar to impairments seen inumans with HD (Klein et al., 2011). This validates the EAA lesionodel as a good model for investigating some aspects of skilled

eaching in HD research.

. Skilled reaching in stroke

.1. Skilled reaching in stroke subjects

Stroke has a unique position in neurodegenerative research, ast is not limited to one transmitter system or area, and there areo progressive neurodegenerative disease mechanisms involved.troke is defined as a sudden disturbance of blood supply to therain which can be caused by ischemia (thrombosis) or hemorrhagerupture of a blood vessel or by traumatic brain injury), elicitingn acute inflammatory response and secondary cascade of neu-

odegenerative processes leading to cell death within weeks andonths after the insult. The behavioral outcome is highly variable

Alaverdashvili et al., 2008b; Whishaw et al., 2008a,b). In partic-lar, symptoms of stroke depend on the site and the extent of

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brain damage, and can be severely disabling, causing impairmentsin sensorimotor, motor, and cognitive tasks. Skilled reaching instroke patients has been described using the movement elementrating scale and other notation scales (Foroud and Whishaw, 2006,2010). Depending on lesion location, impairments and compen-satory strategies for reaching with either hand occur followingstroke in many different brain regions (Foroud and Whishaw, 2006,2010; Michaelsen et al., 2004; Roby-Brami et al., 2003). Reachingfor small food items by stroke subjects is characterized by severalextraneous gestural inclusion (i.e., extra movements not neces-sary to complete the movement) and body-postural compensationfor impaired arm extension and distal motor control (Foroud andWhishaw, 2006, 2010; Roby-Brami et al., 2003). Thus, one of themajor difficulties in studying the effects of stroke on a complexfunction like skilled reaching is the variable extent and locus ofdamage and the highly variable levels of deficit and recovery thatresult.

Nevertheless, some consistent features may be observed. Strokesubjects may initiate a reaching movement with their torso as thehand is passively lifted from the lap through torso rotation. Thehand is carried forward toward the target pedestal by raising thehand as the torso leans forward (Foroud and Whishaw, 2006). Theelbow does not extend to bring the hand to the target, but the torsoraises and leans forward and the shoulder elevates and supinatesto raise the hand above the target. The hand is oriented with thepalm rotated downward in order to facilitate closure of the fingersaround the target object (Foroud and Whishaw, 2010; Roby-Bramiet al., 2003). After the target is grasped, stroke subjects will leanforward and rotate their torso to slide their hand from the pedestal.The hand is then brought toward the mouth by lifting the torso andleaning back, elevating the shoulder to raise the arm, and loweringthe head to meet the hand and release the food item. Thus, thenormal movements of reaching are supplemented with a variety ofcompensatory movements largely dependent upon the use of moreproximal body parts including the shoulder and trunk.

The ipsilateral limb is usually affected in stroke patients as well.That is, the movement elements of aim, supination, and advanceare abnormal compared to healthy controls (Foroud and Whishaw,2010). These impairments are not necessarily the result of deficitsin movement patterns generation on the contralateral (less affectedor healthy) hemisphere, but of abnormal synergy between trunkand limb elicited by the motor dysfunction on the ipsilateral side.

A recent study (Harris-Love et al., 2011) investigating theexcitability of primary motor cortex (M1) in severely impairedstroke subjects using transcranial magnetic stimulation (TMS)revealed beneficial effects of reach training. All subjects showedlesions sparing M1, yet all participants had severely disablingmotor symptoms. Interestingly, despite a macroscopically intactM1, neurophysiological dysfunction of this area was recorded. Theauthors discovered a link between training-induced improvementand training-specific modulation of intrahemispheric mechanismsfollowing reach training. Considering physiotherapy is a standardtherapeutic approach following stroke (Dobkin, 2008; Dobrossyet al., 2010), reach training may translate into post stroke therapy,rather than being a tool for examining motor deficits.

