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1 ENDOGENOUSLY AND EXOGENOUSLY EVOKED INTENTIONAL MOVEMENT IN AGING AND PARKINSONS DISEASE By MATTHEW COHEN A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2013
2 2013 Matthew Cohen
3 To my dad
4 ACKNOWLEDGMENTS I thank my parents for encouraging me to excel, and for providing a life for me where I could prioritize my education. I also thank them for being exemplary role models of how to live as an educated person with values and personal balance. I thank my wife, Megan, for her steadfast love as we navigated graduate school together. I also sincerely thank my research participants and funding sources: The National Institutes of Health, the American Psychological Foundation BentonMeier Scholarship, and the Bryan Robinson Endowment.
5 TABLE OF CONTENTS page ACKNOWLEDGMENTS .................................................................................................. 4 LIST OF TABLES ............................................................................................................ 7 LIST OF FIGURES .......................................................................................................... 8 ABSTRACT ..................................................................................................................... 9 CHAPTER 1 INTRODUCTION .................................................................................................... 11 Statement of the Problem ....................................................................................... 11 Introduction to Attention and Intention .................................................................... 12 Two Routes to Action .............................................................................................. 14 Two Routes to Action Evidence From Macaque Anatomy and Physiology ... 15 Exogenously Evoked Movement ................................................................ 15 Endogenously Evoked Movement ............................................................. 16 Two Routes to Action Evidence from Functional Neuroimaging in Healthy Adults ............................................................................................................ 18 Two Routes to Action Evidence from Clinical Populations ............................ 20 Parkinsons Disease ............................................................................................... 21 Quantification of Akinesia ....................................................................................... 24 Patients Ability to Benefit from External Cues ........................................................ 26 Stopping and Switching Motor Preparation ............................................................. 27 Parkinsons D isease and Mood Symptomatology ................................................... 28 Influence of Healthy Aging ...................................................................................... 29 Summary ................................................................................................................ 30 Specific Aims, Hypotheses and Predictions: ........................................................... 31 2 METHODS .............................................................................................................. 34 Participants ............................................................................................................. 34 Inclusion and Exclusion Criteria .............................................................................. 34 Procedure ............................................................................................................... 35 Computerized Test of Exogenously and Endogenously Evoked Movement .... 35 Apparatus ................................................................................................... 35 Block structure ........................................................................................... 35 Trial structure ............................................................................................. 36 Reaction time variables .............................................................................. 37 Differences between endogenous and exogenous cueing ......................... 38 C ollection of Motor, Mood, Cognitive, and Functional Impairment Variables ... 39 Motor function and symptoms of disease severity ..................................... 39 Mood symptoms ......................................................................................... 39
6 Functional measures .................................................................................. 40 Neuropsychological measures ................................................................... 41 Statistical Analyses ................................................................................................. 42 Effect of PD On Simple and Choice Reaction Time ......................................... 43 Aim 1 : Valid Cued (Stay) Trials ........................................................................ 43 Aim 2: Invalid Cued (Switch) Trials ................................................................... 44 Errors and Omissions ....................................................................................... 44 Comparison of Fatigue and Motivation Ratings ................................................ 44 Aim 3: Functional Impairment and Caregiver Burden ....................................... 45 3 RESULTS ............................................................................................................... 48 Demographic, Clinical, and Neuropsycholog ical Variables ..................................... 48 Effect Of Parkinsons Disease and Aging on Simple and Choice Reaction Time ... 48 Aim 1: Stay trials ..................................................................................................... 48 Valid Cues with Certainty ................................................................................. 49 Valid Trials with Uncertainty ............................................................................. 49 Aim 2: Switch Trials ................................................................................................ 