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Side Onset Influence on Upper Extremity Motor Functioning in Parkinson Disease

Permanent Link: http://ufdc.ufl.edu/UFE0022580/00001

Material Information

Title: Side Onset Influence on Upper Extremity Motor Functioning in Parkinson Disease
Physical Description: 1 online resource (111 p.)
Language: english
Creator: Stewart, Kimberly
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2008

Subjects

Subjects / Keywords: control, coordination, dopaminergic, force, ipsilateral, motor, responses
Applied Physiology and Kinesiology -- Dissertations, Academic -- UF
Genre: Health and Human Performance thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: We sought to determine whether persons with Parkinson disease (PD) maintain asymmetric ipsilateral control of the upper extremities. We hypothesized that PD patients with a right side of symptom onset (RSO) would have greater motor and force coordination deficits in their ipsilateral left hand compared to patients with a left side onset (LSO) would have in their ipsilateral right hand. We also explored the effects of dopaminergic medication on object manipulation and hypothesized that PD patients would show improved manual dexterity while in the ?on? state as compared to the off state (no antiparkinsonian medications within the last 12 hours). Twenty-one right-handed (RH) individuals diagnosed with idiopathic PD (11 RSO, 10 LSO) and 10 RH, healthy controls performed a variety of manual dexterity tasks. Raw scores from the outcome measures were converted to a laterality quotient and used in analysis to compare side onset influences on motor and force coordination. Left and right hand performances in both the off and on states were then compared to examine the effects of medication on all performance measures. Laterality scores for the combined small and large object tasks were significantly larger for the LSO group (?=77.31?57.78) compared to the RSO (?=14.37?22.83; p=0.002) and HC (?=5.54?1.97; p < 0.001) groups. Analysis of the side onset effects on the force coordination task revealed no significant differences for either of the force variables, time within range (p=0.52) or the variability quotient (p=0.60), when comparing the laterality quotient scores of each group. Final comparison showed that the small and large object manipulation measures from both hands across all of the groups had significant improvement while in the ?on? state (p=0.007). The lower laterality quotient among PD patients with a RSO compared to LSO indicated greater motor and force coordination deficits in both hands in these patients. These findings could be interpreted to suggest more ipsilateral involvement of the affected dominant left hemisphere on the left hand. Our data suggest, among RH, PD retains this natural ipsilateral influence. Moreover, the improvement during the on? state confirms that dopaminergic medications do in fact aid the performance of manual dexterous activities.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Kimberly Stewart.
Thesis: Thesis (Ph.D.)--University of Florida, 2008.
Local: Adviser: Hass, Christopher J.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2008
System ID: UFE0022580:00001

Permanent Link: http://ufdc.ufl.edu/UFE0022580/00001

Material Information

Title: Side Onset Influence on Upper Extremity Motor Functioning in Parkinson Disease
Physical Description: 1 online resource (111 p.)
Language: english
Creator: Stewart, Kimberly
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2008

Subjects

Subjects / Keywords: control, coordination, dopaminergic, force, ipsilateral, motor, responses
Applied Physiology and Kinesiology -- Dissertations, Academic -- UF
Genre: Health and Human Performance thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: We sought to determine whether persons with Parkinson disease (PD) maintain asymmetric ipsilateral control of the upper extremities. We hypothesized that PD patients with a right side of symptom onset (RSO) would have greater motor and force coordination deficits in their ipsilateral left hand compared to patients with a left side onset (LSO) would have in their ipsilateral right hand. We also explored the effects of dopaminergic medication on object manipulation and hypothesized that PD patients would show improved manual dexterity while in the ?on? state as compared to the off state (no antiparkinsonian medications within the last 12 hours). Twenty-one right-handed (RH) individuals diagnosed with idiopathic PD (11 RSO, 10 LSO) and 10 RH, healthy controls performed a variety of manual dexterity tasks. Raw scores from the outcome measures were converted to a laterality quotient and used in analysis to compare side onset influences on motor and force coordination. Left and right hand performances in both the off and on states were then compared to examine the effects of medication on all performance measures. Laterality scores for the combined small and large object tasks were significantly larger for the LSO group (?=77.31?57.78) compared to the RSO (?=14.37?22.83; p=0.002) and HC (?=5.54?1.97; p < 0.001) groups. Analysis of the side onset effects on the force coordination task revealed no significant differences for either of the force variables, time within range (p=0.52) or the variability quotient (p=0.60), when comparing the laterality quotient scores of each group. Final comparison showed that the small and large object manipulation measures from both hands across all of the groups had significant improvement while in the ?on? state (p=0.007). The lower laterality quotient among PD patients with a RSO compared to LSO indicated greater motor and force coordination deficits in both hands in these patients. These findings could be interpreted to suggest more ipsilateral involvement of the affected dominant left hemisphere on the left hand. Our data suggest, among RH, PD retains this natural ipsilateral influence. Moreover, the improvement during the on? state confirms that dopaminergic medications do in fact aid the performance of manual dexterous activities.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Kimberly Stewart.
Thesis: Thesis (Ph.D.)--University of Florida, 2008.
Local: Adviser: Hass, Christopher J.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2008
System ID: UFE0022580:00001


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1 SIDE ONSET INFLUENCE ON UPPER EXTREMITY MOTOR FUNCTIONING IN PARKINSON DISEASE By KIM C. STEWART A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2008

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2 2008 Kim C. Stewart

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3 To my family and friends

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4 ACKNOWLEDGMENTS I would like to thank m y committee members for a ll of the time and effort they devoted to me and my research. Dr. Chris Hass has defi nitely gone above and beyond as a mentor and guided me in an amazing research direction. Th e learning and opportunities I experienced this year are extraordinary. He and Dr. Mark Tillman made the completion of my doctoral work possible, and I will forever be grateful for th eir thoughtfulness and honorable actions. They both have many unique and desirable characteristics I hope to emulate in my career. Dr. Hubert Fernandez has also been extremely beneficial and in fluential in my research path this past year. I appreciate his willingness to help me expand my knowledge of neurology, specifically Parkinson disease. Dr. Lorie Richards has taught me to criti cally analyze questions and has been an integral part of my research here at UF. The enthusiasm she has for her resear ch and for guiding others through their learning process is definitely admira ble. I feel very fortunate to have had such awesome committee members. I would also like to thank my mom for her unconditional support and guidance throughout my doctorate work and my friends and family w ho have been there for me throughout this entire process with encouragement, friendship and support.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS...............................................................................................................4 LIST OF TABLES................................................................................................................. ..........8 LIST OF FIGURES.........................................................................................................................9 LIST OF ABBREVIATIONS AND DEFINITIONS.................................................................... 10 ABSTRACT...................................................................................................................................11 CHAPTER 1 INTRODUCTION..................................................................................................................13 Purpose of the Study........................................................................................................... ....15 Specific Aims and Hypotheses............................................................................................... 16 Specific Aim 1.................................................................................................................16 Specific Aim 2.................................................................................................................18 Specific Aim 3.................................................................................................................19 Significance of the Study........................................................................................................19 Limitations and Assumptions................................................................................................. 20 Limitations.................................................................................................................... ...20 Assumptions.................................................................................................................... 21 2 MATERIALS AND METHODS........................................................................................... 22 Participants.............................................................................................................................22 Sample Size Justification.................................................................................................22 Participant Recruitment................................................................................................... 22 Testing Protocol......................................................................................................................23 Outcome Measures............................................................................................................... ..23 Unified Parkinson Disease Rating Scale......................................................................... 24 Box and Blocks Tests......................................................................................................24 Coin Rotation Tasks........................................................................................................25 Lock Rotation Tasks........................................................................................................25 Force Control Task.......................................................................................................... 26 ON versus OFF medications........................................................................................... 27 Statistical Analysis........................................................................................................... .......27

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6 3 REVIEW OF LITERATURE.................................................................................................32 Hemispheric Characteristics...................................................................................................32 Structural and Functional Asymmetries.......................................................................... 32 General Cerebral Responsibilities................................................................................... 33 Hemispheric Approach to Research Dysfunctions.......................................................... 34 Manual Dexterity............................................................................................................... .....37 Brain Areas Involved....................................................................................................... 37 Primary motor cortex............................................................................................... 38 Association areas...................................................................................................... 38 Basal ganglia............................................................................................................39 Corticospinal tract.................................................................................................... 40 Ipsilateral hemisphere.............................................................................................. 41 Mechanisms of Dexterity................................................................................................43 Force control and manual dexterity.......................................................................... 44 Precision versus power grip forces........................................................................... 46 Finger versus multi-finger forces............................................................................. 47 Loss of Dexterity............................................................................................................. 48 Parkinson Disease.............................................................................................................. .....50 Motor Symptoms............................................................................................................. 51 Asymmetry of Motor Symptoms..................................................................................... 52 Asymmetry of Cognitive Deficits...................................................................................53 Motor Deficits................................................................................................................. 54 Force Deficits..................................................................................................................55 Response to Medications................................................................................................. 59 Summary..........................................................................................................................59 4 RESULTS...............................................................................................................................61 Side-Onset Influence........................................................................................................... ...61 Force Influence.......................................................................................................................62 Medication Influence........................................................................................................... ...63 5 DISCUSSION.........................................................................................................................71 Side-Onset Influence........................................................................................................... ...71 Small versus Large Object Manipulation........................................................................ 74 Force Coordination..........................................................................................................76 Force as a Mechanism.....................................................................................................77 Medication Influence........................................................................................................... ...79 Considerations........................................................................................................................81 Conclusion..............................................................................................................................83 6 FUTURE RESEARCH........................................................................................................... 84

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7 APPENDIX A INFORMED CONSENT........................................................................................................85 B DEMOGRAPHIC AND CLINICAL DATA FORM............................................................. 87 C MODIFIED EDINBURGH HANDEDNESS INVENTORY................................................ 88 D BLANK OUTCOME MEASURE FORM............................................................................. 89 E RAW DATA: SIDE ONSET..................................................................................................90 F GROUP MEAN DATA: OFF/ON.................................................................................. 92 G PRELIMINARY PILOT STUDY.......................................................................................... 94 Introduction................................................................................................................... ..........94 Methods..................................................................................................................................94 Results.....................................................................................................................................95 Discussion...............................................................................................................................96 LIST OF REFERENCES...............................................................................................................98 BIOGRAPHICAL SKETCH.......................................................................................................111

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8 LIST OF TABLES Table page 2-1 Upper extremity tasks for part III of the Unified Parkinson Di sease Rating Scale........... 29 4-1 Group demographics for the side onset analysis................................................................ 65 4-2 Means and significance levels of th e laterality quotie nts for each group.......................... 65 4-3 Means and significance levels of the laterality quotients for each group after accounting for inherent handedness diffe rences of the healthy controls........................... 65 4-4 Side onset group means and signifi cance levels using a one-way ANOVA..................... 68 4-5 Pearsons correlations of force coordina tion variables and small outcom e measures....... 68 4-6 Group demographics for the off/on analysis............................................................... 68 4-7 The on and off significance levels a nd mean values of the com bined times for task completion for each hand and side onset from both small and large object manipulation......................................................................................................................69

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9 LIST OF FIGURES Figure page 2-1 Flow chart for the testing protocol of the fluctuators........................................................30 2-2 Force gripper appara tus used during testing................................................................... 31 2-3 Force-Time curves displayed on the mon itor in front of the participant during the target force tracking task.................................................................................................... 31 4-1 Example of individual target precision grip force curves.................................................. 66 4-2 Left and right hand performance for each gr oup during the target precisio n grip task..... 67 4-3 Max force with the left and right hand in both the off and on me dication states....... 69 4-4 Example of an individual target pr ecision grip force curve in the off and on medication states.............................................................................................................. ..70

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10 LIST OF ABBREVIATI ONS AND DEFINITIONS Side onset Indicates the side of the body in which the first motor sym ptoms were apparent RSO Right side onset is where first moto r symptoms were apparent on the right side of the body implying left hemisphere damage LSO Left side onset is where first mo tor symptoms were apparent on the left side of the body implying right hemisphere damage Less-Unaffected Refers to the side of the body th at did not have initial symptoms as well as the side where the symptoms are less affected Bilateral impairment Refers to evident impair ments on both sides of the body not a deficit in simultaneous bimanual movements Contralateral Opposite side of the body (i .e. the left hemisphere controls the contralateral, right hand) Ipsilateral Same side of the body (i.e. the le ft hemisphere controls some ipsilateral, left hand functions) Hemi asym Hemispheric asymmetries; eith er structural (anato mical) or functional differences in the cerebral cortices Cerebral dominance The ability of one cerebral hemisphere to predominately control specific tasks (cognitive/language or motor) Lateralization Loca lization of function or activity on one side of the body in preference to the other LQ Laterality quotient refers to the difference in left and right hand performance TWR Time within range is used as a fo rce coordination measur e that refers to the amount of time the participant was able to keep their produced force within five percent of the targeted force VQ Variability quotient is a normalized r oot mean square erro r calculation that accounts for the differing target forces that each person attempts to match

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11 Abstract of Dissertation Pres ented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy SIDE ONSET INFLUENCE ON UPPER EXTREMITY MOTOR FUNCTIONING IN PARKINSON DISEASE By Kim C. Stewart August 2008 Chair: Chris Hass Major: Health and Human Performance We sought to determine whether persons with Parkinson disease (PD) maintain asymmetric ipsilateral control of the upper extremities. We hypothesized that PD patients with a right side of symptom onset (RSO ) would have greater motor and force coordination deficits in their ipsilateral left hand compared to patients wi th a left side onset (LSO) would have in their ipsilateral right hand. We also explored the effects of dopaminergic medication on object manipulation and hypothesized that PD patients would show impr oved manual dexterity while in the on state as compared to the off state ( no antiparkinsonian medicati ons within the last 12 hours). Twenty-one right-handed (RH) individuals di agnosed with idiopathic PD (11 RSO, 10 LSO) and 10 RH, healthy controls performed a variety of manual dexterity tasks. Raw scores from the outcome measures were converted to a laterality quotient and used in analysis to compare side onset influences on motor a nd force coordination. Left and right hand performances in both the off and on states were then compared to examine the effects of medication on all performance measures.

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12 Laterality scores for the combined small and large object tasks were significantly larger for the LSO group ( =77.31.78) compared to the RSO ( =14.37.83; p =0.002) and HC ( =5.54.97; p<0.001) groups. Analysis of the side onset effects on the force coordination task revealed no significant differences for either of the force variables, time within range ( p=0.52) or the variability quotient ( p =0.60), when comparing the laterality quotient scores of each group. Final comparison showed that the small and larg e object manipulation measures from both hands across all of the groups had significant im provement while in the on state (p =0.007). The lower laterality quotient among PD patient s with a RSO compared to LSO indicated greater motor and force coordinati on deficits in both hands in these patients. These findings could be interpreted to suggest more ipsilate ral involvement of the affected dominant left hemisphere on the left hand. Our data suggest, among RH, PD retains this natural ipsilateral influence. Moreover, the improvement during the on state confirms that dopaminergic medications do in fact aid the performance of manual dexterous activities.