8.2. Skilled reaching in rodent models of stroke

Motor impairments in stroke can be reproduced in rodent mod-els of the disease (DeVries et al., 2001). As these models requireinvasive surgery, the rat rather than the mouse (Bouet et al., 2007),serves as the most common model for stroke research, including

examination of skilled reaching. Models to investigate reach-to-eatmovements under ischemic conditions include lesion to the motorcortex or middle cerebral artery occlusion (MCAO) models to cre-ate focal lesions in subcortical (basal ganglia) and cortical brain

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reas (Gharbawie and Whishaw, 2006; Alaverdashvili et al., 2008b;rabowski et al., 1993; Ploughman et al., 2007; Colbourne et al.,000; Allred et al., 2010).

MCAO lesions in the rat results in lasting impairments in reach-ng success in the staircase test (Marston et al., 1995). Nevertheless,eaching performance can be improved by rehabilitation trainingPloughman et al., 2007) or pre-training (Grabowski et al., 1993),uch that, with repeated motor training, post-stroke success per-ormance can reach near-normal levels. This is in line with thebservations that, after cortical stroke, rats develop a transientuccess impairment that can recover to nearly pre-lesion perfor-ance. This is consistent with findings in human stroke patients,ho, although suffering permanent disabling motor deficits, canevelop strategies to successfully complete a reach (Johansson,000). The qualitative analysis of reaching performance in bothtroke models displays permanent impairments in finger flexion,ensory abnormalities, rotatory movements of the wrist (prona-ion/supination), pellet withdrawal and release into the mouth, asell as in compensatory movement patterns, such as rotation of

he trunk to assist limb movements (Alaverdashvili and Whishaw,010; Gharbawie et al., 2005a; Gharbawie and Whishaw, 2006;hishaw et al., 2008a,b).Similar to human studies (see above), motor cortical plastic-

ty in rat skilled reaching has been investigated before and aftertroke using intracortical microstimulation (ICMS; Gharbawie et al.,005b). The authors report dysfunctional neurophysiological char-cteristics surrounding M1, in a stroke model that spared M1rom lesion. Although the cortical forelimb representation of M1emained disturbed and qualitative assessments of movementlements continued to display impairments after extensive post-urgery reach training, the success rate of consuming food pelletsmproved to normal levels. This underlines that skilled reachingraining can, in fact, improve motor performance and induce plas-icity in the brain (Whishaw et al., 2008a,b; Nudo et al., 1996).

Not all of the aforementioned symptoms are necessarily seenn motor cortex stroke or MCAO. The degree of skilled reachingmpairments depends on lesion location and size. Hence, care-ul choice of stroke model is imperative. Furthermore, long-termbservations may be influenced by (naturally) transient impair-ents, and by the ability of rats to recover from ischemic insults.

his could mask underlying effects in neurorestorative studies.

. Discussion

Skilled reaching serves as a powerful method in translationalesearch. This review has presented a rodent model of skilled reach-ng that can serves as a homologue to human reaching for food.tudies of rodent and human reaching suggest that the behaviors similar in normal humans and intact animals. The similarity inurn suggests that the behavior can serve as a model for inves-igating impairments and treatments of human disease. Therefore,valuating skilled reaching in rodents can offer a tool in pre-clinicalesearch to measure functional effects of new therapies: motoreficits and therapeutic benefits can be directly translated fromodent to human behavior.

The staircase test efficiently analyzes reaching success provid-ng simple objective quantitative data, while allowing multipleats to be tested simultaneously. By contrast, the movement ele-ent analysis in the rodent single pellet reaching task provides

rucial qualitative information about body posture and reachingtrategies that can be easily translated into human reach-to-eatovements. The evaluation of human reaching in a real-world

each-to-eat paradigm discloses important information aboutotor and postural deficits in patients suffering from neurodegen-

rative diseases. Taken together, the application of skilled reachingn rodent and human studies is a helpful tool for measuring

ioral Reviews 36 (2012) 1030–1042

detrimental or beneficial effects of disease or therapy, respectively.Furthermore, there is evidence that skilled reaching training initself improves motor symptoms and induces cortical plasticityand may therefore become part of rehabilitation approaches inneurodegenerative disease.