50 Errors and Omissions ............................................................................................. 51 Fatigue and Motivation ............................................................................................ 51 Aim 3: Functional Impairment and Caregiver Burden ............................................. 51 4 DISCUSSION ......................................................................................................... 62 Parkinsons Patients Compared to Matched Older Adult Controls .......................... 62 Possible Mechanisms of Differences Associated with Parkinsons Disease ........... 65 Younger Versus Older Participants ......................................................................... 68 Possible Mechanisms Associated with Age Related Differences ............................ 68 Implications ............................................................................................................. 69 Limitations ............................................................................................................... 69 Future Direct ions .................................................................................................... 72 Summary and Conclusion ....................................................................................... 73 REFERENCES .............................................................................................................. 75 BIOGRAPHICAL SKETCH ............................................................................................ 87
7 LIST OF TABLES Table page 2 1 Blocks and Trials. ............................................................................................... 46 3 1 Participant Mood, Clinical, and Neuropsychological Characteristics .................. 53 3 2 Reaction time: Group means and standard deviations ....................................... 54 3 3 Hierarchical Multiple Regr ession Analysis Predicting Functional Impairment And Caregiver Burden ........................................................................................ 61
8 LIST OF FIGURES Figure page 2 1 Experimental Stimuli ........................................................................................... 47 3 1 Blocks 1 and 3 stay (without switch) trials. ......................................................... 56 3 2 Correlations between PD and OA participants difference scores and select clinical, demographic, mood, and neuropsychological variables. ....................... 57 3 3 Blocks 2 and 4 stay (with switch) trials. .............................................................. 58 3 4 Blocks 2 and 4 switch trials. ................................................................................ 59 3 5 Fatigue and Motivation. ...................................................................................... 60
9 Abstract of Dissertation Presented to the Graduate School of the University of Florid a i n Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy ENDOGENOUSLY AND EXOGENOUSLY EVOKED INTENTIONAL MOVEMENT IN AGING AND PARKINSONS DISEASE By Matthew Cohen August 2013 Chair: Catherine Price Cochair: Kenneth Heilman Major: Psychol ogy Background: Patients with Parkinsons disease (PD) often demonstrate akinesia, a paucity of endogenously evoked (volitional, internal) movement, but may be better able to move following exogenous (externally specified) cues. There are no objective tes ts to quantify a persons ability to initiate and execute endogenous movements, therefore limiting clinicians ability to test and understand this phenomenon. Purpose: To quantify PD patients ability to (a) initiate and (b) switch motor movements that ar e evoked, either with endogenous or exogenous cues compared with younger and agematched control participants. Method: The three participant groups (idiopathic, nondemented PD on medication n=12; OA n=15; YA n=14) were similar in education and demographics. Participants completed an experimental computerized motor initiation paradigm designed to examine their RT to endogenous versus ex ogenous valid cues (stay trials) T o quantify the cogni tive cost of having to switch motor preparations participants were also presented with invalid cues (i.e., switch trials). N europsychological function,
10 motor symptom severity, functional abilities and mood were also assessed. PD and OA participants significant others completed a measure of caregiver burden. Results: There were two main findings. First, OA participants were slower than YA participants when executing endogenously selected movements (i.e., on stay trials, relative to exogenously selecte d movements). Second, PD patients compared with OA participants showed significantly slower reaction times when switching endogenous ly tha n exogenously evoked movement This comparatively slow endogenous switching occurred in the context of equivalent si mple and uncued choice reaction times, was associated with functional impairment and caregiver burden, as well as poorer performance on neuropsychological tests of executive functioning, semantic fluency, and finger tapping speed. Conclusions : Patients wit h PD on dopaminergic medications were slower when disengaging and switching endogenously than exogenously evoked action, and this bradykinesia correlated with poorer neuropsychological functioning and greater functional impairments and caregiver burden. Th ese results have implicatio ns for compensatory strategies, and are concordant with recent evidence that PD patients difficulties with activities of daily living stem from errors of commission (e.g., perseveration) rather than omission (e.g., not performing a task). However, the relationships between dopaminergic medication and the engagement and disengagement of endogenously planned actions need to be further investigated.