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13 CHAPTER 1 INTRODUCTION Parkinson disease (PD) is a progressive neurode generative d isorder that affects cortical and sub-cortical connections as dopaminergic cells wi thin the substantia nigr a of the basal ganglia undergo accelerated cell death. Once the loss of dopamine reaches a certain threshold level (about 70%),1, 2 parkinsonian movement dysfunctions b ecome more noticeable usually leading patients to seek medical attenti on. The cardinal motor features of PD include postural instability, bradykinesia, resting tremor, and rigidity. These consequences occu r in either or both upper and lower extremities and eventually impede activities of daily living, cause social discomfort, and affect quality of life. While lower extremity m ovement dysfunction creates difficulty in social outings and maintenance of physical activity, upper extremity problems affect many everyday manipulation tasks such as buttoning a shirt or picking up small objects. Because manipulation activities are performed over 83.4% of the time during normal daily activities,3 a loss of finger and manual dexterity can be quite debilitating and frustrating. In addition to the location of the impairments, th e side of symptom onset is also of clinical importance. While not absolute, patients most often present asymmetric symptomatology due to impairments beginning on one side of the body. Di sruptions within the left hemisphere cause symptoms on the right side of the body [termed a right side onset (RSO)] whereas dysfunctions within the right hemisphere cause symptoms on the left side of the body (LSO). The lateralization of PD is perhaps due to initial asymmetric levels of dopamine or a more rapid depletion in one hemisphere.4-6 With disease progression, the sy mptoms may become evident on both sides of the body; however, the side of onset often remains more affected.6 Considering PD is essentially a lateralized disorder and each hemisphere has specific motor and cognitive responsibilities, persons wi th a RSO versus a LSO are likely to have

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14 differing disease sequela. Researchers have examin ed the influence of the side of symptom onset on domains such as cognitive, visiospatial and perceptuomotor functions.7-18 Though there are some reports with no association of side onset to cognitive functioning,11, 14 the majority of studies do show some association especially when accounting fo r specific cognitive functions that correspond to each hemisphere.7, 9, 12, 13, 16, 17 The side of onset may also influence motor functioning; motor deficits in th e dominant hand tend to be more disabling than deficits in the non-dominant hand. Since the control of movement originates in the contralateral hemisphere, damage to the left hemisphere results in ri ght side impairments and damage to the right hemisphere results in left side impairments. Ther efore, in right-handers (RH), damage in the left hemisphere show impairments on the dominant, ri ght side and affect patients differently than damage to the right hemisphere that impairs the non-dominant, left side of body. Besides these greater debilitating effects of an involved dominant hand, other differing motor problems may occur with a RSO or a LSO in PD. Unfortunately these possible consequences have not been explored. One plausible LSO versus RSO motor differe nce involves the asymmetric ipsilateral control of upper extremity dexterit y. In particular, the left hemisphere has been shown to have a definitive role for controlling ipsilateral, left finger and hand movements in RH. Conversely, the right hemisphere does not have this same ipsilateral control of the right hand.19-27 In other neurologically disordered populations, such as st roke patients and epilep tic patients undergoing anesthesia, researchers have observed hemispheric asymmetry and have documented that the side of damage significantly influences performan ce of precise finger and hand manipulation tasks.28-35 For example, RH stroke patients with da mage to the left hemisphere show more deficits in the ipsilateral, less-affected, left hand than patients with right hemisphere damage

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15 show in their ipsilateral less-affected, right hand.28, 29, 33-35 However, these ipsilateral upper extremity deficits during activities of daily living have not been examined in PD. Given the asymmetric ipsilateral control and that the predominantly affected hemisphere influences cognitive dysfunction in PD and mo tor dysfunctions in other neurologically disordered populations, it is reasonable to exp ect that the involved hemisphere differently influences upper extremity motor functioning. Speci fically, in RH, motor de ficits would be more apparent in the left, ipsilateral hand in persons with left hemisphere damage (RSO) than in the right, ipsilateral hand in persons with right hemisphere damage (L SO). Experiencing deficits in both hands after a RSO may cause greater prob lems with dexterous unimanual and bimanual movements thereby possibly increasing the re liance of compensational techniques or a caregivers help. Furthermore, research regarding the effect s of dopaminergic medications on dexterous manipulation tasks of both the affected and less -affected hands is equi vocal; therefore, it is necessary to explore fine moto r performance in both on and off states. More precise objective measures of fine motor skills would also help clinicians, therapists and patients understand differing drug responses beyond the subjective impairment ratings currently used. Purpose of the Study The asymmetric motor presentation of the PD population may be helpful in deciphering and confirming som e known hemispheric respon sibilities and asymmetries and support the notion that left or right hemispheric damage affects motor performance differently. Because the left hemisphere has greater ipsilateral contro l, damage to the left hemisphere may cause additional motor deficits in both hands whereas damage to the right hemisphere would impair motor performance more solely of the left hand. Therefore, the pur pose of this investigation was

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16 to examine the influence of side of sympto m onset on upper extremity motor functioning in Parkinson disease To determine the influence of the side of onset on upper extremity dexterity, we had healthy controls and persons with PD perform a variety of finger and hand manipulation tasks. In addition, since the skillful mani pulation of objects requires preci se coordination of fingertip forces, we analyzed force coordination output as a possible mechanism that may disrupt movements. Finally, we also examined motor de ficits while in the off and on state to confirm the effects of dopaminergic medicati ons on finger and hand de xterity in both the affected and lessaffected hands. Specific Aims and Hypotheses Specific Aim 1 To determine if, in RH, PD patients with lef t hemispher e damage (RSO) have greater ipsilateral motor coordination deficits than patients with right hemisphere damage (LSO) The objective of this aim was to determine if the greater left hemispheric ipsilateral control, as seen in healthy and other neurologically disordered popul ations, had more of an affect on motor coordination of left hand movements than the right hemisphere had on right hand movements in persons with PD. The analysis of motor coordination deficits was divided into two parts to answer the following questions: 1a. Do PD patients with left hemisphere damage (RSO) have greater ipsilateral deficits during finger-thumb and multi-finger thumb grasping tasks than patients with right hemisphere damage (LSO)? The pincher grasp (index finger-thumb oppo sition) is required for many fine manipulation activities. Many pers ons with PD have difficulty performing these tasks in an appropriate manner with the involved hand.36-38 For analysis of pincher grasp deficits, in this protocol, we used the box and block, lock rota tion, and coin rotation as functionally relevant

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17 clinical measures that provided information regarding precise finger thumb coordination detriments. Tasks that involve whole hand graspi ng or manipulation of la rger objects such as holding a cup or turning a doorknob involve multiple fingers in opposition with the thumb and are also commonly used during activities of da ily living. Control of multiple effectors and coordination of multi-finger-thumb opposition, or seque ncing, are also disrupted in persons with Parkinsons disease.39-42 To determine multi-finger-thumb grasping dysfunctions, we used the similar tasks procedures as de scribed above; however, the object was a larger version that required multiple fingers for manipulation. Due to gr eater ipsilateral, left-hemisphere control of dexterity, we hypothesized that PD patients with a RSO (damage in the dominant hemisphere) would show greater finger coordina tion deficits in the ipsilateral left hand than patients with a LSO (damage in the non-dominant hemisphere) woul d have in their ipsilateral right hand. This finding would mean that right and left hand tasks involving finger-thumb and multi-finger-thumb grasping movements would be more problem atic for PD patients with a RSO. 1b. A re these multi-finger-thumb grasping deficits greater than the finger-thumb grasping deficits? Santello and Soechting43 suggested that grasping mechanisms are more difficult when all five digits are involved because the e quilibrium of forces can be achieved by many combinations of the fingertip force distributi ons. Thus, we hypothesized that the tasks requiring multi-finger-thumb grasping movements would show greater laterality deficits than those observed during the finger-thumb tasks. Since multi-finger thumb movements are typically more complex, they require more processing to plan and execute. Furthermore, as a taskcomplexity is increased, a greater involvement of the ipsilateral, left hemisphere is necessary.25, 44 Therefore, between-hand deficits are more likely in the more complex task.

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18 Specific Aim 2 To determine the inf luence of side of sympto m onset on force coordi nation deficits and its impact on dexterity This aim was explored in two sub-parts. 2a. Do patients with a RSO show greater ipsilate ral force coordination de ficits than patients with a LSO? The objective of this aim was to determine if the side of symptom onset influences the force coordination of hand movements in pe rsons with PD. To measure force coordination, we analyzed force variability during a target precis ion grip task. We hypothesized that PD patients with a RSO would show great er precision grip deficits in both hands than patients with a LSO as measured by variability in specific target precision grip force. Therefore, not only would persons with PD show force coor dination detriments in their affe cted hand, but patients with a RSO would also experience force co ordination deficits in their ipsilateral, left hand more than patients with a LSO would experience in their ipsilateral, right hand. 2b. Is precision grip a mechanism that affects the finger-thumb dexterity? The exact mechanisms necessary to achieve the appropr iate movements during manual finger and hand dexterous tasks are mostly unknown. One theorize d mechanism is force coordination where the appropriate fingertip forces between the ti ps of the thumb and index finger during the manipulation of small objects requir e a precise coordination between the grip and load force. In PD, both the skillful manipulation of objects and precise coordination of fingertip forces are impaired. We compared deficits of force coordi nation via the va riability of forces during the target precision grip task to deficits in mo tor coordination via the outcome during the small object manipulation tasks to determine if fo rce coordination was indeed a mechanism of dexterity. We hypothesized that precision grip was a mechanism of dexterity whereby the

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19 deficits observed in finger-thumb grasping tasks would correspond to the increased variability in specific target precision grip force. Specific Aim 3 To determine the effect of dopamin ergic me dications on upper extremity finger and manual dexterity in both the affected and less-affected hands Dopaminergic medications are prescribed to prevent or minimize the cardinal mo tor impairments such as tremor, rigidity or bradykinesia often observed in patients with PD. In this aim, patients performed the series of finger and hand manipulation tasks in the off state (no dopaminergic medications within 12 hours of testing) as well as in the on state to explore the eff ects of these medications on motor coordination in both the affected and less-affected hands. We hypothesized that dopaminergic medications would promote improvements during the skillful manipulat ion of objects manual dexterity in PD patients who are self-reported as fluctuators (experience a clear and consistent wearing off period between medication dosages). Drug treatment for parkinsonian symptoms improves clinical motor scores as measured by the UPDRS. We believe that these improvements would translate to the improvements during everyday dexterity tasks. Significance of the Study Determining if the left hemispheres ipsilate ral control of finger movements extends to persons with PD is important for recognizing that differing motor consequences can occur in a specific subset of patients. Furthermore, knowing that the benefits of dopaminergic medicines transfers from the clinical motor impairment ra tings to actual finger and hand manipulation task improvement is invaluable for PD patients. The significance of the findings may not only help clinicians, therapist, and patients understand differences in motor consequences in PD, but should also transfer the understanding of possible dominant hemisphere control mechanis ms of ipsilateral manual skills in the healthy

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20 population. From this study, we were able to sh ow 1) different motor consequences exist depending on the side of motor symptom onset in PD 2) the loss of dexterity in the ipsilateral, left hand extended to patients with PD, 3) the loss of dexterity was not only limited to fingerthumb tasks but includes all digits and more manu al skills, 4) the greater bilateral impairments found in patients with RSO transferred to f unctional motor tasks performed daily, 5) the importance of precision grip during dexterous movements and the impact of PD on the variability of precision grip in both affected and lessaffected hands, 6) fo rce coordination is indeed a mechanism of skillful object manipulat ion, and 7) the positive dopaminergic effect on manual dexterous task in both the affected and less -affected hands. Limitations and Assumptions Limitations The differing types of PD (tremo r dominant, ak inetic rigidity, and mixed) may influence the performance on the selected outcome measures The selected outcome measures are fairly si mple finger and hand tasks that do not require extremely complex manipulation of objects The Unified Parkinson Disease Rating Scale is a subjective measure of motor impairment severity with low inter-rater reliability and the scoring as sensitive to less severe levels of impairment Each patient differed in the amount of time th ey experienced symptoms before visiting a neurologist or being correctly diagnosed. The duration (once diagnosed) at a given stage for each patient is quite variable making it difficult to predict the length of time before the disease is no longer unilateral reaching severityStage 2.5.

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21 The inherent variability in left and right hand performances exists among PD patients as well as healthy controls. Patients willing to participate may not have as severe motor fluctuations between off and on states thereby lessening the on/off motor dysfunction differences Assumptions All right-handed subjects have a do mi nant left hemisphere control All subjects were not initially bilaterally affected The on state has been reached at the start of the second testing

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22 CHAPTER 2 MATERIALS AND METHODS Participants Twenty-one right-handed indivi duals diagnosed with idiopa thic PD and 10 right-handed, age-m atched healthy controls were recruited to participate. The PD patients must have shown clear evidence of a unilateral ons et (11 RSO and 10 LSO) and no evidence of dementia (MMSE <24)or significant/unstable cardi ovascular problems. Moreover, pa tients with history of other neurological disorders or other orthopedic im pairments affecting upper extremity functioning or who had undergone any neurosurgical operations we re excluded. In addition, 11 of these overall 21 PD patients were self-reported as fluctuators (self-reported as showi ng a clear and consistent wearing off period between medication dosages th ereby scoring at least a on question 39 of the Unified Parkinson Disease Rating Scale (UPDRS)) and used to determine dopaminergic effects on dexterity measures. Sample Size Justification After performi ng a power analysis set at a power of 0.90 and a alpha level of 0.05 and using the mean differences and standard deviatio ns from the outcome measures calculated from our pilot data (N=12), the projected sample size included 10 particip ants in each group. Participant Recruitment Retrospectiv e chart review a nd prospective recruitment from the University of Florida Movement Disorder Center (MDC) was used to identify persons with PD meeting the inclusion/exclusion criteria. Prospective recr uitment occurred via th e MDC doctors who log eligible contact information and secure permission from patients interested in participating in this study protocol. Healthy controls were recruited from pre-exis ting research participant pools and/or patient spouses or olde r adults recruited from the gr eater Gainesville community.

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23 Testing Protocol Participants eithe r visited the Biomechanics La b at the University of Floridas Center for Exercise Science or met at a neutral site. After reading and signing an informed consent, they completed the demographic questionnaire and were made aware of the upcoming protocol and procedures. The following demographic and clinical data were recorded: Age, gender, years of education, disease duration since diagnosis, side onset, first symptom type and location, time since medication, medication list and dosages, scor e from question 39 of the UPDRS (0-4), hand preference, and their laterality quotient calculated from the modified Edinburgh Handedness Inventory.45-47 Prior to the testing of each outcome m easure, participants were provided the opportunity to practice each task un til they felt comfortable with th e rules and task manipulation. As for the fluctuators the protocol was identical except they were expected to begin the testing in the off medication state (no antiparkinsonian medicat ions within the last 12 hours). Once they completed the first testing session, the pa rticipants were asked to take their medications and then wait at l east 45 minutes until reaching their self described on state where their medicines were working optimally. The on state testing protocol was performed in the same order as during the off state. Figure 2-1 shows a flow chart for the experimental protocol for the fluctuators. Video Recording : To record task performance, a video camera was positioned directly in front of and slightly above the participant and used for the box and bl ock task and the UPDRS scoring. Outcome Measures The outcome measures included: 1) questions 20 -25 of the motor section of the UPDRS, 2) motor perform ance during: a) two modified versio ns of the Box and Block Test (BBT), b) two coin rotation tasks, and c) two lock rotation tasks, and 3) a force control task. All outcome

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24 measures were performed in the same order for ev ery participant, but the hand that performed the task initially was selected in a randomized fash ion. The BBT and the coin rotation task using a nickel are commonly used outcome measur es to test manual and finger dexterity.30, 48, 49 These tests were also used as a comparison measure to our additional new a nd modified tasks to provide other commonly performed movements for researchers and clinicians to easily incorporate as objective measures in testing and practice. The measures where two tasks are involved (a-c) were performed identically, except the object being manipulated differed in size. The different sized objects were used to measure and compare coordinated finger-thumb movements (pincher grasp) versus larger multi-finger/hand movements (multi-finger grasp). Finally, the force control task provided inform ation regarding maximum grip force and the variability to reach, maintain and release 20% of max force. The latter was used as a measure of precision force which is required for successful completion of finger-hand manipulation tasks Unified Parkinson Disease Rating Scale The motor section of UPDRS is clinical m eas ure used to determine severity of motor impairments. Using a 5 point ordinal rating system, each measure is scored from zero (absent impairment) to four (severe impairment), and the total score from each item is totaled. A greater score represents greater motor dysfunction. In this study, only the upper extremity motor questions 20-25 (see Table 2-1 for an explanation of each task) were completed and totaled for both the left and right hand. Box and Blocks Tests Participants performe d two vers ions of the Box and Blocks Test (BBT). The first version required the grasp, transport and release of 2.54 cm bl ocks as fast as possible from one side of a container to the other while goi ng over a midline barrier. The obj ective was to move 30 blocks, one at a time, where time to completion was r ecorded and used in analysis. For the second