This review has not been directed to describing the neural mech-anisms that mediate skilled reaching in rodents and humans. It isimportant to recognize that skilled reaching is likely a compos-ite movement in which the transport component of the reach andthe withdrawal component of the reach are partially different. Inrodents, the transport component of reaching is a ballistic move-ment that is organized on the basis of olfactory detection of thefood. For humans, hand transport is guided by vision. For bothrodents and humans, the withdrawal component of skilled reach-ing is guided by somatosensory information (Sacrey and Whishaw,2011). Investigations of motor cortex organization of movementalso suggest that hand transport is mediated by a more dorsallylocated region of motor cortex and hand withdrawal to the mouthis mediated by a more ventrally located region of motor cortex(Karl et al., 2008; Whishaw et al., 2008a,b). This complexity doesnot detract from the use of the rodent analogue of skilled reachingfor investigating human disease, but rather suggests that poten-tial therapies for improving transport and withdrawal might bedifferent. The richness of the behavior of skilled reaching andits similarities in rodent models and humans recommends theanalogue as a promising behavioral model for investigating thetreatment of human neurological impairments. As present andfuture research on therapeutic approaches to recovery of brainfunction after disease and injury will continue to feature genetic,biochemical, and cellular manipulations, the similarities in thesubstrates and behavior in rodents and primate will simplify trans-lational generalization.

Acknowledgments

AK and SBD thank the Medical Research Council, UK, the CHDIFoundation, and the EU FP7 REPLACES (EC contract number 222918FP7 – Thematic priority HEALTH) and EU FP7 NeuroStem programsfor their financial support; IQW and LAS thank the Alberta Her-itage Foundation for Medical Research and the Natural Sciencesand Engineering Research Council of Canada.

Author contributions: A.K. and L.-A.R.S. contributed equally topreparing the original outline and in writing the first draft of thetext, as well as in finalizing the manuscript for submission. S.B.D.and I.Q.W. contributed equally in finalizing the manuscript for sub-mission.

References

Abrous, D.N., Wareham, A.T., Torres, E.M., Dunnett, S.B., 1992. Unilateral dopaminelesions in neonatal, weanling and adult rats: comparison of rotation and reachingdeficits. Behav. Brain Res. 51, 67–75.

Alaverdashvili, M., Leblond, H., Rossignol, S., Whishaw, I.Q., 2008a. Cineradiographic(video X-ray) analysis of skilled reaching in a single pellet reaching task providesinsight into relative contribution of body, head, oral, and forelimb movement inrats. Behav. Brain Res. 192, 232–247.

Alaverdashvili, M., Moon, S.K., Beckman, C.D., Virag, A., Whishaw, I.Q., 2008b. Acutebut not chronic differences in skilled reaching for food following motor cor-tex devascularization vs. photothrombotic stroke in the rat. Neuroscience 157,297–308.

Alaverdashvili, M., Whishaw, I.Q., 2010. Compensation aids skilled reaching in agingand in recovery from forelimb motor cortex stroke in the rat. Neuroscience 167,21–30.

Albin, R.L., Reiner, A., Anderson, K.D., Penney, J.B., Young, A.B., 1990. Striatal andnigral neuron subpopulations in rigid Huntington’s disease: implications for thefunctional anatomy of chorea and rigidity-akinesia. Ann. Neurol. 27, 357–365.

Albin, R.L., Young, A.B., Penney, J.B., 1989. The functional anatomy of basal gangliadisorders. Trends Neurosci. 12, 366–375.