11 CHAPTER 1 INTRODUCTION Statement of the Problem Parkinsons disease (PD) is the second most common neurodegenerative disease. It affects 1 million people in the U.S. and up to 5 million worldwide (Olanow, Stern, & Sethi, 2009) and its incidence is expected to double by 2030 (Dorsey et al., 2007). The economic impact of PD in the U.S. is estimated at $10.8 billion, 58% of which is related to direct medical costs ($10,043$12,491 per patient annually)(O'Brien, Ward, Michels, Tzi velekis, & Brandt, 2009). The indirect costs associated with lost workdays for patients and caregivers is estimated at $9,135 per patient annually(O'Brien et al., 2009). Patients, caregivers, and clinicians report that one of the most disabling signs of this disease is patients difficulty with self initiated behaviors. For example, patients with severe PD will often fail to initiate procedures needed for self hygiene, inc luding bathing and brushing teeth. However, when prompted by someone else the patient may execute these behaviors. More subtle impairments might result in the lack of initiation of household chores or physical activity. These patients demonstrate a relat ive lack of spontaneous movement (akinesia) that is motivated by their own volition, but tend to respond better when movements are externally guided. Thus, patients are said to have kinesia paradoxica, or a paradoxical lack of spontaneous movements given t heir preserved ability to move in response to external stimuli. Caregivers informally report that the lack or paucity of spontaneous behaviors in patients with PD is highly related to the degree of care and assistance that the patient
12 requires. However, t he impact of this disability cannot be fully known because there are no current means to objectively quantify an individuals level of impairment. Thus, it is difficult to identify the onset of kinesia paradoxica in the course of the disease, how it accomp anies other signs and symptoms of PD, how functionally impairing it may be, or how to assist affected patients either by directly treating it or by teaching compensatory strategies. This study aims to quantify individual participants discrepancies between internally prepared and externally evoked behavior, as well as the cognitive cost of having to switch behaviors. Additionally, this study will learn if kinesia paradoxica causes unique functional impairment and caregiver burden beyond the well known mot or (tremor, rigidity, and bradykinesia) and mood symptoms (apathy, depression) associated with PD. This knowledge would support what caregivers informally report and would support future systematic research into this very common but poorly understood and poorly appreciated neurological phenomenon. Introduction to Attention a nd Intention The brain contains 20 billion neocortical neurons, each with over 7000 connections to other neurons, for a total of 500 trillion connections (Drachman, 2005). In order for the brain to be effective and efficient, it has evolved ways of efficiently processing information, developing behavioral plans, and programming actions. One method is by functional organization, that is, physically grouping together neurons with similar functions. As with the spinal cord, the posterior half of the cortex is dedicated to sensory functions, while the anterior half is devoted to action functions. In addition to the physical organization of functions, each half also has i ts own means of focusing processing resources, like the beam of a spotlight. The posterior, sensory half employs attention to triage and target important sensory and cognitive events for further
13 processing. For example, the reader is encouraged to attend t o the feeling of his/her left foot inside of the shoe. Although this information had always been available, the reader was presumably not attending to (i.e., not devoting processing resources to) those sensory inputs before instructed to do so. Thus, attention is the process by which resources are allocated to sensory or cognitive events for further processing. The anterior, actionoriented regions of the cortex employ a process called intention to select, initiate, and execute to completion, actions move ments, cognitive activities, and emotional states. Attention and intention are also mediated by the basal ganglia and the thalamus, which serve to selectively gate information to the cortex (Mink, 1996) Attention and intention are intimately intertwined in every action, emotion, and thought that we have. Their unique natures are only visible in healthy persons with the use of neuroimaging techniques (Crosson et al., 2001), and in persons with neurological disorders who have deficits primarily limited to one system (Cohen, Burtis, Kwon, Williamson, & Heilman, 2010). The project described here proposes a novel approach to behaviorally quantifying a particular kind of actionintentional disturbance in persons with Parkinsons disease (PD). William James (2010) described the ideomotor theory of action: that an idea precedes any voluntary (i.e., nonautomatic) action. He hypothesized that even when movements have become (seemingly) automatic, as in an experienced typist typing on a keyboard, the idea or representation of the action is still presented in consciousness, however briefly. Heilman & Watson (1991) defined intention as the ability to select for execution one action among multiple, competing actions and to initiate the selected action. These authors disc ussed how intention governs the when aspects of behavior:
14 when to act (an impairment of which results in akinesia or apathy, discussed later), when to continue to act (impairment results in motor impersistence), when not to act (impairment results in dis inhibition and defective response inhibition), and when to stop acting (impairment results in perseveration). Others have described the role of intention with interrogative words: what (behavior to select), when (to do so), and whether (to execute or to st op)(Brass & Haggard, 2008). Many have discussed the intentional system as being synonymous, or at least highly overlapping with the concept of volition and free will (Haggard, 2008; Hallett, 2007; Nachev, Rees, Parton, Kennard, & Husain, 2005). Operational ly defined, this is the ability to choose between alternatives without there being any external cue (Pockett, Banks, & Gallagher, 2006) Two Routes t o Action Based on the early work of Sanides ( 1964) and Goldberg ( 1985) many researchers have supported the hypothesis that there are separate functional neuroanato mic networks underlying the initi ation of ac tion that is externally guided, or exo genously evoked (exo evoked) versus the initiation of action that is internally motivated, or endogenously evoked (endoevoked). An example of a more strongly exogenously evoked action is getting up out of a chair to answer a ringing telephone, whereas a more endogenously evoked behavior would be deciding to make a telephone call. The former is a response to an environmental stimulus whereas the latter relies more on the individuals self generated, goal ori ented behavior. In both scenarios, t he same motor neurons in the primary motor cortex produce the muscle movements associated with rising from a chair and leaving the room, but the motor initiation processes preceding these behavior s are distinct. Thus, there are two routes to