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25 version, the task was exactly the same as the fi rst except the block size was larger (4.5 cm). The smaller block required more of a pincher grasp wi th precise prehension using the index or middle finger and thumb. The larger block involves the c oordination of at least three fingers and the thumb and requires less precise finger movement s but more of a multi-finger coordination. Coin Rotation Tasks On the command go, participants rotated a nickel 180 degrees as rapidly as possible for 10 rotations using the index a nd m iddle fingers and thumb.30, 48, 49 The second object was a small plastic container similar in weight and shape but larger in size (2 cm thick, 4 cm in diameter). The time to completion was used in analysis as an indicator of finger-thumb and hand dexterity. The number of drops during the trials was also recorded. Lock Rotation Tasks On the command go, participants rotated (a ) regular com bination lock using their index finger and thumb and (b) a second combination lock with a larger surface using a multi-fingerthumb grasp in a random order. The time to complete 10 full turns, startin g and ending, at zero was recorded and used in analysis. The smaller handle required more of a pincher grasp between the index finger and the thumb while the larger handle required multi-finger and thumb opposition and higher degrees of fr eedom necessary for task comp letion. These tasks simulate many activities of daily living such as turning on a lamp, turning a door handle, unscrewing a lid to a water bottle or a tube of toothpaste, all of which require the coordinated movements either via finger-thumb opposition or multiple fingerthumb opposition with pos sible slight wrist rotation. While seemingly similar, both coin and lock ro tation tasks provide slightly different fingerthumb-hand movements. The difference in the coin rotation task and the lock rotation task are the independent finger movements necessary to co mplete the rotations. With the lock task, the

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26 finger and thumb both contract simultaneously to produce the correct manipulation. However, with the coin rotation task, two or three digits ar e contracting at subtly different times in a more sequenced pattern. Force Control Task Grasping forces, norma l (grip) and tangential (l oad), for both limbs were recorded using a six-dimensional force-torque transducer meas uring 75 mm in diameter and 35 mm in thickness (Gamma model, Assurance Technol ogies Inc., Apex, NC) (Figure 2-2). Grip force is defined as the force along the axis normal to the flat surfaces of the transducer; load force is defined as the force along the axis tangential to the flat surfaces of the transducer. Before using the transducer, participants washed their hands with antibacterial hand sanitizer to remove any oils from the skin. Maximum precision grip (MPG), where patients squeezed the transducer with the index finger and thumb with as much force as possible for four seconds, was recorded for each hand unilatera lly. The maximal force achieved was used to calculate the target zone for the targ et precision grip (TPG) conditions. In the TPG conditions, the target force was 20% of the participants MPG. The target force and actual produced force were displayed on a mon itor directly in front of the participants. Participants were instructed to track, as accura tely as possible, the target force for 15s and performed two trials. An auditory stimulus re ady, go signaled the participants to start matching their force to the target force. Measures of force variability in cluded time within range (TWR) and a variability quotient (VQ). VQ is a nor malized root mean square error calculation that accounts for the differing targ et forces that each person attempts to match while TWR is the amount of time the patient actually produced a force that was within five pe rcent of the targeted force value. The performance from both trials wa s averaged for analysis. Figure 2-3 displays an image of the force gripper apparatus and th e force curves as seen on the monitor.

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27 ON versus OFF medications To help address Specific Aim 3, PD patients, who were considered fluctuators, tested in both off and on medication states. Fluctuators are patients who can determine a clear and consistent wearing off of the dopaminergic medications and score at least a one on question 39 of the UPDRS. To reiterate, testing in the on an d off states was used to determine the influence of dopaminergic medications on upper ex tremity manual dexterous tasks. Statistical Analysis Similar to Rigal, raw sco res from each hand fo r all outcome measures were converted to a z -score using the overall mean and standard devi ation calculated from both the left and right hand scores of every subject for each particular task. For tests where a low performance yielded a high score (tasks where time for completion was recorded), z -scores were multiplied by -1. To account for negative values (scores below the mean) and avoid where the sum of positive and negative values could equal zero, each z -score was converted to a T score using a linear transformation [T = ( z -score*10) +50].50 The same procedure was applied for all outcome measures. To compare the left and right hand scores, the following laterality quotient was calculated for each outcome measure using a per centage formula that adjusts for difference scores across participants: [(preferred hand non-preferred hand) /(preferred hand + nonpreferred hand)]*100. A smaller quotient equates to a smaller difference between the left and right hand performances and thereby represents deficits in the ipsilateral hand as well. To determine side onset effects, three different latera lity totals, small object total, large object total and combined total, were then compared by usin g an analysis of variance (ANOVA). To provide more meaning to these difference scores and to de termine clinical relevance, we compared each laterality quotient to SD of th e control participants laterality score.51 Since inherent differences between the two hands exist, especially in strong-RH, we also subtracted the mean

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28 LQ of the healthy controls from the LQ of each patient. Next, we compared the differences in large and small object laterality scores (Sp ecific Aim 1b) via a 3 x 2 (group, object size) ANOVA with repeated measur es on the last factor. To address the differences in force coordina tion deficits among th e groups (Specific Aim 2a), we used a one-way ANOVA with the calculated laterality quotient from left and right hands on the following variability measures: a) amount of time the participant was able to remain within five percent of the targeted value whic h was set at 20% of each individuals max force (TWR) and b) variability quotient comparing targ et and actual force (VQ). Secondary analysis was then performed using combined left and ri ght hand scores on the TWR and VQ measures to determine the overall force coordi nation deficits among the groups. Pearsons one-tailed bivariate correlations were performed to determine if force coordination is a mechanism of finger-thumb dexterity (Specific Aim 2b). Force variability measures included TWR and VQ while finger-thumb dexterity measures included the scores from the small box and block test, the small lo ck rotation task, and the coin rotation task. Moderate and strong correlation magnitude wa s set at r >0.3 and r >0.5, respectively while significance was set at an alpha level of 0.05.52 To examine the effects of medica tions of manual dexterity (Specific Aim 3), we used a 2 x 2 x 2 x 2 (group, object size, hand, state) ANOVA with repeated measur es on the last three factors. For the on/off UPDRS scoring, we used a two point change as a clinically relevant difference. This change is consistent with the estimates of Schrag et al.53 but was adjusted for the fewer motor items (questions 20-25; right and left hand only) that were incl uded in our overall score.

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29 Table 2-1. Upper extremity tasks for part III of the Unified Parkinson Disease Rating Scale Question Impairment Task 20 Rest Tremor Patients hands rest quietly on thei r lap; patient recites the months of the year in reverse 21 Action/Postural Tremor Patient bends elbows holding forearms parallel to the floor at chest height for 10 seconds; patient also touches finger to nose and then to testers hand 22 Rigidity Patient sits in a relaxed position while tester judges the passive range of motion of the patients major upper extremity joints (wrist and elbow) 23 Bradykinesia Finger taps: Patient taps thum b with index finger in rapid succession with widest amplitude; each hand separately 24 Bradykinesia Hand movements: Patient opens and closes hands in rapid succession with widest amplitude; each hand separately (fist to open) 25 Bradykinesia Rapid alternating movements: Patient rapidly pronates and supinates hands with widest amplitude possible; both hands simultaneously

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30 Figure 2-1. Flow chart for th e testing protocol of the fluctuators. Participant Consent Demographic and Clinical Data Practice Trials Perform Tasks Take Medications Rest & Wait Perform Tasks 1. UPDRS Measures 2. Three Box & Block Tests 3. Two Lock Rotation Tasks 4. Two Coin Rotation Tasks 5. Force Control Trials 1. Age 2. Disease Duration 3. Gender 4. Side of Onset 5. Type of 1st Symptom 6. Location of 1st Symptom 7. Time since Medication 8. Hand Pref (laterality quot.) 9. Years of Education

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31 Figure 2-2. Force gripper appa ratus used during testing. The arrows point to the embedded force transducers and the location for wh ich the index finger and thumb applied forces Figure 2-3. Force-Time curves displayed on the m onitor in front of the participant during the target force tracking task. The green line is the target force and the red line is the actual force produced. The x-axis is the time frame (128 Hz for 15 seconds) and the y-axis is the force measured in Newtons Index fin g er and thumb forces

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32 CHAPTER 3 REVIEW OF LITERATURE Hemispheric Characteristics The human brain is an am azingly complex, yet highly organized struct ure that regulates virtually all human activity. Separa ted into four distinct lobes a nd comprised of cortical and subcortical structures, the cerebrum is divided into right and left hemispheres that communicate to each other via the corpus callosum. While each side mostly resembles one another, micro structural and obvious functional differences exis t. Generalizations about control of certain functions are not only associated to a specific area of the brain, but are often lateralized to either the left or right hemisphere. In the early 20th century, a German anatomist, Korbinian Brodmann observed that a particular anatom ical structure corresponded to a particular function. Therefore, he developed a map of the brain based on the di fferences in the cellular architecture of the various parts of the cortex and assigned these functionally distinct areas a number. Though each area of the brain has an associ ated function, the brain function s as a whole and associates a number of different areas to complete a task. Bi llions of neurons create this vast network for communication to neighboring areas and to areas in the contralatera l hemisphere in order for an action to occur. Countless researchers have expl ored the structural a nd functional organization between and within the hemispheres uncovering mo tor, cognitive and behavioral responsibilities of each area and asymmetries that exist between hemispheres. Structural and Functional Asymmetries More recently researchers have used analysis of hemisphere pathologies in conjunction with brain imaging techniques to investig ate asymmetries and particular functional responsibilities for each hemisphere. In right-ha nders (RH), anatomical left-right asymmetries include larger left: front al and occipital lobes,54, 55 motor cortex and representation of hand

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33 muscles,26, 56, 57 hippocampal and amygdalar volumes,58 corticospinal tract,59 neuropil volume representing increased connectivity,60 planum temporale and parietale,61-65 postcentral gyrus representative of the prim ary somatosensory cortex,66 white matter density,67, 68 globus pallidus and higher amounts of dopamine,69 and deeper central sulcus in the hand representation region.60, 70, 71 Some functional asymmetries in RH include more efficient intracortical excitability, stronger interhemispheric inhibition and lower motor thresholds,22, 72-77 faster interhemispheric transfer time and hemispheric interactions73, 78 and stronger involvement during ipsilateral hand movements19-21, 23, 26, 27, 72, 74, 79-81 all in the dominant, left motor cortex. In lefthanders (LH), these structural and functional hemi spheric asymmetries are e ither not apparent or less pronounced than RH.19, 20, 22, 24, 25, 58, 72, 74, 79 Others reported that LH have a larger corpus callosum,82 more efficient hemispheric interactions73 and higher functional connectivity83 than their RH counterparts. The magnitude of these asymmetries depends on the degree of handedness.26, 84-88 General Cerebral Responsibilities Knowledge of these asymmetries led author s to examine left and right hem ispheric responsibilities in different task s. In RH, findings s how that not only is the left hemisphere responsible for the contralateral right side of the body, but in gene ral it is also responsible for bimanual and sequential movements,89-92 the control of preprogrammed ballistic movements,90, 93 movement planning, organization and selection,81, 94-96 verbal memory,97, 98 temporal attention,99 precise and coordinated i ndependent finger movements,30, 32, 99 and grip force scaling.100 More specifically and a focus of this research is th e role the left hemisphe re has during in some ipsilateral (left) hand movements such as precise and coordinated independent finger movements.19-27 Conversely, the right hemisphere is responsible for the contralateral, nondominant (left) side of body, realiz ation of goal-directed behavior,101, 102 control of limb

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34 positioning and end phase of reaching a target,103, 104 preparation of movement,105 and visiospatial memory/spatial attention.99, 101, 106 These responsibilities are well documented for right-handed subjects; however, in left-handers, the specific role of each hemisphere remains more ambiguous. The lack of consensus is due to irregularity of br ain organization among LH and the increased difficulty in fi nding and grouping LH individuals especially in a disordered population. In addition to the previously menti oned differences, about 90-97% of RH have language dominance in the left hemisphere wher eas anywhere from 40-70% of LH are reported to have a left language dominant. The remaining percent of LH either have bilateral or right hemisphere language dominance.61, 86, 87, 107 These language-dominant in consistencies may affect other hemispheric responsibilities for motor task s in LH. Taken together these findings suggest that LH are not just inverted RH. To avoid decreasing the chance of including those with a nondominant, left hemisphere, we limited our c ohort to only strong (above 65% on the Edinburgh handedness inventory) RH patients. Hemispheric Approach to Research Dysfunctions As previously noted, each area as well as each hemi sphere has a different responsibility in the partial or whole completion of specific task. Therefore, the area or hemisphere injured may cause certain disruptions in functioning that depend on the location of insult. Applying this asymmetric hemisphere functioning and observi ng specific dysfunctions after left or right hemisphere injury is useful to contrast he mispheric cognitive and motor responsibilities for specific tasks or skills. Researchers have recen tly examined the relationship among the side of symptom onset and particular c ognitive tasks in PD patients a nd have been better able to decipher and confirm some cognitive roles of ea ch hemisphere. Though there are some reports with no association of side onset to cognitive functioning,11, 14 the majority of studies do show some association7, 8, 10, 12, 13, 15-18, 108, 109 (see PD section for a detail ed discussion). While it is

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35 obvious that motor consequences occur with neurological problems, specific impairments depending on the side of hemispheric insult differ. This effect of side onset on motor consequences in PD has not been investigated; nevertheless, researchers have compared left versus right hemispheric damage in ot her neurological disordered populations. Apraxia, the inability to carry out learne d and purposeful activities not explained by primary motor and sensory deficits, has been found to be commonly associated to lefthemisphere damage. In 1920, Liepmann reported that right-handed patients experienced ideomotor apraxia (spatial and temporal errors ) more often after left hemisphere damage. Heilman and colleagues32 later reported that, in RH pe rsons undergoing Wada testing for intractable epilepsy, conceptual apraxia (a loss of mechanical and tool knowledge) was more frequently associated with left than right hemis phere lesions. In addition, errors in limb-kinetic apraxia, which affects precise, i ndependent finger movements, were similar for the left and right hand during left hemisphere anesthesia but more le ft than right errors were observed during right hemisphere anesthesia. This asymmetry where the left-hemisphere mediates motor deftness in both hands and the right hemisphere mediates mo tor deftness only in the contralateral left hand was only observed in RH with left hemisphere language dominance (typical brain organization). Conversely, patients with right or bilateral hemisphere dominan ce or non-right handed patients (atypical brain organization) had a contra lateral hemispheric control of each hand. The observation that the left hemisphere po ssesses significant control over ipsilateral movements appears to be a comm on finding among several research groups. For example, stroke researchers have shown that afte r a unilateral hemispheric stroke, the unaffected ipsilateral arm may not have normal function.28, 29, 31, 33, 93, 110-112 Haaland and Harrington29 and Sunderland et al. 33 observed that RH patients with left hemisphere damage had deficits in both the right

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36 (contralateral) and left (ipsilate ral) hand during a variety of motor tasks whereas those with right hemisphere damage were more prone to produce only contralateral deficits. Schaefer113 also investigated motor deficits following stroke a nd found that patients with left, but not right, hemisphere damage produced deficits in specifica tion of initial trajectory features by showing a reduced modulation of acceleration amplitude and pa tients with right, but not left, hemisphere damage produced deficits in final position accura cy. These findings support the notion that each hemisphere contributes differentially to the contro l of initial trajectory an d final position thereby reflecting lateralization in cont rol of specific movements. Task specific motor disabilities also depend on the side that is damaged. Spinazzolas group114 examined two types of errors that ha mper trunk movements: apraxia and postural instability. They reported postural reactions we re more frequent am ong patients with right hemisphere lesions and apraxic responses were overwhelming in those with left hemisphere lesions. Hanna-Pladdy et al.30 examined the speed, precision, and independence of finger movements in patients with unilateral lesi ons. They found persons with left unilateral hemisphere lesions had contralateral and ipsilatera l deficits with greatest ipsilateral deficits on tasks requiring precision and coordinated inde pendent finger movements and suggested that hemispheric specialization is dependent upon the natu re of the motor task. To determine if this hemispheric specialization extends to larger hand movements, we incorporated tasks that involve multi-finger-thumb grasping in addition to index finger-thumb tasks that are often analyzed. Altogether, these studies pr ovide evidence for differing motor consequences depending on the side of injury and indeed s how a stronger ipsilatera l role of the left hemisphere for dexterous movements in right-handed patients. Many research ers have examined the relationship of side of symptom onset to particular c ognitive decline in PD and to motor impairments in other