Allred, R.P., Cappellini, C.H., Jones, T.A., 2010. The good limb makes the bad limbworse: experience-dependent interhemispheric disruption of functional out-come after cortical infarcts in rats. Behav. Neurosci. 124 (1), 124–132.

behav

A

B

B

B

B

C

C

d

D

D

D

D

D

D

D

D

D

D

D

E

F

F

F

F

F

F

G

G

G

G

G

A. Klein et al. / Neuroscience and Bio

nnett, L.E., Torres, E.M., Ridley, R.M., Baker, H.F., Dunnett, S.B., 1995. A comparisonof the behavioural effects of embryonic nigral grafts in the caudate nucleus andin the putamen of marmosets with unilateral 6-OHDA lesions. Exp. Brain Res.103, 355–371.

aird, A.L., Meldrum, A., Dunnett, S.B., 2001. The staircase test of skilled reaching inmice. Brain Res. Bull. 54, 243–250.

lock, F., Kunkel, M., Schwarz, M., 1993. Quinolinic acid lesion of the striatum inducesimpairment in spatial learning and motor performance in rats. Neurosci. Lett.149, 126–128.

ouet, V., Freret, T., Toutain, J., Divoux, D., Boulouard, M., Schumann-Bard, P., 2007.Sensorimotor and cognitive deficits after transient middle cerebral artery occlu-sion in the mouse. Exp. Neurol. 203, 555–567.

rooks, S.P., Dunnett, S.B., 2009. Tests to assess motor phenotype in mice: a user’sguide. Nat. Rev. Neurosci. 10, 519–529.

enci, M.A., Whishaw, I.Q., Schallert, T., 2002. Animal models of neurological deficits:how relevant is the rat? Nat. Rev. Neurosci. 3, 574–579.

olbourne, F., Corbett, D., Zhao, Z., Yang, J., Buchan, A.M., 2000. Prolonged but delayedpostischemic hypothermia: a long-term outcome study in the rat middle cere-bral artery occlusion model. J. Cereb. Blood Flow Metab. 20, 1702–1708.

e Bruin, N., Sacrey, L.A., Brown, L.A., Doan, J., Whishaw, I.Q., 2008. Visual guid-ance for hand advance but not hand withdrawal in a reach-to-eat task in adulthumans: reaching is a composite movement. J. Mot. Behav. 40, 337–346.

eVries, A.C., Nelson, R.J., Traystman, R.J., Hurn, P.D., 2001. Cognitive and behav-ioral assessment in experimental stroke research: will it prove useful? Neurosci.Biobehav. Rev. 25, 325–342.

ivac, I., Markowitsch, H.J., Pritzel, M., 1978. Behavioral and anatomical conse-quences of small intrastriatal injections of kainic acid in the rat. Brain Res. 151,523–532.

oan, J.B., Melvin, K.G., Whishaw, I.Q., Suchowersky, O., 2008. Bilateral impairmentsof skilled reach-to-eat in early Parkinson’s disease patients presenting withunilateral or asymmetrical symptoms. Behav. Brain Res. 194, 207–213.

obkin, B.H., 2008. Training and exercise to drive poststroke recovery. Nat. Rev.Neurol. 4, 76–85.

obrossy, M., Busse, M., Piroth, T., Rosser, A., Dunnett, S., Nikkhah, G., 2010. Neu-rorehabilitation with neural transplantation. Neurorehabil. Neural Repair 24,692.

obrossy, M.D., Dunnett, S.B., 2001. The influence of environment and experienceon neural grafts. Nat. Rev. Neurosci. 2, 871–879.

obrossy, M.D., Dunnett, S.B., 2003. Motor training effects on recovery of functionafter striatal lesions and striatal grafts. Exp. Neurol. 184, 274–284.

obrossy, M.D., Dunnett, S.B., 2005a. Optimising plasticity: environmental andtraining associated factors in transplant-mediated brain repair. Rev. Neurosci.16, 1–21.

obrossy, M.D., Dunnett, S.B., 2005b. Training specificity, graft development andgraft-mediated functional recovery in a rodent model of Huntington’s disease.Neuroscience 132, 543–552.

unnett, S.B., Lelos, M., 2010. Behavioral analysis of motor and non-motor symptomsin rodent models of Parkinson’s disease. Prog. Brain Res. 184, 35–51.

unnett, S.B., Nathwani, F., Brasted, P.J., 1999. Medial prefrontal and neostriatallesions disrupt performance in an operant delayed alternation task in rats.Behav. Brain Res. 106, 13–28.

shkol, N., Wachman, A., 1958. Movement Notation. Weidenfeld and Nicholson,London.

araji, J., Metz, G.A., 2007. Sequential bilateral striatal lesions have additive effectson single skilled limb use in rats. Behav. Brain Res. 177, 195–204.

arr, T.D., Whishaw, I.Q., 2002. Quantitative and qualitative impairments in skilledreaching in the mouse (Mus musculus) after a focal motor cortex stroke. Stroke33, 1869–1875.

ielding, S.A., Brooks, S.P., Klein, A., Bayram-Weston, Z., Jones, L., Dunnett, S.B., 2011.Profiles of motor and cognitive impairment in the transgenic rat model of Hunt-ington’s disease. Brain Res. Bull., doi:10.1016/j.brainresbull.2011.09.011.

oroud, A., Whishaw, I.Q., 2006. Changes in the kinematic structure and non-kinematic features of movements during skilled reaching after stroke: aLaban Movement Analysis in two case studies. J. Neurosci. Methods 158,137–149.

oroud, A., Whishaw, I.Q., 2010. Reaching-to-eat in humans post-stroke: fluctuatingcomponents within a constant pattern. Behav. Neurosci. 124, 851–867.

ricker-Gates, R.A., Smith, R., Muhith, J., Dunnett, S.B., 2003. The role of pretraining onskilled forelimb use in an animal model of Huntington’s disease. Cell Transplant.12, 257–264.

harbawie, O.A., Gonzalez, C.L., Whishaw, I.Q., 2005a. Skilled reaching impairmentsfrom the lateral frontal cortex component of middle cerebral artery stroke: aqualitative and quantitative comparison to focal motor cortex lesions in rats.Behav. Brain Res. 156, 125–137.

harbawie, O.A., Gonzalez, C.L., Williams, P.T., Kleim, J.A., Whishaw, I.Q., 2005b.Middle cerebral artery (MCA) stroke produces dysfunction in adjacent motorcortex as detected by intracortical microstimulation in rats. Neuroscience 130(3), 601–610.

harbawie, O.A., Whishaw, I.Q., 2006. Parallel stages of learning and recovery ofskilled reaching after motor cortex stroke: oppositions organize normal andcompensatory movements. Behav. Brain Res. 175, 249–262.

harbawie, O.A., Williams, P.T., Kolb, B., Whishaw, I.Q., 2008. Transient middle cere-bral artery occlusion disrupts the forelimb movement representations of ratmotor cortex. Eur. J. Neurosci. 28, 951–963.

rabowski, M., Brundin, P., Johansson, B.B., 1993. Paw-reaching, sensorimotor, androtational behavior after brain infarction in rats. Stroke 24, 889–895.

ioral Reviews 36 (2012) 1030–1042 1041

Graybiel, A.M., 1990. The basal ganglia and the initiation of movement. Rev. Neurol.(Paris) 146, 570–574.

Graybiel, A.M., 2000. The basal ganglia. Curr. Biol. 10, R509–R511.Harris-Love, M.L., Morton, S.M., Perez, M.A., Cohen, L.G., 2011. Mechanisms of short-

term training-induced reaching improvement in severely hemiparetic strokepatients: a TMS study. Neurorehabil. Neural Repair 25 (5), 398–411.

Hobbs, N.Z., Henley, S.M., Ridgway, G.R., Wild, E.J., Barker, R.A., Scahill, R.I., Barnes, J.,Fox, N.C., Tabrizi, S.J., 2010. The progression of regional atrophy in premanifestand early Huntington’s disease: a longitudinal voxel-based morphometry study.J. Neurol. Neurosurg. Psychiatry 81, 756–763.