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37 neurologically disordered populations. Yet speci fic motor problems, such as finger and hand dexterity, depending on the side of symptom onset have not been thoroughly investigated in PD. A detailed discussion of the both control of manual dexterity and consequences of PD that could disrupt fine movements is necessary before attempting to examine this side of onset influence on upper extremity motor dysfunction. Manual Dexterity Manual dexterity is defined as the ease and skill in using the hands and manipulating objects. Previously, dexterity was specif ic to the ability of the ri ght hand; therefore, the term deftness was used to refer to the dexterity of eith er the left or the right hand. Deftness is further defined as the ability to perform skilled, precis e, coordinated and independent finger movements and the hand with better performance is said to be the dominant hand. More recently, these terms for many authors are used interchangeably where bot h terms refer to skillful movements of either hand. During fine manipulation tasks or more gr oss hand movements, the brain areas activated and the underlying mechanisms necessary to perform the appropriate movement for each specific task have been investigated. Brain Areas Involved Many researchers have examined the areas of the brain involved when perfor ming dexterous finger and hand movements using both PET and functional MRI. While the main activation sites include the prim ary motor cortex and the motor association areas (also known as the lateral premotor cortex and supplementa ry motor area (SMA)) of the contralateral hemisphere, other areas that are concurrently acti ve include the basal ganglia, corticospinal tract, bilateral secondary somatosensory areas (supe rior and inferior pa rietal cortex), and cerebellum.115 As previously discussed, parts of the ip silateral primary motor cortex are also activated during hand movements es pecially for RH during left ha nd tasks. Some of these brain

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38 areas will be discussed briefly to highlight their functional respons ibilities during manual dexterous activities. Primary motor cortex The mo tor cortex is located in the precentral gyrus which is in the rear portion of the frontal lobe, just before the centr al sulcus and is divided into two main areas, Area 4 and Area 6. Along the central sulcus, Area 4, known as the primar y motor (M1) cortex, is one of the principal areas involved in motor function by generating the neural impulses that c ontrol the execution of movements. Corticospinal cells in area 4 proj ect directly to the lower motor neurons and communicate the appropriate commands to the specific muscles necessary for task completion.116-118 Association areas Immediately rostral to Area 4, th e motor associ ation area, also termed premotor area (Area 6) includes the supplementary motor area (SMA) and lateral premotor area and is involved with the planning of a movement. Many motor actions ar e often responses to visual or auditory cues, and cells in the premotor area are active during su ch externally cued movements. Therefore, the main role of the premotor cortex involves sensory guidance of movements and helps to orient the body before reaching for an object. Alternatively, the SMA is involved in the programming of all movement sequences. For example, the reaching movement needs to be sequenced by the SMA after the premotor area provides the proper coordi nates in extrapersonal space. The SMA is also involved in internally generated movements, such as grabbing an object that is not precipitated by an external cue. The memory/m otor patterns necessary for this movement are encoded in cells within the SMA and send the instructions for th e movement to M1. Therefore, the appropriate muscles can then be innervated with the corr ect amount of force and speed (execution of the

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39 movement). Both the premotor cortex and the SMA send information to the M1, basically guiding it as to which movements to execute. Basal ganglia As their name suggests, the basal ganglia consis t of a set of neural structures buried deep inside the cortex. The main basal ganglia are the caudate nucleus, th e putamen, and the globus pallidus (also known as the striatum). These ganglia, or clusters of nerve cells, receive information from almost all regions of the surr ounding cerebral cortex, process it, and then feed it back to motor areas of the cortex a nd down to the brainstem via the thalamus. The basal ganglia are involved in the pla nning and execution of a particular movement pattern and the inhibition control of certain movements. If damaged, extraneous, purposeless movements (tics, tardive dyskinesias) will appear. Th is role of the basal ganglia in initiating and regulating motor commands becomes clearly appare nt in people whose basal ganglia have been damaged, such as persons with PD. These indivi duals often struggle to initiate and execute planned movements as well as experience trembli ng of a body part or ar e slow to complete a movement once initiated. Furthermore, since th e SMA is a major projection area for the basal ganglia and is important for internally generate d movements, patients with damage to the basal ganglia show greater abnormalities during thes e self-generated movements as opposed to movements made in response to external environmental cues.119 These internally driven motor programs are essential to complete numerous manual dexterous movements. For example, using a prec ision grip during a lif ting task requires a complex yet reproducible sequence of activity th at involves arm position, pr eparation of fingers for gripping the object and then th e appropriate development of finger forces. Cutaneous afferent (sensory) information is necessary during object ma nipulation and modifies the parameter set if a change in loading of th e object is encountered.120 With a loss of or misleading afferent

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40 information due to a disruption of the basal gangli a circuit to the SMA, inappropriate force levels occur. In patients with PD, abnormally high levels of grip forces, delays in reaching max force, and prolonged force decays (force release) are common.121, 122 These deficits create problems during many fine precise finger and hand activitie s (more on basal ganglia and loss of dexterous movements in the Parkins ons disease section). Corticospinal tract The M1 relays the neural output to the appropr iate mu sculature via the corticospinal tract (CST). The corticospinal or pyramidal tract is a massive collection of mo tor axons that carries signals from the cerebral cortex of the brain and the spinal cor d. Most of the axons in the CST originate in the regions of the M1 and form syna pses, directly or via interneurons, with motor neurons in the gray matter of the spinal cord in the lateral part of the ventral horn. These motor neurons are especially important for fine motor control of the di stal musculature and for steering extremities and manipulating objects in the enviro nment. Lesions involving the CST result in the inability to make fractionated (independent) movements of the wrist or fingers. Lawrence and Kuypers116 transected both pyramidal tracts in monkeys in order to assess their motor functions. Within six to ten hours after recovery from the anesthesia, the animals were able to sit upright, but th eir arms hung loosely from their shoulders. By six weeks, the monkeys could walk and climb rapidly. However, the animals' manual dexterity was poor. They could reach for objects and grasp them with an unfractionated finger hold, but they could not manipulate their fingers independently to pick up small pieces of food. They also incurred difficulty in releasing their grip. In contrast, they had no difficulty releasing their grip when they were climbing the bars of their cage. The result s confirm that the CST controls hand and finger movements and is indispensable for moving th e fingers independently when reaching and manipulating. Similarly, Porter123 suggests that the principal constituent of the motor system

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41 underlying the performance of highly skilled finger movements is the corticospinal pathway and, more specifically, its corticomotoneuronal component. About 80% of these motor neurons of the CST decussate to the contralateral side in th e medulla oblongata and travel in the lateral corticospinal tract and synapse with either inte rneurons or lower motor neurons at the correct level of the spinal cord. Theref ore, in general, one side of the body is controlled by the opposite side of the brain. Ipsilateral hemisphere Since some motor neurons remain on the ipsila teral (same) side of the body, the ipsilateral hemisphere has been theorized to play a role in certain motor functions. This ipsilateral activation is larger in RH indivi duals and is not as apparent in the right hemisphere during right hand movements. Besides the lesion or damaged hemisphere research, as previously reviewed, numerous studies using brain imaging techniques support this asymmetry of ipsilateral control.20, 21, 23, 24, 26, 80 Kim et al.20 revealed that the right moto r cortex was activated mostly during contralateral finger movements in both RH a nd LH subjects, but the left motor cortex was activated substantially during ipsilateral movements in left-handed subjects and even more so in right-handed subjects. Singh et al.24 confirmed that during alternati ng finger apposition tasks, the contralateral sensorimotor cortex in RH was significantly larger than that of the ipsilateral cortex for tasks with either hand while the ipsilateral activated area was significa ntly larger during lefthanded tasks. For LH, there was no significant difference. Mattay et al.21 revealed that there is more ipsilateral activation in sensorimotor cortex the less automatic the task that is performed and argued that differences in th e degree of ipsilateral activation could reflect differences in the degree of automaticity in performing the task. Li and colleagues80 also observed this greater activation of the left hemisphere during ipsilate ral left-hand motor task s; however, they found no significant differences in the ac tivation of the ipsilateral hemi sphere during sensory tasks.

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42 Possible reasons for this greater ipsilatera l activation during non-dom inant, left handed movements have been theorized. One possible theo ry is the predominance the left hemisphere has for planning motor actions.95, 96 Therefore, whether the right or left hand is involved in the task, the left hemisphere is responsible for the planning of that particular movement. For right hand movements, the message is sent directly from the left hemisphere to the right hand; however, for left hand movements, the message is se nt from the left hemisphere to the left hand either via the right hemisphere or possibly via the ipsilateral corticospinal tracts directly.26 Ziemann26 reported that hemispheric asymmetry of ips ilateral motor cortex activation existed in distal musculature and suggested it was one property of motor dominance of the left cortex. He examined MEP amplitude in the non-task hand during complex finger sequences to determine the hemispheric asymmetry of ipsilateral cont rol. The MEP amplitude was significantly less when the right hand rather than the left hand was the task hand. To explain this phenomenon, he proposed two ideas: in right-hand dominant individuals (1) the left motor cort ex is more active in ipsilateral hand movements; in other words, left hand movements have more than the typical 10% of ipsilateral tracts aiding movements, or (2) the left motor cortex exerts more of an inhibitory control over the righ t cortex decreasing the bilateral synergy when the right hand moves. Todor and Lazarus124 theorized that the right hemis phere is diffusely represented whereby neural activation is more likely to spread into motor ar eas of the left hemisphere. In contrast, the left hemisphere is more foca lly represented and does not rely on the right hemisphere for motor planning or execution. The diffuse networking of the right hemisphere results in a reliance of the left-hemisphere dur ing left hand movements and further provides support for the ipsilateral hemispheric asymmetries.

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43 The neural mechanisms that create the greate r ipsilateral control f ound in RH during left movements is still debatable and quite controversia l; however, its existence as well as the other brain areas involved during finger and hand moveme nts is fairly well-established. Furthermore, the exact mechanisms, such as force coordi nation, necessary to achieve the appropriate movements during manual dexterous tasks are mostly unknown due to the extremely complex structure of the hand and the multitude of movements it performs. Mechanisms of Dexterity Nume rous manual tasks that are essential for everyday life, such as pressing a cell phone button, picking up a penny, or fastening a watch or necklace, are the result of a complex neuromotor-mechanical process orchestrated with pr ecision timing by the brain, nervous system and muscles of the hand. Depending on the nature of th e task, the hand arrangem ent may be slightly similar or quite different. For example, a precision, pincher grasp between the thumb and index finger may be necessary to pick up a small object or turn a screw by hand, whereas a whole hand (multi-digit) grasp may be necessary to grab and turn a doorknob. In both cases, the fingers and thumb contract simultaneously. Actions such as typing, buttoning a shirt or tying a knot require more sequenced, independent, coordinated actions of the fingers alone or in conjunction with the thumb. In other words, manual dexterous moveme nts can require one finger or the whole hand in unison or in sequence; therefore, the num ber of arrangements the hand must undergo is limitless. The appropriate motor program involving these hand maneuvers must be present to successfully manipulate an object or to perform a manual task. While it is difficult to know how each of the hands 30-plus muscles contributes to everyday functions, some underlying neural mechanisms of the relevant motor program include the direction and magnitude of force, availability of sensory feedbac k, temporal and spatial accurac y, and joints and muscle groups involved. Though all mechanisms are extremely im portant and must be considered for task

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44 completion, the force coordination of the finger-thumb and multi-finger and thumb opposition involved during precision grip wa s a focus in this research. Force control and manual dexterity Moveme nt of the fingers and hand relies on a sophisticated motor system with complex biomechanical and neural architecture. Understanding the control strategies that underlie coordination of movements and forces necessary fo r the infinite array of tasks is challenging to understand. As previously reviewed, the human hand is used both to grasp objects of all shapes and sizes through the use of two or more digits as well as perform the skill ed, individuated finger movements necessary for more dexterous activitie s, such as handwriting, threading a needle, and playing a musical instrument. A key feature of su ch tool use and manipula tion is the ability to control fine movements and forces of the whole hand and at individual fi ngers. Milner et al.125 noted that in tasks such as gr asping that require isometric fo rce, stability is achieved by regulating finger stiffness via correct joint angl es with corresponding muscle forces. He further separated the requirements necessary during activ ities such as gripping and manipulating objects into force direction and finger posture and their corresponding musculatur e necessary for each. Force direction includes the production of appropr iate fingertip forces and is controlled by intrinsic finger muscles that provide finely graded forces during pinch. Conversely, finger posture includes the insurance of m echanical stability of the joints and is controlled by extrinsic finger muscles, which have greater stiffne ss and are more suitable stabilizers. These appropriate fingertip forces between th e tips of the thumb and index finger during the manipulation of small objects require a precise coordination between the grip force (normal to the grip surface) and load force (tangential to the gr ip surface). This `grip-lift synergy' is characterized by smooth and parallel increa ses in both the grip and load forces.126 In addition, the appropriate direction and magnitude of torque at each of the finger joints that must be

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45 selected depends on the segment lengths and joint angles of the finger(s). While segment lengths remain constant, comparable fingertip force vectors can be achieved by changing the joint angles. Since at least two or more muscles contribut e to torque at each joint (seven muscles exist in the index finger alone) and the joint angles have numerous degrees of freedom available to execute a task, it is safe to conc lude that an infinite number of muscle force combinations can be applied to achieve ones final goal of movement.125 To help combat this motor programming complexity, coordination patterns with simultaneous motion and force of the fingers are developed to reduce the number of independent degrees of freedom during finger and hand grasps.127 The use of individuated finger movements in which a coordinated timing sequence involving rapid contraction and re laxation of each digit at different moments requires additional control to individuate the motion or force of each di git. In types of hand use, such as tying a knot or fine manipulation of a small object, finger movements are individuate d considerably more, although multiple fingers still tend to move together. For example, an elegant pianist performance is achieved when one finger move s enough to strike the intended key while the other fingers move little enough not to strike any unintended keys. For increasingly fine manipulation tasks, the need for independent control of individua l degrees of freedom increases where each degree of freedom becomes necessary for some particular manipulative finger movement. Whether the task requires individuated, yet coordinated finger movement or simultaneous grasping using a single digit or multi-digit-thumb opposition grip, hemispheric damage can result in inadequate control of the fingers and hand th ereby affecting proper task completion. In past experiments, maximum force has been analyzed as a measure of lo ss of motor functioning.128, 129

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46 However, when analyzing activities that invo lve the manipulation of small objects, it is important to also consider pr ecision force coordination defici ts as the limiting factor of performance detriments. Differences in these two types of grips exist and are explored next. Precision versus power grip forces Handgrips can be divided into precision a nd power grips from a functional and a phylogenetic perspective.130 During the power grip, all digits are flexed around an object to provide high stability and is considered palm ar opposition grasp. During the precision grip, the tips of the thumb and fingers are used for the manipulation of small objects, and it requires the stability of independent finge r movements involving fine cont rol of the directions and magnitudes of fingertip forces.131, 132 Several decades ago, Lemon133 discovered, in primates, that control of fingertip actions with a precisi on grip engage different neural circuits than a power grip and reported that corticomotoneurona l cells (pyramidal trac t neurons) were more active during fractionate d movements of the fingers than during a ball or power grip. Though target muscles may be activated during both a precision and a power grip, a sub-population of M1 neurons innervating hand muscles are excl usively activated while conducting a precision grip. This indicates that a precis ion grip engages neural circuits that are different from those engaged during the power grip.134 A few years follo wing, Datta et al.135 found that, in humans, TMS produced a larger EMG response of first dorsal interosseous during finger abduction compared to a power grip and that the motor co rtex was more excitable, hence more active, during independent finger movements compared nonprecision muscle contraction. He suggested that these findings support the theory that the CST was primarily responsi ble for the control of independent, coordinated, precise an d fast finger movements. Ehrrson136 also compared precision versus power grips and re ported that the primary motor cortex, premotor and parietal areas were important for control of fingertip forces during precision gr ip. Moreover, the power

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47 grip was associated predominately with contrala teral left-sided activity, whereas the precisiongrip task involved extensive activatio ns in both hemispheres. Duque et al.137 investigated deficits in the coordination of fingertip forces when grasping and lifting an object between the thumb and index finger in patients with congenital hemiplegia (CH). The duration of the preloading and loading phases and the time-shift be tween the profiles of the grip and load force rates were significantly longer. Because the time-shift was also significantly co rrelated with impaired dexterity, the authors suggested that impaired finger dexterity may be due to the deficits in precise fingertip fo rces. In addition, they reported th at digital and manual dexterity was also altered in the non-paretic hand of CH pa tients and concluded that this deficit may reveal the contribution of the lesioned hemisphere to the control of ipsilateral skilled finger movements.137 These findings not only show the differences in precision and power grips and how a measure of one may not be specific to a detriment of the other, but also further support the responsibility of the ipsilateral hemisphere during fine finger and hand movements. In our research, we measured both maximum voluntary force as well as targeted precision grip coordination during a pincher grasp task to explore the role of precise grip forces on manual dexterous tasks. Finger versus multi-finger forces In addition to the importance of a precision gras p as a factor for manual dexterity, the involvement of particular finge rs to make the appropriate grasp must also be considered. Precision grasps are necessary for the majority of behavioral uses of the hand. Grasping tasks can be broadly divided into those requiring simu ltaneous use of multi-digit-thumb opposition or single digit-thumb opposition. Although the fina l postures of the fingers differ and must conform to the shape of the object, the movement s that close the fingers around an object are in a coordinated fashion and actually start long befo re contact. During a multi-finger grasp, the