Iwaniuk, A.N., Whishaw, I.Q., 2000. On the origin of skilled forelimb movements.Trends Neurosci. 23, 372–376.

Jeyasingham, R.A., Baird, A.L., Meldrum, A., Dunnett, S.B., 2001. Differential effects ofunilateral striatal and nigrostriatal lesions on grip strength, skilled paw reachingand drug-induced rotation in the rat. Brain Res. Bull. 55, 541–548.

Johansson, B.B., 2000. Brain plasticity and stroke rehabilitation. The Willis lecture.Stroke 31, 223–230.

Karl, J.M., Sacrey, L.A., McDonald, R.J., Whishaw, I.Q., 2008. Intact intracorticalmicrostimulation (ICMS) representations of rostral and caudal forelimb areasin rats with quinolinic acid lesions of the medial or lateral caudate–putamen inan animal model of Huntington’s disease. Brain Res. Bull. 77, 42–48.

Klein, A., Dunnett, S.B., 2011. Skilled forelimb movement analysis in rats: the singlepellet reaching test and the staircase test. Curr. Protoc. Neurosci., in press.

Klein, A., Metz, G.A., Papazoglou, A., Nikkhah, G., 2007. Differential effects onforelimb grasping behavior induced by fetal dopaminergic grafts in hemiparkin-sonian rats. Neurobiol. Dis. 27, 24–35.

Klein, A., Sacrey, L.A., Dunnett, S.B., Whishaw, I.Q., Nikkhah, G., 2011. Proximal move-ments compensate for distal forelimb movement impairments in a reach-to-eattask in Huntington’s disease: new insights into motor impairments in a real-world skill. Neurobiol. Dis. 41, 560–569.

Klein, A., Wessolleck, J., Papazoglou, A., Metz, G.A., Nikkhah, G., 2009. Walkingpattern analysis after unilateral 6-OHDA lesion and transplantation of foetaldopaminergic progenitor cells in rats. Behav. Brain Res. 199, 317–325.

Kloth, V., Klein, A., Loettrich, D., Nikkhah, G., 2006. Colour-coded pellets increase thesensitivity of the staircase test to differentiate skilled forelimb performances ofcontrol and 6-hydroxydopamine lesioned rats. Brain Res. Bull. 70, 68–80.

Marsden, C.D., 1990. Parkinson’s disease. Lancet 335, 948–952.Marston, H.M., Faber, E.S., Crawford, J.H., Butcher, S.P., Sharkey, J., 1995. Behavioural

assessment of endothelin-1 induced middle cerebral artery occlusion in the rat.Neuroreport 6, 1067–1071.

Melvin, K.G., Doan, J., Pellis, S.M., Brown, L., Whishaw, I.Q., Suchowersky, O.,2005. Pallidal deep brain stimulation and l-dopa do not improve qualita-tive aspects of skilled reaching in Parkinson’s disease. Behav. Brain Res. 160,188–194.

Metz, G.A., Whishaw, I.Q., 2000. Skilled reaching an action pattern: stability in rat(Rattus norvegicus) grasping movements as a function of changing food pelletsize. Behav. Brain Res. 116, 111–122.

Michaelsen, S.M., Jacobs, S., Roby-Brami, A., Levin, M.F., 2004. Compensation fordistal impairments of grasping in adults with hemiparesis. Exp. Brain Res. 157,162–173.

Miklyaeva, E.I., Castaneda, E., Whishaw, I.Q., 1994. Skilled reaching deficits in uni-lateral dopamine-depleted rats: impairments in movement and posture andcompensatory adjustments. J. Neurosci. 14, 7148–7158.

Montoya, C.P., Astell, S., Dunnett, S.B., 1990. Effects of nigral and striatal grafts onskilled forelimb use in the rat. Prog. Brain Res. 82, 459–466.