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48 simultaneous motion or force production of the joints are constrained to move or exert force in a relatively small number of coordi native patterns (or synergies) that might simplify the control of the large number of mechanical degrees of freedom and muscles of the hand. Thus, twofingered precision grips are theorized to be inhe rently less stable than multi-digit grips. The control of direction and magnitude of the applied finger forces needs to be more constrained at the level of individual digits thereby making the precision grip to be more demanding in terms of neural control.131 In contrast, Santello and Soechting43 stated that when only two digits grasp and hold an object only one for ce sharing pattern between the thumb and the opposing finger is available (the force of the opposing finger must be the same as the force of the thumb). Yet, when all five digits are involved in grasping and holding an object, the equilibrium of forces can be achieved by many combinations of the fingertip force distribution exist among the digits as long as the sum of the forces of the four fingers is equal to the force of the thumb.43 In either the precision grip with a single digit and thumb opposition or with a multi-digit and thumb opposition, coordinated, precise fingertip forces are necessary to insure proper completion of a given task. A common technique currently used to determine the ability or deficits in producing the appropria te force level requirements is to reproduce a constant isometric target force for a given period of time at a set percentage of ones maximum voluntary contraction.128, 138-140 Voelcker-Rehage and Alberts140 applied this procedure using elbow flexion and reported more variability in th e release of grip force in olde r adults. Also after hemispheric damage, both single-digit-thumb opposition grips and multi-digit grasping can be compromised resulting in a loss of fi nger and hand dexterity. Loss of Dexterity Disabilities with finger and hand function occur as a conseq uence of age as well as m any types of neurological disorders su ch as stroke, PD, dystonia, et c. as well as damage to the

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49 musculoskeletal system. With respect to neurologi cal disorders, a wide range of dysfunctions can occur depending on the area(s) that are affected. Cell death or dama ge to any aspect involved in any portion of a skillful hand movement, such as areas involved in the motor planning or executing the action to association areas necessary to integrate sensory information as well as neurotransmitters that are necessary to relay th at message, can disrupt the proper completion of that task. For example, dopamine depletion in th e basal ganglia causes a dysfunction that affects these movements by disturbing the cortico-basal ganglia loop which aids in initiating the movement as well as inhibition of extraneous movements thereby disrupting hand and finger dexterous movements. These motor disturbances can be as minor as slowness to initiate a contraction to complete inability to generate a movement whatsoever. A broad term used to describe some difficulties in executing motor tasks is apraxia (previously define d as the inability to execute a skilled motor act when disability is not entirely caused by impaired comprehension, weakness, sensory loss, ataxia or involuntary movements). While apra xia has been subdivided into many forms, limbkinetic apraxia (LKA), is a loss of dexterity or deftness that has been associated with PD and other movement disorders. With LKA, movements are slowed, stiff, coarse and clumsy which results in a loss of fine and precise, indepe ndent finger movements and problems coordinating simultaneous movements.32, 141 In the case of PD consequences, these movement deficits may or may not be related to the cardinal parkinsonian impairments such as bradykinesia or rigidity. Similarly, it is also unknown if the insufficient muscle force and the under-scaling of motor output during movements is the cause of parkin sonian dysfunctions th ereby affecting manual dexterity.

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50 Moreover, due to the left hemisphere having some control over the ipsilateral hand in RH, some loss of dexterity has also been witne ssed in the hand ipsilateral to the affected hemisphere.28, 29, 31, 33, 93, 112 In this study, we analy zed ipsilateral and contralateral deficits during finger-thumb and multi-finger-thumb grasping and precision grip targeting in persons with PD. More specific force coordination and finger and manual dexterity problems in persons with PD are discussed in detail in the next section. Parkinson Disease Idiopathic (of unknown cause) Parkinson disease is a slowly progressive neurodegenerative disorder that affects move ment muscle control, and balance. The symptoms of PD develop as nearly 70-80% of the dopaminerg ic cells of the basal ganglia are destroyed. As briefly discussed previously, the basal ganglia are sub-cortical, in terconnected nucle i that receive projections from the motor and premotor areas of the frontal cortex and areas of the parietal cortex as well as the limbic system and project back to the frontal cortex via the thalamic nuclei. These parallel circuits are quite complex yet highly organized an atomically and neurochemically and function to select and facilitate certain mo tor behaviors while suppressing other conflicting activities. Each circuit is also involved in sensorimotor integration or in the translation of specific sensory data into information for movement production and is involved in the transformation of action plans, or movement formulas, to motor acts.142 Mink143 succinctly described the role of the basal ga nglia in terms of a gate that moderates a response by selectively inhibiting competing input from the cortex. Theref ore, basal ganglia lesi ons or disorders could disrupt the organized production of purposeful movement by floodi ng the system with competing response options leading to inco rrect movements or problems initiating those movements. The depletion of dopamine, an essential neurotransmitter of the basal ganglia, affects the activity of the major inhibitory output nucle i and final thalamic inhibition thereby creating flawed motor

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51 outputs.144 These movement and coordination problems from the dopamine deficiency create the major symptomatology of PD. While the exact mechanism of how dopamine is lost is still unidentified, a combination of genetic susceptibil ity, biologic factors, and environmental assaults may be possibilities. Motor Symptoms Specifi c motor symptoms or impairments are characteristic of PD. To clinically diagnose PD, patients must show a sustained response to dopaminergic medication as well as two of the following four cardinal features: ri gidity, bradykinesia, resting tremor, and/or postural instability with at least one feature being ri gidity or bradykinesia. Clinicians and researchers often clinically sub-divide patients depending on type of symptoms and/or age of the patient. Signs and symptoms could lead to a tremo r dominant, akinetic rigid, or mixed labeling of PD while age of onset could categorize patien ts into early or late PD sub-t ypes. A final classification used to group patients is based on the site of symptom onset (distribution and side ). Patients can either have symptoms more prevalent in the upper (UE) or lower extremity (LE) as well as on the right or left side of the body. The terms right and left side onset (RSO and LSO, respectively) are commonly used when referring to which side of the body (not hemisphere) displayed the impairments initially. While initial symptoms can occur bilaterally (about nine percent145) most often symptoms are asymmetric in nature. These unilateral symptoms typically serve as a clinical parameter to differentiate the disease from other neurodegenerative parkinsonian symptoms.146 With disease progression, symptoms can develop on the non-impaired side; however, the side with the initial first symptoms usually remain s more affected throughout the course of the disease.6 Researchers have analyzed these sub-clinical categories of PD as possible predictors of differing motor, cognitive, behavioral and other consequences. Gasparoli determined that a slow

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52 course progression was characte rized by earlier age onset and more lateralized motor signs. Stewart et al. investigated the differences in upper (UE) and lower extremity (LE) on the motor and behavioral quality of life and reported that LE was more st rongly correlated to ones QoL compared to the UE.145 Katzen et al.12 reported that patients who de velop tremor on the right side of the body represent a distinct subgroup of PD patients who exhibit relative sparing of cognitive function while those who develop br adykinesia or rigidity or left side tremor demonstrate greater cognitive deficits. The asymmetr ic symptomtology of PD has sp arked a plethora of research7-10, 12, 16, 17, 147 to understand possible mechanisms behind th e lateralized motor impairments and to inspect different consequences that result with both left and right sided symptoms. Asymmetry of Motor Symptoms Wh ile the asymmetry of motor symptoms is co mmon and fairly apparent in persons with PD, the explanation or reasoning of why this occurs is largely unknown. Researchers propose different theories on this asymmetr y. One theory is the normal inbor n variations in the number of nigral dopaminergic neurons where the dege nerative process affects both sides equally;6 however, the side with the reduced initial numbe r of neurons reaches the critical point of vulnerability earlier.148 A second theory is the greater vulner ability of one substantia nigra. Once degenerative process starts, accelerated cell death occurs first on that side.5 A final theory they suggest is a congenital or acquired weakening of the blood brain barrier that is more pronounced in one side of the nigra than the other. In th is case, weakness would allow toxic environmental factors to invade vulnerable st ructures and initiate the dege nerative process on one side.148 Though these theories are just possibilities in why asymmetries exist, Knable et al.149 examined reuptake differences and dopamine amount s and reported a significant lateralization of dopamine-D2 receptor availability where extracellu lar concentration of dopamine was less in the striatum contralateral to maximal clinical signs compared to ipsilateral striatum. Similarly,

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53 Innis,150 using single positron emission computed tomography imaging, found changes in dopamine transporter binding cont ralateral to the side of initial motor symptoms. Finally, Huang151 associated the ventricular enlargement (bra in atrophy) to motor symptoms whereby the more symptomatic side showed greater contra lateral ventricular enla rgement/ brain atrophy on that side. Whether theory or facts, mechanis ms do exist and affect th e basal ganglia thereby disturbing cognitive, psychological and motor func tioning. Using the asymmetric nature of PD, researchers have explored specific consequences that occu r with a left versus a right side onset. Asymmetry of Cognitive Deficits PD is a useful model in which to understand the effects of sub-cort ical degeneration on cognitive functions associated with each hem isphere. The amount of asymmetry and side affected may influence particular cognitive deficits. Researchers have shown that cognitive decline is highly correlated to motor severity152 and that the side of motor symptom onset can affect different cognitive, visiospa tial and perceptuomotor functions.7-10, 12, 13, 15-18, 108 In 1984, Direnfield108 found patients with a RSO had more cogni tive sparing while those with a LSO showed more widespread cogniti ve deficits. Rogers et al.109 examined patients with prefrontal damage and asymmetric PD onset and discovered that only those with left frontal lesion showed impaired task-switching, a component of ex ecutive function. Moreover, Tomer and colleagues16 reported that patients with LSO (a right hemis phere dysfunction) consis tently performed more poorly on cognitive measures than patients with RSO whereas Williams et al.17 found that a RSO (a left hemisphere dysfunction) was a stronger pr edictor of cognitive function as measured by the Mini Mental Status Examination and the Dementia Rating Scale than a LSO. Katzen, Levin and Weiner12 correlated the type and side of symptoms to general cogni tive functioning and specified that RSO patients with only tremor-dominant sy mptoms had relative cognitive sparing. Due to the inconsistencies, a growing number of research ers are considering the specific attributes that

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54 each cognitive task measures when associating side onset with cognitive disability. In Amick et als study,7 PD patients with a LSO performed poorer on visual memory tasks and those with a RSO did worse on verbal memory tasks. Spicer et al.13 demonstrated that RH with RSO had problems with serial digit learning, confronta tional naming and verbal associative fluency (responsibility of dominant hemisphere) but not with form sequencing learning, line orientation and facial recognition (responsibil ity of non-dominant hemisphere ). Similarly, performance on a spatial memory task theorized to involve the ri ght-hemisphere was worse for PD patients with LSO.9 Furthermore, some authors noted hemineglect or perceptuomotor problems with tasks on the left side after a LSO. PD patients with a LSO had more difficulty with correctly bisecting a line,15 drawing a rectangle10 and more occurrences of bumpin g into left doorways and walls.8 While these studies prove that side onset infl uences cognitive functioni ng, motor consequences and side onset has not been sy stematically explored. Understa nding the possible motor deficits that occur with PD is essential before trying to decipher the possible differing motor effects of each damaged hemisphere. Motor Deficits Impaired m anual dexterity and object manipulat ion is often a debil itating consequence of PD. As discussed, the basal ganglia is responsi ble for regulating movements via selecting and initiating certain motor behaviors while suppress ing or inhibiting other conflicting activities. For persons with PD (dysfunctional ba sal ganglia), dexterous tasks beco me problematic such that the delayed initiation or slowness (bradykinesia, ri gidity) during the movement and/or trembling (tremor) or other undesired movements interferes with the tasks requirements. Furthermore, some researchers believe that deficits in inde pendent but coordinated finger movements extend beyond tremor, rigidity and bradykinesia impair ments such as limb-kinetic apraxia (LKA)

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55 (previously described in the loss of de xterity section). Quencer and colleagues49 examined LKA via coin rotation and speed of movements via finge r tapping in persons with PD. They found that while speed of movements was not affected, the ability to manipulate and rotate the coin was affected thereby suggesting that LKA is independ ent of bradykinesia and rigidity. Because the tests were performed in the on state, th ey also concluded LKA might not respond to dopaminergic medications. Whether or not it is tremor, rigidity or bradykinesia as the root cause of the manual dexterous deficits or some other disorder of def tness such as LKA, it is well understood that many persons with PD struggle or are slow to perfor m activities such as fastening a button, turning on a la mp, twisting off a top, clasping a necklace, etc. Unfortunately, the exact neural mechanisms underlying thes e cardinal features are mostly unknown. Force Deficits Since the skillful ma nipulation of objects that requires prec ise coordination of fingertip forces126 is quite impaired in PD, many researchers ha ve analyzed force output as a main motor output parameter disrupting movements. Milner-Brown153 showed that damage to the basal ganglia produced abnormalities in force recruitment. More recently, Spraker et al.154 used functional magnetic resonance imag ing to determine the regions of the basal ganglia, thalamus, and motor cortex that were involved during pi nch-grip contractions with increasing force amplitudes. They confirmed the role of the basal ganglia in force production and reported specifically that the internal por tion of the globus pallidus and the subthalamic nucleus had an increase in percent signal change with the increas ing force that was not apparent in the external globus pallidus or other areas of the basal ganglia. These findings imply that the basal ganglia as a whole do affect force output and that the role of the individual basal ganglia nuclei is specific to specific parameters of motor output.

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56 As for specific force deficits in persons with PD, researchers have examined several force outcome measures during a variety of object mani pulation tasks, such as grasp, lift and hold or release, precision and power grips as well a finger-thumb and multi-digit-thumb opposition tasks. Research on grasping using precision grip with the thumb and index finger has also shown that PD patients tend to exhibit a slow ing of the preloading phase and a stepwise development of grip force.121, 155 Fellows et al.121 also noted that patients tended to produce excessive forces, both in peak and in static grip forcewhile Ingvarsson et al.155 reported no differences in peak force amplitude between PD subjects and controls. Stelmach and colleagues139, 156 observed that PD patients exhibit a preserved ability to scale the force amplitude; however, their responses show a prolonged development of the required force rate with segmented force increases resulting in several oscillations making the timing of the overall movement much slower. They concluded that PD patients have an inhere nt limitation in the rate at wh ich they can develop and quickly alter force during rapid and discrete isomet ric contractions. Moreover, Gordon et al.37, 157 observed that patients were slow to initiate grip force and had prolonged transitions between the various phases of grasping and lifting a small devi ce using the precision grip but most aspects of object release during preferred speed s, coordination of the grip a nd load forces, and the duration of isometric force increase we re not greatly disrupted in PD In contrast,, Corcos et al.158 did find that patients had a slower cessation of force durin g elbow flexion of a specified percent of their max force and Wing et al.159 observed a slower decrease of pincher force with their more affected hand. In a review article, Berardelli38 suggested that parkinsonian patients with bradykinesia do under-scale the appropriate muscle force to the ta sk at hand noted via decreased amount of EMG activity thereby undershoo ting their target and approaching it in several smaller steps. This

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57 under-scaling is due to insufficient recruitment of muscle force during the initiation of movement rather than to any intrinsic limitation in motor execution or rigidity, tremor or muscle weakness and may reflect the role of the basal ganglia in selecting and reinforcing appropriate cortical activity patterns duri ng movement planning.38 Though many inconsistent findings, the majority of researchers examining the mechanisms of impa ired hand dexterity duri ng precision grip tasks have found certain deficits in force coor dination depending on the task paradigms. In addition to precision finger-thumb tasks, othe r force coordination grasps as well as tasks involving multiple digits or limb segments have been investigated. Since every-day tasks often involve whole-hand grasping and in dividuals with PD have diffi culty temporally coordinating multiple effectors during movement, Muratori and colleagues41 examined the ability of individual fingertip forces to counter balan ce forces exerted by the thumb during whole-hand grasping and lifting of an object. They found anticipatory force mechanisms appear to be a) greatly increased in multi-digit grasping as opposed to findings from two-digit grasping studies, b) inaccurate in initial scaling of fingertip force amplitude and sharing patterns before object lift (yet recovered during object lift), c) significantly delayed in the appropriate force amplitude and sharing among the digits during the lift occu rs compared to controls. Rearick et al.42 also examined the coordination of multiple digits and analyzed the sequencing of force development, object lift and hold, and the contro l of force output in persons w ith PD. Unlike Muratori, they found PD patients had preserved global features of five-digit grasping observed via normal developing and maintaining approp riate force amplitudes and force sharing patterns, but patients did have subtle systematic disruptions of in -phase force synchroniza tion patterns that should occur between the digits. These results are in cont rast to the findings that describe an increased variability of force control in PD. The author s concluded that PD pa tients can accurately

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58 preprogram grip forces across all five digits during grasping and that any small disruption in force coupling of the digits doe s not really contribut e to the overall grasp and lift or manual dexterity problems observed in PD.42 These differences in findings may be due to differing task constraints. More research comparing the mo tor coordination during similar finger-thumb and multi-finger-thumb tasks is necessary to determine which grasping technique is more impaired in persons with PD. In summary, numerous factor s affect the differences in significant and non-significant findings of force deficits in manual dexterous tasks. For example, the type of grip, (precision versus power), the number of digits and/or jo ints involved (pincher grasp versus multi-digitthumb grasp), and the percentage of force require d to target is important to consider and may affect the final outcome. While research has pr ovided diverse information about the control or loss of control of force with PD, the relevant and analogous message to consider is that these impairments in PD are seemingly task specific. More research which explores the precise regulation of forces as well as its influen ce on manual and digital dexterity was necessary; therefore, we examined the precision force coor dination deficits of pers ons with PD via their ability to maintain a targeted force using a pincher grasp. Additionally, we correlated these deficits with their performance on skillful manipulation of objects to determine if precision grip forces were a mechanism for manual dexterous tasks. A final factor that must be considered is the effects of medications that are prescribed to prevent or aid these dexterity and force coordi nation problems. Unfortunately, not all patients respond in a similar manner to particular medicati ons and only a handful of studies consider on and off states or have testing occur at the same time after medication intake. Examining force

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59 coordination, manual dexterity and other motor consequences of PD and their response to medications is indeed imperative. Response to Medications Differing medication responses in PD exist and depend on the patient, the type of symptoms and severity and duration of the disease. Due to the ra nge of impairments in PD and the tasks under consideration, to date the findings on drug responses for upper extremity functioning has been largely inconsistent. For example, Corcos and colleagues158 measured the strength at the elbow while in the off and on states and found a 30% and 10% reduction in the maximum elbow extension and flexion (re spectively) during the off period. Gordon157 compared fingertip forces both off and on medications during the previously mentioned object release study. Half of the s ubjects had 25% greater increases of their gr ip force during the on period, yet no other significant differences were f ound. Similarly, Quencer et al.49 found no effects of dopaminergic medication for precise, independent finger movements as measured via coin rotation, yet Mu ratori and colleagues41 reported that medication improved the temporal recovery of multi-digit force coordination during multi-digit grasping. We expanded the responsiveness to drugs research by analyzing force co ordination variability and motor coordination deficits during object manipulation while in the off and on state in order to verify and distinguish drug effects on manual dexterity. Summary In this research, we extended findings from our prelim inary pilot study and measure finger and hand dexterity of persons with PD using a va riety of fine manipulations tasks that require both finger and multi-finger-thumb grasps. We also analyzed the variability in matching a target precision force set at 20% of the participants voluntary maximal fo rce output to determine force coordination of the index and t humb pincher grasp. These target precision force outcomes and

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60 the scores on the fine manipulation tasks were th en compared to determine if force coordination is indeed a mechanism of dexterous tasks. As just previously stated, we also examined motor deficits while in the off and on state in order to distinguish drug effects on finger and hand dexterity and force coordination in both th e affected and less affected hands.

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61 CHAPTER 4 RESULTS Overall, the participants had a mean ag e of 68 years and possessed an Edinburgh handedness laterality quotient of 85.4.1 The PD patients on aver age were 5.6.7 years since disease diagnosis and scored 9.2.8 on items 20-25 of the UPDRS. Demographics were similar for each group (Table 4-1). Side-Onset Influence Laterality sc ores from the small object mani pulation tasks, those requiring finger-thumb grasping, were significantly di fferent among the three groups ( p=0.001). Tukeys HSD post hoc analysis revealed that the laterality impairm ent quotient, measuring the difference between the left and right hand performance, was significantly larger for the LSO group ( =36.33.94) compared to the RSO ( =6.07.61; p=0.005) and HC ( =2.00.77; p=0.002) groups. No statistical difference was found between the RSO and HC groups ( p=0.889). Performance on the large object manipulation tasks, requiring multi-finger-thumb grasping, were also significantly different among the three groups ( p<0.001). The laterality impairme nt quotient was significantly larger for the LSO ( =40.98.29) group compared to both the RSO ( =0.81.93; p<0.001) and HC ( =2.18.50; p <0.001) groups. No significant difference was detected between the RSO and HC groups ( p =0.987) (Table 4-2). Clinical relevance was determined if the mean was outside 95.4% of the normal distri bution using a SD of the c ontrol participants laterality score placing relevant means in the extreme ends of the normal dist ribution of behavior.51 The mean laterality quotient for both the small and large objects for the LSO group (77.31) was indeed beyond the control participants mean SD (1.59-10.49). Afte r adjusting for the inherent differences of the left and right hand during object manipulation task s, the statistically significant difference between the groups was maintained (Table 4-3).

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62 We compared the laterality quotients for the sm all and large object manipulation tasks for each group (LSO and RSO) to evaluate whether the side of onset would selectively effect dexterous movements. Results from the 2 x 2 (Group Task) repeated measures ANOVA failed to detect a significant main effect between the two grasping styles ( p=0.96). Furthermore, there was no interaction between the group s and the two different tasks ( p=0.30). Force Influence Analysis of the latera lity quotient scores from the force coordination task revealed no significant differences for TWR ( p=0.52) or the VQ ( p=0.60). However, when including both left and right hand performances (rathe r than quotient scores), the anal ysis revealed that the groups were significantly different for both TWR ( p<0.001) and VQ ( p=0.001). For the TWR, the RSO group ( =52.50.88) was significantly lower than the HC group ( =73.68.69; p< 0.001) and the LSO ( =68.06.51; p=0.004); however, the LSO and HC groups were not significantly different ( p =0.514). Similar results were observe d for the VQ measure. The VQ for the RSO group ( =0.15.08) was significantly lower than the LSO group ( =0.10.04; p=0.002) and the HC group ( =0.11.05; p=0.017). Again, no stat istical difference was detected between LSO and HC groups ( p=0.850) (Table 4-4). Figure 41 shows an illustration of both a LSO and a RSO patients targ et precision grip force curve with the left and right hands. Figure 4-2 displays a graph of the TWR and VQ for each group separated by hand. To determine if force control as measured herein was a contributory mechanism of dexterity, we evaluated the relationship among th e small object manipulation performances and the force outcome variables. Pearsons bivariate anal ysis of each of the sm all object scores were statistically significant ( p<0.001) and moderately (r>0.3) to st rongly (r>0.5) correlated to TWR. However, there was no correlation between the VQ and performance on any of the small object

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63 tasks. Table 4-5 provides the magnitude and sta tistical significance of the correlations between the separate small object tasks and force variability measures. Medication Influence Patients who were considered fluctuators (scored at least a on question 39 of the UPDRS) were f irst tested in the off state (no dopaminergic medicine within 12 hours of testing) and again in the on st ate (after at least 45 minutes of taking their medicine and when they reported it was working optimally) to determine the effects of antiparkinsonian medication on manual dexterity. The demographics and totals fo r the UPDRS in the off and on states are similar for each group (Table 4-6). Analysis using a 2 x 2 x 2 x 2 ANOVA with repeated measures on the last three fact ors (hand, object, medication state) identified a significant main effect for medication state ( p=0.007). The small and large obj ect manipulation measures from both hands across all of the groups had significant improvement while in the on compared to off state. There were no interaction effects between medication state a nd any of the factors: group ( p=0.908), size of object ( p=0.128), hand ( p=0.239), or all factors ( p=0.878) (Table 4-7). In addition, when comparing the total UE scores from both the left and right hand of the UPDRS, the off ( =14.2.7) and on ( =9.7.4) states were si gnificantly different ( p=0.001). This difference of 4.5 indicated a clinically relevant difference in impairments. The response of dopaminergic medications on force coordination varied for each measure. There was no significant effect of medications on the MVC (OFF: =44.13.26; ON: =46.43.03; p<0.349) or for the VQ (OFF: =0.113.010; ON: =0.099.011; p<0.176) (Figure 4-3). Similarly, tremor was observed durin g the force tracking task in both the off and on states (Figure 4-4) and did not show clinically releva nt improvement in the on state ( =2.4) compared to the off state ( =1.4) as measured by the mean tremor scores from items

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64 20-21 of the UPDRS. Alternatively, the mean TW R was significantly lower (improved) in the on condition ( =69.00.87) compared to the off condition ( =60.45.80; p<0.016).

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65 Table 4-1. Group demographics for the side onset analysis AGE (yrs) HLQ DDD (yrs) UPDRS Group N MeanSD MeanSD MeanSD MeanSD LSO 10 67. 86.92.15 6.0.0 9.0.27 RSO 10 69 83.08.57 5.3.5 9.5.5 HC 10 68 86.05.61 n/a n/a ALL 30 68 85.35.11 5.6.7 9.2.8 SD=standard deviation; RSO=right side onset; LSO=left side onset; DDD=duration since disease diagnosis; HLQ=handedness laterality quotie nt; UPDRS= total from questions 20-25 Table 4-2. Means and significance levels of the laterality quo tients for each group Task LSO RSO HC p-value Post Hoc RSO vs LSO Small Objects 36.33.94 6.07.61 2.00.77 0.001 0.005 Large Objects 40.98.29 0.81.93 2.18.50 <0.001 <0.001 Total 77.31.79 14.37.83 5.54.98 <0.001 0.002 RSO= right side onset; LSO= left side onset; HC= healthy controls Note. Tukey HSD was used for post hoc multiple comparisons Table 4-3. Means and significance levels of th e laterality quotient s for each group after accounting for inherent handedness differences of the healthy controls Task LSO RSO RSO vs LSO Small Objects 34.33.94 4.07.61 0.005 Large Objects 38.80.29 -1.38.93 <0.001 Total 71.77.79 8.83.83 =0.002 RSO= right side onset; LSO= left side onset

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66 Target Force Curve0 20 40 60 80 100 120 2.334.677.029.3611.7014.05 Time (s)Target Force (%) LH RH Target Force Curve0 20 40 60 80 100 120 2.334.677.029.3611.7014.05 Time (s)Target Force (%) LH RH A B Figure 4-1. Example of individual target precision grip force curv es. A. Left-side onset patient (Participant A3). B. Right-s ide onset patient (Participant B26. LH = left hand; RH = right hand

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67 A B Figure 4-2. Left and right hand performance for each group during the target precision grip task A. Time within range of target and B. Variability quotie nt. Note. Significance between RSO and both LSO and HC; p<0.05; ** p<0.001 Target Precision Force 0 10 20 30 40 50 60 70 80 90 LSO RSO HC GroupTime Within Range (%) LH RH ** Target Precision Force 0 0.05 0.1 0.15 0.2 0.25 LSO RSO HC GroupVariability Quotient LH RH *

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68 Table 4-4. Side onset group means and significance levels using a one-way ANOVA TWR-LQ VQ-LQ TWR-ALL VQ-ALL LSO: meanSD 2.65.13 0.64.93 68.06.51 0.10.04 RSO: meanSD 2.46.02 0.51.08 52.50.88 0.15.08 HC: meanSD 6.46.37 5.74.19 73.68.69 0.11.04 p-value 0.524 0.596 <0.001** 0.001** Post Hoc RSO vs LSO n/a n/a 0.004* 0.002* Post Hoc RSO vs HC n/a n/a 0.001** 0.017* Post Hoc LSO vs HC n/a n/a 0.514 0.850 RSO= right side onset; LSO= left side onset ; HC= healthy controls; LQ=laterality quotient; SD=standard deviation; TWR= time within ra nge; VQ= variability quot ient; ALL= combines performance of left and right hands Note. Tukey HSD was used for post hoc multiple comparisons; p<0.05; ** p<0.001 Table 4-5. Pearsons correlations of force coor dination variables and small outcome measures SBB SLR SCR Total TWR -0.44** -0.50** -0.51** -0.53** VQ 0.05 0.09 0.05 0.06 SBB=small box and block test; SLR=small lock ro tation; SCR=small coin rotation; TWR=time within range; VQ=variability quotient **p<0.001 Table 4-6. Group demographics for the off/on analysis AGE DDD HLQ UPDRS OFF UPDRS ON Group N MeanSD MeanSD MeanSD MeanSD MeanSD LSO 5 65 6.1.2 83.18.60 14.6.6 9.2.7 RSO 6 71 8.4.4 85.85.75 13.8.5 10.2.3 ALL 11 68 7.2.1 84.64.54 14.2.7 9.7.4 SD=standard deviation; RSO=right side onset; LSO=left side onset; DDD=duration since disease diagnosis; HLQ=handedness laterality quotient

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69 Max Force0 10 20 30 40 50 60 70 80 90 LSO RSO HC GroupForce (N) LH OFF LH ON RH OFF RH ON Table 4-7. The on and off significance levels and mean values of the combined times for task completion for each hand and side onset from both small and large object manipulation OFF ON MeanSD MeanSD Interaction p-value Small 75.46.33 60.11.52 Large 90.30.91 68.59.76 Size p-value 0.003* 0.128 LH 92.52.81 69.65.20 RH 73.24.31 58.98.06 Hand p-value 0.026* 0.238 LSO 80.55.29 62.62.35 RSO 85.21.15 66.01 .64 SO p-value 0.779 0.908 ALL 82.88.46 64.31.79 Total p-value 0.007* 0.878# SO= side-onset; RSO= right side onset; LSO= le ft side onset; LH= left hand; RH= right hand; SE= standard error Note. *p<0.05; Interaction p-values are the interaction effects with medication state (off/on); # p-value for the interaction of all factors; Means are the time for task completion in seconds Figure 4-3. Max force with the left and right hand in both the o ff and on medication states

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70 Target Precision Force Curve A80 20 40 60 80 100 120 140 2.324.667.019.3511.7014.04 Time (s)Target Force (%) LH OFF LH ON Target Precision Force Curves A80 20 40 60 80 100 120 140 2.324.667.019.3511.7014.04 Time (s)Target Force (%) RH OFF RH ON A B Figure 4-4. Example of an individual target preci sion grip force curve in the off and on medication states. A. Left-ha nd (LH) performance. B. Right -hand (RH) performance.