Montoya, C.P., Campbell-Hope, L.J., Pemberton, K.D., Dunnett, S.B., 1991. The stair-case test: a measure of independent forelimb reaching and grasping abilities inrats. J. Neurosci. Methods 36, 219–228.

Nikkhah, G., Falkenstein, G., Rosenthal, C., 2001. Restorative plasticity of dopamineneuronal transplants depends on the degree of hemispheric dominance. J. Neu-rosci. 21, 6252–6263.

Nikkhah, G., Rosenthal, C., Hedrich, H.J., Samii, M., 1998. Differences in acquisitionand full performance in skilled forelimb use as measured by the ‘staircase test’in five rat strains. Behav. Brain Res. 92, 85–95.

Nudo, R.J., Wise, B.M., SiFuentes, F., Milliken, G.W., 1996. Neural substrates for theeffects of rehabilitative training on motor recovery after ischemic infarct. Science272, 1791–1794.

Olsson, M., Nikkhah, G., Bentlage, C., Bjorklund, A., 1995. Forelimb akinesia in therat Parkinson model: differential effects of dopamine agonists and nigral trans-plants as assessed by a new stepping test. J. Neurosci. 15, 3863–3875.

Ploughman, M., Attwood, Z., White, N., Dore, J.J., Corbett, D., 2007. Endurance exer-cise facilitates relearning of forelimb motor skill after focal ischemia. Eur. J.Neurosci. 25, 3453–3460.

Roby-Brami, A., Feydy, A., Combeaud, M., Biryukova, E.V., Bussel, B., Levin, M.F., 2003.Motor compensation and recovery for reaching in stroke patients. Acta Neurol.Scand. 107, 369–381.

Rodter, A., Winkler, C., Samii, M., Nikkhah, G., 2000. Complex sensorimotor behav-ioral changes after terminal striatal 6-OHDA lesion and transplantation ofdopaminergic embryonic micrografts. Cell Transplant. 9, 197–214.

Sacrey, L.A., Alaverdashvili, M., Whishaw, I.Q., 2009a. Similar hand shaping inreaching-for-food (skilled reaching) in rats and humans provides evidence of

homology in release, collection, and manipulation movements. Behav. Brain Res.204, 153–161.

Sacrey, L.A., Clark, C.A., Whishaw, I.Q., 2009b. Music attenuates excessive visual guid-ance of skilled reaching in advanced but not mild Parkinson’s disease. PLoS One4, e6841.

1 behav

S

S

S

S

T

T

V

v

W

W

W

W

042 A. Klein et al. / Neuroscience and Bio

acrey, L.A., Travis, S.G., Whishaw, I.Q., 2011. Drug treatment and familiar music aidsan attention shift from vision to somatosensation in Parkinson’s disease on thereach-to-eat task. Behav. Brain Res. 217, 391–398.

acrey, L.A., Whishaw, I.Q., 2010. Development of collection precedes targetedreaching: resting shapes of the hands and digits in 1–6-month-old humaninfants. Behav. Brain Res. 214, 125–129.

acrey, L.A., Whishaw, I.Q., 2011. Subsystems of sensory attention for skilled reach-ing: vision for transport and pre-shaping and somatosensation for grasping,withdrawal and release. Behav. Brain Res., doi:10.1016/j.bbr.2011.07.031.

challert, T., Hall, S., 1988. ‘Disengage’ sensorimotor deficit following apparentrecovery from unilateral dopamine depletion. Behav. Brain Res. 30, 15–24.

aub, E., Uswatte, G., 2003. Constraint-induced movement therapy: bridging fromthe primate laboratory to the stroke rehabilitation laboratory. J. Rehabil. Med.Suppl. 41, 34–40.

illerson, J.L., Cohen, A.D., Philhower, J., Miller, G.W., Zigmond, M.J., Schallert, T.,2001. Forced limb-use effects on the behavioral and neurochemical effects of6-hydroxydopamine. J. Neurosci. 21 (12), 4427–4435.