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71 CHAPTER 5 DISCUSSION Side-Onset Influence Using the natural asymmetries of hemi spheric responsibilities, previous ly researchers have observed that differing cognitive dysfunctions exist and depend on the side of initial symptom onset. 7, 8, 10, 12, 13, 15-18, 108, 109 Therefore, in this research, we in vestigated the infl uence of side of symptom onset on motor and force coordination in persons with PD. The primary finding of this investigation is that RH patients with a RSO had greater symmetry of motor impairments (both sides more equally impaired) when compared to those with a LSO. While there was no significant difference in the LQ when compar ing the HC and RSO groups, the slower times across all tasks for both hands in the RSO group and for the left-h and in the LSO group indicate motor coordination deficits in PD. Essentially, among RH, persons with an affected dominant, left hemisphere (RSO) had detriments in both the contralateral and ipsilateral hands whereas patients with an affected non-dominant, right hemi sphere (LSO) demonstrated deficits primarily in their contralateral left hand. Therefore, we suggest that the left-hem ispheric control of the ipsilateral, left hand is greater than the right hemispheric contro l off its ipsilateral, right hand. These findings support our hypothesis whereby th e asymmetry of ipsilateral control is maintained in persons with PD. Thus, we conclude that the side of symp tom onset significantly influences motor functioning and results in greate r ipsilateral dysfunction when the left dominant hemisphere is involved. Previously, we have shown that the side of symptom onset infl uenced clinical measures of upper extremity function in PD. Unfortunately, no other studies, to our knowledge, have evaluated this relationship in more functionally related behavioral tasks. The present study builds

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72 upon our previous work and provi des more support for the noti on that there is a stronger ipsilateral control from the dominant, left hemisphere as found in the healthy population 20, 21, 23, 24, 26, 80 and in other neurologica lly disordered populations.28-31, 33, 93, 110-112 For example, Sunderland et al.33 found stroke patients with left hemispheric lesions had dexterity impairments in both the right (cont ralateral) and left (ipsilateral) hand, while those with a lesion in the right hemisphere did not appear to have these deficits in both hands. Desrosiers and colleagues28 detected significant deficits in gross and fine manual dexterity as well as motor coordination in the unaffected upper extremity of stroke su bjects. Moreover, Heilman and colleagues32 examined kinetic-limb apraxia and found si milar left and right-handed errors during left hemisphere anesthesia but more left than ri ght errors during right hemispheric anesthesia. To follow-up this finding, Hanna-Pladdy et al.30 reported that persons with left unilateral hemispheric lesions had greater ipsilateral deficits on tasks re quiring precision and coordinated independent finger movements. In addition, this asymmetric ipsilateral control has also been confirmed in healthy populations via st udies using brain imaging techniques.20, 21, 23, 24, 26, 80 Kim et al.20 revealed that the right motor cortex was activated during contralateral finger movements in both RH and LH subjects; however, the left motor cortex was activated more substantively during ipsilateral movements in left-h anded subjects. Similarly, Singh et al.24 confirmed that during alternating finger opposition tasks, the contrala teral sensorimotor cortex in RH was significantly larger than that of the ipsilateral cortex for tasks with either hand. The ipsilateral activated area was significantly la rger during left-handed tasks. For LH, there was no significant difference. Together, these studie s provide evidence for a stronger ipsilateral role of the left hemisphere in RH and prove motor functioning differences after left or right hemisphere damage. Though PD is a dysfunction of the basal ganglia versus a purely cortical dysfunction,

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73 our findings are congruent with the previous research. Asymmetr ic ipsilateral control effects extend to the PD population by possibly affec ting the entire ipsilateral circuitry. The exact neural circuitry underlying this asymmetric ipsilateral co ntrol in the healthy population and its effects on motor functioning after right or left hemisphere damage is largely unknown. One possible theory is the predominance for the left hemisphere to control the planning of motor actions.95, 96 In other words, whether a left or right hand movement occurs, the left-hemisphere is involved in the planning of that action. Therefore, if there is left-hemisphere damage, both hands will show deficits. However, since the right hemisphere does not have this ipsilateral and contralateral control, a right-he misphere dysfunction will on ly result in left hand deficits. A second theory regarding the asymmetr ic ipsilateral control is the diffuse neural representation of the right hemisphere which is more focal in the left hemisphere. During left hand movements, the neural activity of the right hemisphere is more likely to spread to the contralateral, left hemisphere showing an in creased reliance on the dominant hemisphere. During right hand movements, reliance on the ipsilateral, non-dominant, right hemisphere does not exist.124 Applying this theory, damage to the left hemisphere will also affect both the left and right hands. Whether it is due to the predominance of the left hemisphere for motor planning or the diffusely represented neural activation, deficits after a co rtical lesion or basal ganglia dysfunction are apparent and differ dependi ng on which hemisphere is affected. Our present results confirm the side of symptom influence on upper extremity motor functioning that was revealed in our preliminary research. Therefore, not only does the asymmetrical ipsilateral control differently aff ect motor impairments as measured by subjective clinical scores of the UPDRS, but it also extends to quantifiable objective measures similar to those performed during routine act ivities. In general, side of symptom onset could potentially

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74 influence the evaluation of motor consequences based on either subjective impairment scores or object manipulation performances. Small versus Large Object Manipulation In this study, we not only an alyzed activities that require d finger-thumb grasping, but we also in cluded measures, which required multi-fi nger-thumb grasping techniques. In both the large and small tasks, those patients with a RSO had similar dys function in both hands compared to LSO. Therefore, we conclude that the ipsilateral c ontrol of the left hemisphere as found in the previously discussed studies also extends to larger multi-segment movements. When comparing side onset effects on larg e and small object mani pulation, no significant difference in performance was observed between the two grasping styles on the overall group means. These findings do not support our hypothesis in that the tasks requiring multi-fingerthumb tasks did not show greater laterality de ficits than those obser ved during the finger-thumb tasks across all particip ants. However, in some individuals (approximately 38.1% of patients), greater deficits in the larger object manipulation were apparent. Thus, those observations are in partial agreement with the findi ngs of Santello and Soechting.43 They reported that when only two digits grasp and hold an object, only one force sharing pattern between the thumb and the opposing finger is required (the for ce of the opposing finger must be the same as the force of the thumb). Yet, when all five digits are involve d in grasping and holding an object, the equilibrium of forces can be achieved by many combinations of force distribution as long as the sum of the forces of the four fingers is equal to the force of the thumb.43 Conversely, the observation of some individuals with greater laterality defi cits in the small object manipulation tasks is congruent with reports of Flannagan et al.131 They concluded that tw o-fingered precision grips are inherently less stable than multi-digit grips in that the control of direction and magnitude of the applied finger forces needs to be more constrai ned at the level of individual digits. Therefore,

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75 they suggest that the precision grip was more demanding in terms of neural control.131 In relation to deficits within PD, again the literature is inconsistent. Muratori and colleagues41 reported greater multi-digit grasping deficits compared to two finger deficits while Rearick et al.42 found preserved global features of five digit grasping. Our lack of greater deficits for one object over the other parallels these inconsis tent reports of the literature. Inconsistent results regarding which task is more problematic may be partially explained by constraints of the tasks and/or other factors. Since the constraints were similar for both the large and small tasks in this study, other factors must be considered. The varying amounts of time each participant continued to perform manual act ivities after diagnosis could be influential. Further, the dexterous abilities of the participants before the onset of PD could possibly affect their current scores on these measures. Following the neuroplasticity principles, performance capabilities of the neuromuscular system are affected by the type and amount of daily practice or activity. Motor training alters the movement representations within primary motor cortex thereby making movements more efficient and accurate.160 Furthermore, Remple et al.161 noted the importance of skilled movement for this functional reorganization within motor cortex. As people practice certain movements, those moveme nts and movements similar in nature become more automatic and easier to perform (less complex). Persons who continually perform more finger-thumb activities will be better at performing those types of activities while those who use more multi-finger movements will become more profic ient at those activities. In contrast, disuse may also influence task performance whereby a decrease in practice after PD will further enhance the motor impairments as observed with the progression of the disease. However, with continued use of both hands, this progression is slowed. In this research, some participants commented on their continued use of both hands during manipulation tasks such as knitting or

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76 tool usage whereas others were clear to admit their lack of use of the more affected hand. Similarly, there was a distinct preference of the large object manipulations tasks for some and for the smaller tasks for others. Since task comple xity affects the amount of ipsilateral control21, 25, 44 and each individual differed in their preference and experience with small or large object manipulation, it was difficult to interpret which t ype of movement showed, small or large object, more deficits. These factors should be considered in future investigations. Force Coordination Force variability was unaffected by the side of mo tor symptom onset as measured via the target precision grip force coordination task. There were no significant differences for either force variables when comparing the laterality scores of each group. However, when combining left and right hand performances, the LSO group s howed significantly less variability than the RSO group. In other words, patients with a LSO were able to produce a fo rce that was within a five percent range of the targ eted force (TWR) for a longer period of time. The difference between the predicted force and actual force produced (VQ) was also smaller in the LSO group. Our findings also revealed significant differences between RSO patients and HC and agree with other studies that have reported greater force variability in PD patients via a target force paradigm.129, 139, 162 The analysis of side of symptom onset provided new insight into our understanding of force variability among PD patients. We found a significant difference in patients with a LSO and a RSO but not between the LSO and HC groups. Since we have shown that the ipsilateral, left hand in patients with a RSO also have more deficits during our manipulation tasks than the ipsilateral, right hand has in pati ents with a LSO, it seems congruent that those with a RSO should have more combin ed variability during th e precision grip force task.

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77 Force as a Mechanism We comp ared the small object manipulation performances to the force variability measures to provide insight as to whet her force control is an underlyi ng mechanism of dexterity. The observed statistically significant and the moderate to strong relationship between the time within range to small object performance support that force is indeed one mechanism of dexterity. These significant correla tions suggest that the less time an individual is able to produce the targeted force, the lower their scores will be on the dexterity measures. In agreement to Johansson et al.,126 our findings highlight the necessity of appropriate fingertip forces between the tips of the thumb and fingers for appropr iate and efficient ma nipulation of objects. Conversely, there was not a si gnificant correlatio n between the VQ and the small object performance scores. Some participants produced la rge variability dur ing the target precision task, yet their performance on the small object manipulat ion was comparable to the healthy controls. An explanation of this mismatch possibly could be due to other underlying mechanisms or task constraints. The magnitude of the correlations with TWR and lack of correlation of the VQ to our small manipulation tasks suggests that other mech anisms of dexterity beyond force coordination exist. For example, the differing muscle recruitm ent patterns of each task, the type of action (discrete versus continuous), the availability of an open or closed loop system, and type of feedback that pertained to each task are othe r possible constraints th at could affect object manipulation. The precision force ta sk required a constant muscle contraction between the index finger and the thumb. This cont inuous contraction a nd slower movement speed allowed for a closed-loop system of control a nd visual feedback as a main source of error correction.163, 164 Instead, the small manipulation ta sks required a combined series of discrete movements more ballistic in nature. These movements typically rely upon an open-loop system where corrections

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78 can only be made for the next movement.163, 164 Moreover, the reliance on visual feedback seemed to be less during the manipulation tasks, especially the lock and coin rotation tasks, as compared to the target precision grip tasks. In actuality, some patients tended to look up and not at the coin during the coin rotation task. Even though the literature is ambiguous on the tactile deficits in PD,165, 166 the additional visual feedback our pati ents utilized during the tracking task increased the differences in the task constr aints. Moreover, for many persons with PD, researchers have shown both the importance of visual feedback for task completion167-169 and the deficits that are apparent during the generation of accurate ballistic action.163, 170 Finally, the differing timing and sequencing of muscle recr uitment was problematic for many. The task constraints of the target precisi on grip required fewer degrees of freedom and a constant flexion of the index finger and the thumb. Conversely, the small manipulation tasks required quick sequencing of muscle recruitment, many on/off periods, and alternating contractions of the digits. Using a tracking task more similar in natu re might yield greater in sight into the role of force control and dexterous performance. Nevertheless, the disparity in the correlations of the TWR and the VQ on the small object manipulation did provide further insight into force and dexterity. Tremor during the target precision grip task produced a sinusoidal wave fo rm which in turn creat ed larger variability scores. Even when there was clear evidence of tr emor, some patients were still able to match their produced force within a five percent range of the target force. In those situations, their force VQ was higher yet their TWR was mostly unaffecte d. In other words, it is possible to produce a force that is within a range of th e targeted value and still have mu ch variability with that range. Since the tremor, in many cases, did not cause ob vious deficits in object manipulation, the VQ as a measure of force coordination in persons w ith PD may not accurately explain performance

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79 during dexterous tasks. These findings are al so supported by the significant improvement in object manipulation and TWR coupled with the l ack of significance in VQ and continued visible tremor during the target precision grip task af ter medication (Figure 44, more on tremor, VQ, and dopaminergic effects in the next section). Medication Influence Due to the paucity of inform ation that exists for the effects of dopaminergic therapy on objective manual dexterity measures, we analyz ed motor coordination deficits during object manipulation while in the off and on states. We found that PD patient s who were considered fluctuators definitively had a positive response to their medication for both the quantitative, object manipulation performances as well as the subjective, clinical impairment scores. Our results indicated an improved performance during both finger-thumb and multi-finger thumb tasks while in the on state. These findings are in direct contrast to the work of Quencer and colleagues.49 They concluded that dopaminergic me dication was not influential for precise, independent finger movements as measured via coin rotation. However, the authors did not actually analyze fine dexterity during both the on and the off states. Our results are in partial agreement with Muratori and colleagues41 who reported that medica tion improved the temporal recovery of multi-digit force coordination during multi-digit grasping. Though we did not measure force coordination using a multi-finge r grasp, we did find improvements from medications during a finger-thumb force control paradigm as well as during finger-thumb and multi-finger-thumb motor dexterity tasks. The analysis of medication responses revealed mixed results on the fo rce control measures. While we found a significant improvement for the TWR in the on state, there was no significant difference in the max force or VQ after medicine. As previously mentioned, disparity of these results may be due to the evident trem or that affects the VQ and not TWR. While there

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80 was improvement in both the object manipulatio n tasks and the amount of time patients were able to produce the appropriate force, there was no difference in their VQ. This finding represents the improvements in the amount of time the produced force was within a five percent range of the targeted force yet no significant difference in the ma gnitude of force oscillations around the targeted force. Interes tingly, many cases of tremor also did not show an improvement in the on state as observed from the force curv e or in a clinically relevant decrease in the UPDRS tremor score. These results agree wi th the findings of Raethjen and may provide evidence for the relationship between tremor and VQ. Raethjen and colleagues171 examined levodopa response to action tremor and manual dexterity during a pinc h grip coordination task in patients with PD. They reported action tremor did not show a clear levodopa response and did not affect dexterity in patients with little, if any, clinical arm akinesia. Visible akinesias were only mild in some of our particip ants; therefore, our re sults confirm the findings of Raethjen et al.171 Conversely, our results are only in partial agreement with Frossberg and colleagues.172 While the authors did find a decrease in the tota l amplitude of the tremor during a grip-lift task, they did not observe a consis tent change in the frequency of tremors after dopaminergic medications. Thus, it appears more research is ne eded to confirm the relationship between TWR, VQ and tremor on manual dexterity and their re sponses to dopaminergic medication. In addition, dopaminergic medicine had no eff ect on MVC. Our lack of improvement in pincher grip max force is inconsistent w ith other research. Corcos and colleagues158 measured the strength at the elbow while in the off and on states and found a 30% and 10% reduction in the maximum elbow extension and flexion (r espectively) during the off period. Similarly, Lou et al.173 observed that levodopa impr oved fatigue in finger tapping and force generation during wrist extension and suggest ed that dopamine deficiency a nd fatigue in PD are partially

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81 related. The discrepancy between our findings and the previously mentioned studies could be due to the differing muscles groups test ed. While their tasks required large muscle recruitment, our study only required a pincher grasp using th e finger and the thumb. Gordon et al.157 used similar tasks constraints and reported th at medications did not systematic ally influence their measures. They did, however, note that half of their subjects had 25% greate r increases of their grip force during the on period. In our cas e, any increase or decrease in force was insignificant. A difference in these studies could be due diffe ring disease severity or possible drug induced hyperkinesias of the participants. The performance gains without an improved MV C of the pincher grip after medications were not totally unexpected. Ma nipulation tasks of the fingers and thumb do not require maximum strength for accurate performance. In actuality, applying additional forces often creates a movement that can be counter-produ ctive and inefficient. These problems can be common in persons with PD. Patients have the ability to produce enough force; however, they usually lack the ability to produ ce the appropriate amount for a give n task. In some instances, patients produce too little force38 or have a prolonged development of the correct force, 37, 139, 156, 157 while in other cases, they may produce too much force.121 Considerations While our results provide important insight into the influence of side onset and m edication response, this study was not wit hout its limitations. The differing types of PD (tremor dominant, akinetic rigidity, and mixed) and duration of th e disease may have influenced the performance on the selected outcome measures. While the dura tion since disease diagnosis was similar among the LSO and RSO groups, each patient differed in the amount of time they experienced symptoms before visiting a neurologist or be ing correctly diagnosed. Often times with PD patients, they are unable to recall when or wh ere their first symptoms began. Though we limited

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82 our cohort to those who could recall the location and type of symptom onset, the variability in the time before seeking diagnos is existed. This vari ability is a common limitation in the PD research and may have affected the differences in de ficits in this research in that it is typical for those with longer duration of sympto ms to have more severity in impairments as well as be more bilaterally affected. However, to limit the testing of patients who were more bilaterally affected, we included PD patients who had been more rece ntly diagnosed. Similar to the differing times since actual symptom onset, the duration (once diagnosed) at a given stage for each patient is quite variable making it difficult to predict the length of time before the disease is no longer unilateral reaching severityStag e 2.5. Similarly, while we lim ited our cohort to only include those with an asymmetric symptom onset, some subjects unknowingly may have had dysfunctions in their opposite hemisphere and hand at initial onset. Another limitation within our participants is the inherent vari ability in left and right hand pe rformances that exists among PD patients as well as healthy controls. While we addressed this issue by subtracting the hand difference (laterality quotient) of the healthy controls from bo th PD groups, these inherent differences may still affect the laterality quo tients among the groups. Next, each participants varying previous ability and continued use of both of their upper extremities could possibly affect the amount of deficits in each hand. Usi ng age-matched healthy controls and comparisons of their other hand use may help account for some of this variability. As for our outcome measures, interpretation of the performance scores of the UPDRS, a typically administered rating scale to determine motor severity, must be taken with caution as this measure has low inter-rater reliability and the scoring is not sensitive to the different levels of severity especially when symptoms are less severe. However, our other outcome measures were quantifiable, objective measures of finger and hand dexterity which can easily be incorporated into motor deficit testing.

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83 Finally, the actual off state may have differed from patient to patient depending on their level of fluctuation between medication dosage, ther eby altering the on/ off motor dysfunction differences. Even though these lim itations were possible, the findings of this research are quite valuable. Conclusion In summary, laterality of motor functioning, using right and left upper extremity difference scores from small and large object manipulation task s, were less apparent in patients with a RSO (left hemisphere damage) than in those with a LSO (right hemisphere damage). The symmetry of deficits in RSO patients supports the stronger ipsilateral control of the left hemisphere in RH. Because both hands appear to have more deficits in this subgroup of patients, training protocols that incorporate object manipulatio n with both hands might be benefi cial. Still, more research is needed to determine the direct effects and gr eater real world implicat ions of these differing motor consequences that occur with a left or a right side onset. Our significant correlations of the target precision grip to our small object manipulation measures confirm that force coordination is one mechanism of dexterity. Fi nally, our results reveal ed that dopaminergic medications do indeed promote improved motor dexterity for those patients who fluctuate from dose to dose. However, for non-fluctuators, the evidence still remains to be determined.

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84 CHAPTER 6 FUTURE RESEARCH To determine the r eal world significance of the asymmetric ipsilateral control that affects motor functioning depending on the side of symp tom onset, more research is necessary. For example, applying brain imaging techniques during object manipulation tasks (similar to outcome measures included in this study) would prove beneficial in confirming the asymmetric hemisphere activation during ipsilateral hand move ments. Imaging techniques could also help to compare and unveil possible differing brain area s involved during these finger-thumb and multifinger-thumb tasks. In addition, determining if this asymmetric ipsilatera l control or side of symptom onset affects deep brain stimulation is im portant for doctors and patients. Knowing that there might be differences in unilateral versus bilateral stimulation depending on the hemisphere affected could be quite time and cost beneficial. Other possible extensions of this research could include the examination of: a) a lefthanded PD population to determine if the ipsilate ral hemisphere control of the upper extremity parallels the previous brain imaging techniques in the healthy population whereby the ipsilateral control is less asymmetric than that of RH, b) a tremor-dominant-only cohort with similar tremor severity to determine the effects of dopamine rgic medications on tremor and its effects on manual dexterity, and c) fluctuators who are similar in the am ount of wearing off they experience between medication dosages to provide a more consistent measure of testing during the off state. Future studies are also n ecessary to determine whether these identified differences in motor and cognitive performances due to side of symptom onset affect the clinical outcomes and/or the progression of the disease.

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85 APPENDIX A INFORMED CONSENT Informed Consent Agreement Project Title: Side onset and upper extrem ity motor functioning in Parkinson's disease: Examining bilateral deficits Investigator: Kim C. Stewart; PhD candidate in Applied Physiology and Kinesiology Faculty Supervisors: Chris J. Hass (Chair), Mark D. Tillman Please read this consent form carefully be fore you decide to participate in the study. Purpose of this study: The purpose of this research study is to examin e the influence of side of symptom onset on motor functioning of the upper extremity in individuals with Parkinson's disease. What you will do in the study: You will either visit the Biomechanics Laboratory, Cent er for Exercise Science, at UF or meet at an agreed upon, neutral location one time for independent finger and hand movement testing. You will arrive in the off state (less than 2 hour delay in taking morning medicine) and fill out a demographics and clinical questionnaire. Y ou will practice and then perform a variety of unimanual skills including picking up and transp orting small objects, rotating a coin or a combination lock and squeezing a block to determine force output. Both hands will perform every task. After taking your medicine and verifying on stat e, you will again perform those same manual tasks. As you complete each tas k, a video camera will be recording your hand movements for third party evaluation. Time required: One visit lasting approximately 2 hours Risks and Benefits: Participating in this study offers no greater risk than in normal activities of daily living. Also, there is no direct benefit for pa rticipating in this study except to help researchers, therapists, clinicians and other PD patient s better understand motor deficits and the mechanisms underlying loss of upper extremity dexterity. These results of the study may, therefore, have implications on surgical and training treatments for i ndividuals with Parkinson's disease. Compensation: No compensation will be given for your participation in this study. Confidentiality: The information you provide will be handled conf identially to the extent provided by the law. Your information will be assigne d a code number and the list connecting your name to this number will be kept in a locked file. Only researchers directly involved with the project will

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86 have access to the data. When the study is completed and the data an alyzed, the list and data will be destroyed. Your name will not be used in any report. Voluntary Participation: Your participation in the study is completely vol untary. There is no penalty for not participating. Right to withdraw from the study: You have the right to withdraw from the study at anytime without penalty. Whom to contact if you have any questions about the study: Kim C. Stewart, MS, Doctoral Student, PO Box 118206, Dept. of Applied Physiology and Kinesiology, 151 FLG, University of Florid a, Gainesville FL 32611; 352-392-0584 ext. 1321, stew18@ufl.edu Chris J. Hass, PhD, Assistant Professor, PO Box 118206, Dept. of Applied Physiology and Kinesiology, 122 FLG, University of Florid a, Gainesville FL 32611; 352-392-9575 ext. 1294, cjhass@hhp.ufl.edu Whom to contact about your rights in the study: UFIRB Office, Box 112250, University of Florida, Gainesville, FL 62611-2550 Agreement: I, __________________________ have read the procedure de scribed above and I voluntarily (participant's name) agree to participate in the procedure. I also understand that I will receive a copy of this form upon request. Participant : __________________________________ Date : ________________________ Principle Investigator: __________________________ Date : ________________________

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87 APPENDIX B DEMOGRAPHIC AND CLINICAL DATA FORM Demographics: Circle (w here applicable) # Subject: x Age: ---------------> Gender: 1. Male / 2. Female Years of education: ---------------> Hand preference: 1. Right / 2. Left / 3. Ambi Laterality score: complete questionnaire Disease duration: ---------------> Side of symptom onset: 1. RSO / 2. LSO / 3. Both / 4. Unsure Site of symptom onset: 1. Upper / 2. Lower / 3. Both / 4. Unsure Type of symptom onset: 1. Tremor / 2. Rigidity / 3. Bradykinesia / 4. Po stural Instability 5. Other:_________________________ Time since meds: ---------------> Type of motor PD meds: x All meds and dosages:

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88 APPENDIX C MODIFIED EDINBURGH HANDEDNESS INVENTORY Laterality Questionnaire When/Task Which hand do you prefer? Do you ever use the other hand? 1 Writing RightLeftEitherYes No 2 Drawing RightLeftEitherYes No 3 Throwing RightLeftEitherYes No 4 Using Scissors RightLeftEitherYes No 5 Using a toothbrush RightLeftEitherYes No 6 Using a knife (without a fork) RightLeftEitherYes No 7 Using a spoon RightLeftEitherYes No 8 Using a broom (upper hand) RightLeftEitherYes No 9 Striking a match RightLeftEitherYes No 10 Opening a box (lid) RightLeftEitherYes No

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89 APPENDIX D BLANK OUTCOME MEASURE FORM

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90 APPENDIX E RAW DATA: SIDE ONSET

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91 Demographics and raw data fror the LSO, RSO, and HC groups

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92 APPENDIX F GROUP MEAN DATA: OFF/ON

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93Group data for each outcome measure and task UPDRSL UPDRSR Total SBB L SBB R LBB L LBB R SLR L SLR R LLR L LLR R SCR L SCR R LCR L LCR R MFLMFR LSO OFF 10 4.6 14.6 35.45 30.63 37.20 29.56 26.57 15.18 37.78 21.10 30.84 12.05 30.51 15.33 47.15 49.89 ON 6.6 2.6 9.2 31.34 28.37 30.64 27.16 17.04 12.10 26.79 16.49 16.89 9.15 20.64 13.88 45.31 50.60 RSO OFF 6.167 7.667 13.8 36.39 35.99 35.39 32.74 21.94 21.94 31.07 29.00 17.02 17.86 29.93 31.57 37.71 41.07 ON 4.5 5.667 10.2 30.60 30.57 32.25 30.12 19.15 17.55 19.39 16.60 14.01 13.69 19.88 20.24 46.37 44.17 HC n/a n/a n/a 24.51 23.81 25.83 24.27 11.37 11.37 16.06 14.69 7.62 7.91 10.12 10.19 55.41 58.12 Outcome measure abbreviations and meanings UPDRS Unified PD rating scale SBB small box & block LBB large box and block SLR small lock rotation LLR large lock rotation SCR small coin rotation LCR large coin rotation MFL max force left MFR max force right LSO left-side onset RSO right-side onset HC healthy controls

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94 APPENDIX G PRELIMINARY PILOT STUDY Introduction Given that di ffering cognitive dysfunctions corr espond to the side of symptom onset in PD and that asymmetric hemisphere responsibilities of motor functions exist, we deduced that motor deficits may also differ depending on which he mispheric is affected. To our knowledge, the influence of side of symptom onset on motor impa irments has not been previously examined in PD. Since in healthy RH, the dominant left hemisphere has greater ipsilateral control of the left arm than the non-dominant right hemisphere has on the right arm, we sought to determine whether Parkinson disease (PD), a progressive syndrome often with initial asymmetric symptomatology, maintains this natural influence of ipsilateral control of upper extremity motor performance. Specifically, our aim was to determin e if in RH (or left-hemisphere dominant) PD patients, upper extremity motor deficits are more bilateral when the dominant left hemisphere was more affected (RSO patients). Due to the le ft hemisphere control of both contralateral and ipsilateral hands, we hypothesized that PD pa tients with RSO, where the dominant left hemisphere is primarily involved, would have greater bilaterality in motor deficits than patients with LSO, where the non-dominant right hemisphere was primarily affected. Methods Non-deme nted (i.e. MMSE > 25) individuals dia gnosed with idiopathic PD (i.e. satisfying the United Kingdom Brain Bank Criteria for Parkin son Disease (Hughes)) at the University of Florida Movement Disorders Center between 2002 and 2006 were prospectively administered Part III of the Unified Parkinson Disease Rating Scale (UPDRS) in the off medication state. Only subjects with a clear side of onset were included in the anal ysis. In addition, subjects with previous deep brain stimulation surgery or ot her neurological disord ers were also excluded.

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95 Right and left hand composite scores were then derived from the UPDRS Part III (item # 20-25). The difference between the right and left hand co mposite scores were computed to create a bilateral impairment measure (termed the bilate ral impairment score). To avoid convergence due to positive and negative va lues, the non-reported side of symp tom onset was subtracted from the reported side of symptom onset. A bilateral impairment score closer to zero implies that both sides had similar impairments whereas a score fu rther from zero implied more asymmetric motor deficits. To differentiate the bilateral defic its based on handedness and predominant hemispheric involvement, individuals were th en stratified into 4 groups: (r ight hand-right side onset (RHRSO), right hand-left si de onset (RH-LSO), left hand-right side onset (LH-RSO), and left handleft side onset (LH-LSO). One-way ANOVA was used to determine si gnificant differences in the bilateral impairment measure of our four cohort groups. If a significant main effect was identified, Tukeys HSD post hoc analysis was then applied to compare the specific group differences in both RH groups: RH-LSO and RH-RSO. Due to the la ck of a consistent dominant hemisphere in LH, the RH dominant hemisphe re group (RH-RSO) was compared to both LH groups (LH-LSO and LH-RSO). Results Of the 762 non-deme nted subjects diagnosed with PD between 2002 and 2006, 425 reported unequivocal RSO or LSO and were included in analyses. Subjects had a mean: age of 65.97.99, disease duration of 7.88.83 years a nd UPDRS motor score of 38.72.01 in the off state. Demographics were similar for ea ch group (Table 1). Nine ty-two percent of the participants were RH. Fifty-nine percent reported a right side ons et. In all 61.4% reported that the symptoms began on their dominant side. Intere stingly, the location of the side of onset was

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96 significantly correlated with the side of dominance ( 2= 10.48; p<0.001), i.e., the side of onset was more frequently on the same side as the dominant hand. The mean of the UPDRS composite upper extremity score was 11.39.42 for the right hand and 11.82.73 for the left hand indicating si milar impairment of both hands across all subjects. Comparison of the bila teral impairment scores reve aled the RH-RSO group possessed significantly lower scores ( =2.09) indicating more bilateral im pairment than the other three groups (RH-LSO: =4.06, p<0.001; LH-LSO: =4.52, p<0.05; and LH-RSO: =4.27, p<0.05). Discussion Similar to previous studies investigating c ognitive abilities, this study showed that the hemispheric dominance and the si de of disease onset can influe nce the degree of upper extremity motor decrement whereby RH with a RSO had more bilaterality of impairments than RH with a LSO. In other words, among RH, when the domin ant left hemisphere was primarily affected (resulting in RSO parkinsonism), there was a greater detriment in the supposedly less controlled ipsilateral left side, as compar ed to RH whose non-dominant right hemisphere (resulting in LSO parkinsonism) was primarily affected. These findings supported our hypothesis confirming that side onset does indeed influenc e motor impairments and that some ipsilateral control was maintained in persons with PD, especially among RH. While our results are important, this study was not without its limitations. Our study was cross-sectional, taken from a single, tertiary center and subject to bias. PD patient whose dominant side is more affected may be more likely to seek consultation than the reverse. Nonetheless, we believe that our PD cohort repr esents a wide spectrum of disease severity and describes one of the largest prospectively acquired data sets for anal ysis of the influence of side onset and hand-preference of motor impairment.

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97 In summary, bilaterality of impairments, using right and left uppe r extremity difference scores from the UPDRS, were more apparent in RH with a right, dom inant side onset (left hemisphere damage) than in RH with a left, non-dominant side onset (right hemisphere damage). This supports the stronger ipsi lateral control of hand and fi nger movements of the left hemisphere in RH. Side of motor symptom ons et should be considered when measuring or determining motor impairments in persons with Parkinson disease. This current research will further investigate the effect of these impairments on quantifia ble upper extremity motor tasks.

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111 BIOGRAPHICAL SKETCH Kim Stewart was born on March 14, 1972 to her parents Elsie Holliday and Peter Stewart in Norfolk, Virginia. She has two older sister s, Joanna Felts and Mary Beth Dixon, a younger brother, James Stewart, four ni eces, one nephew and a step-father, George Holiday. Kim lived in Norfolk throughout her childhood until moving away for college. She spent two years at the University of Arkansas where she played soccer before transferring to Mercer University where she play ed both soccer and basketball and received her B.A. in Mathematics. After college, she became th e assistant soccer coach at Furman University, the head coach at Southeastern Louisiana University, and then again the assistant coach at Virginia Tech University where she also rece ived her M.S. in Human, Nutrition, Foods and Exercise. From Virginia she moved to Gainesvi lle, Florida to teach middle school Algebra and Pre-Algebra and to begin her doctorate in Applied Physiology and Kinesiology. After two years, she began her program full-time and taught several UF courses as a graduate assistant (Motor Learning and Control, Soccer I and II, and Anatomy and Physiology Labs). Kim has accepted a faculty position as Assistan t Professor at Mars Hill College in North Carolina. She will be teaching a variety of c ourses such as coaching theory and methodology, kinesiology, exercise physiology, biomechanics, we llness, and exercise test and prescription. She also plans to continue doing rese arch and publishing these findings.