ergara-Aragon, P., Gonzalez, C.L., Whishaw, I.Q., 2003. A novel skilled-reachingimpairment in paw supination on the good side of the hemi-Parkinson ratimproved with rehabilitation. J. Neurosci. 23, 579–586.

on Horsten, S., et al., 2003. Transgenic rat model of Huntington’s disease. Hum. Mol.Genet 12, 617–624.

hishaw, I.Q., Alaverdashvili, M., Kolb, B., 2008a. The problem of relating plasticityand skilled reaching after motor cortex stroke in the rat. Behav. Brain Res. 192,124–136.

hishaw, I.Q., Gorny, B., Foroud, A., Kleim, J.A., 2003. Long-Evans and Sprague-Dawley rats have similar skilled reaching success and limb representations inmotor cortex but different movements: some cautionary insights into the selec-tion of rat strains for neurobiological motor research. Behav. Brain Res. 145,221–232.

hishaw, I.Q., Kolb, B., 2005. The Behavior of the Laboratory Rat. Oxford UniversityPress, New York City.

hishaw, I.Q., O’Connor, W.T., Dunnett, S.B., 1986. The contributions of motor cor-tex, nigrostriatal dopamine and caudate–putamen to skilled forelimb use in therat. Brain 109 (Pt 5), 805–843.

ioral Reviews 36 (2012) 1030–1042

Whishaw, I.Q., Pellis, S.M., 1990. The structure of skilled forelimb reaching in the rat:a proximally driven movement with a single distal rotatory component. Behav.Brain Res. 41, 49–59.

Whishaw, I.Q., Pellis, S.M., Gorny, B.P., 1992. Skilled reaching in rats andhumans: evidence for parallel development or homology. Behav. Brain Res. 47,59–70.

Whishaw, I.Q., Pellis, S.M., Gorny, B.P., Pellis, V.C., 1991. The impairments in reach-ing and the movements of compensation in rats with motor cortex lesions: anendpoint, videorecording, and movement notation analysis. Behav. Brain Res.42, 77–91.

Whishaw, I.Q., Suchowersky, O., Davis, L., Sarna, J., Metz, G.A., Pellis, S.M., 2002.Impairment of pronation, supination, and body co-ordination in reach-to-grasptasks in human Parkinson’s disease (PD) reveals homology to deficits in animalmodels. Behav. Brain Res. 133, 165–176.

Whishaw, I.Q., Travis, S.G., Koppe, S.W., Sacrey, L.A., Gholamrezaei, G., Gorny, B.,2010. Hand shaping in the rat: conserved release and collection vs. flexiblemanipulation in overground walking, ladder rung walking, cylinder exploration,and skilled reaching. Behav. Brain Res. 206, 21–31.

Whishaw, I.Q., Woodward, N.C., Miklyaeva, E., Pellis, S.M., 1997. Analysis of limbuse by control rats and unilateral DA-depleted rats in the Montoya staircasetest: movements, impairments and compensatory strategies. Behav. Brain Res.89 (1–2), 167–177.

Whishaw, I.Q., Whishaw, P., Gorny, B., 2008b. The structure of skilled forelimb reach-ing in the rat: a movement rating scale. J. Vis. Exp. 18, pii: 816.

Whishaw, I.Q., Zeeb, F., Erickson, C., McDonald, R.J., 2007. Neurotoxic lesionsof the caudate–putamen on a reaching for food task in the rat: acute sen-sorimotor neglect and chronic qualitative motor impairment follow laterallesions and improved success follows medial lesions. Neuroscience 146,86–97.

Wolfarth, S., Konieczny, J., Smialowska, M., Schulze, G., Ossowska, K., 1996. Influ-

ence of 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathwayon the muscle tone and electromyographic activity measured during passivemovements. Neuroscience 74, 985–996.

Zigmond, M.J., Stricker, E.M., 1972. Deficits in feeding behavior after intraventricularinjection of 6-hydroxydopamine in rats. Science 177, 1211–1214.