15 action ( Frith & Done, 1986) However, in everyday actions these systems are complementary, and most behaviors fall on a continuum between being completely endogenous or exogenous ( Krieghoff, Waszak, Prinz, & Brass, 2011 ) Two Routes to Action Evidence From Macaque Anatomy a nd Physiology The theory that there are two subsystems of intention is supported by distinct neuroanatomical substrates that support each subsystem. Specifically, regions of the lateral prefrontal cortex mediate exoevoked movement, whereas regions of the medial prefrontal cortex mediate endoevoked movement ( Krieghoff et al., 2011) These regions have distinct connections with subcortical structures ( Alexander, DeLong, & Strick, 1986 ) ; thus, there are circumscribed regions of subcortical s tructures as well that correspond with these medial and lateral (i.e., exo and end o evoked) processing centers ( Gerardin et al., 2004) This sectio n will briefly review the most relevant areas and their properties and follows the overview presented by Krieghoff et al. ( 2011) Most anatomical regions presented here are identified as Brodmann areas (BAs) ( Brodmann, 1909) Each section will also briefly describe major findings from physiological research with ma caques. Exogenously Evoked Movement E xo evoked movement appears to be mediated by the lateral frontal lobe structures, such as the dorsolateral prefron tal cortex (dlPFC; BA 9, 46) The dlPFC receives strong inputs from the temporal and parietal lobes. From the parietal lobe of monkeys it receives input mainly from BA 7 ( Cavada & GoldmanRakic, 1989) and has reciprocal connections with this area ( Knzle, 1978) From the temporal lobe, it receives input from the upper bank of the superior temporal sulcus ( Seltzer & Pandya, 1989) which is strongly interc onnected with the inferior parietal cortex ( Seltzer & Pandya,
16 1984) The dlPFC also receives projections from the inferotemporal cortex ( Barbas & Pandya, 1989) V5 (MT), and V5a (MST)( Seltzer & Pandya, 1989) Regarding output, there are no direct connections between t he dlPFC and M1 ( Leichnetz, 1986) ; rather, the dlPFC influences motor movement indirectly through lateral ( Barbas & Pandya, 1989) and medial BA 6 ( Luppino, Matelli, & Rizzolatti, 1990; Wiesendanger & Wiesendanger, 1984) It also projects to the hippocampus and parahippocampal gyrus both direc tly ( Selemon & GoldmanRakic, 1988 ) and indirectly through the entorhinal cortex ( GoldmanRakic, Selemon, & Schw artz, 1984) cingulate cortex (BA 24, 23) and retrosplenial cortex ( Mufson & Pandya, 1984; Vogt & Pandya, 1987) Endogenously Evoked Movement The endoevoked network appears to include the medial structures of the brain (Figure 1) including the supplementary motor area (SMA; posterior BA 6), pre SMA (anterior BA 6), anterior cingulate cortex (ACC; BA 24), mesial frontal cortex (BA 32), and rostral cingulate zone (RCZ; dorsal BA 32) ( Krieghoff et al., 2011) Immediately anterior to the primary motor cortex (M1; BA 4) lies BA 6. At the medial portion of BA6 is the supplementary motor area (SMA) and presupplementary area, which contribute to the planning and sequenc ing of motor movements that are then executed by M1. These areas have distinct cytoarchitectures and connectivities and can roughly be divided by envisioning a coronal line that passes through the anterior commissure of an AC PC (anterior commissure poster ior commissure) aligned brain image ( Picard & Strick, 1996) The preSMA is anterior to this line within medial BA6 and the SMA proper is posterior to this line. The SMA receives inputs from the caudal internal globus pallidus (GPi) ( Akkal, Dum, & Strick, 2007 ) while the preSMA receives inputs from the rostral GPi ( Akkal et al., 2007) Regarding output, the SMA is
17 somatotopically organized and projects directly to M1 and the spinal cord (Dum & Strick, 1991) The preSMA is not clearly somatotopically organized, and has almost no output projections to M1 or the spinal cord ( Krieghoff et al., 2011) Instead, preSMA outputs go to the prefrontal cortex and nonprimary motor areas ( Lu, Preston, & Strick, 1994; Luppino, Matelli, Camarda, & Rizzolatti, 1993) Because of its unique connectivity, it is believed that the PreSMA is not a typical motor area, but rather a prefrontal area. The cingulate cortex wraps around the corpus callosum and is oft en subdivided based on cytoarchitecture, patterns of connectivity, and function. Within the anterior cingulate cortex (ACC), researchers have distinguished between a rostral ventral affective (i.e., emotion) division (ACad; responsible for limbic functions ), consisting of BAs 25, 33, and ventral BAs 24 and 32, and a dorsal cognitive division (ACcd), consisting of dorsal BAs 24 and 32 ( Bush, Luu, & Posner, 2000) For the present investigation, the ACcd is most strongly implicated. In macaques, a region within the ACcd is called the cingulate motor area (CMA) and is dedicated to the processing of motor events. Based on different functional influences on the spinal cord, this area is also subdivided into two regions rostral and dorsal (CMAr; CMAd) ( Dum & Strick, 1991 ; Picard & Strick, 1996) It has been proposed that humans have analogues to these regions ( Picard & Strick, 1996) called the rostral cingulate zone (RCZ) and caudal cingulate zone (CCZ). Like Krieghoff et al. ( Krieghoff et al., 2011) we will refer to the RCZ as the brain area at the border between proisocortical parts of the anterior cingulate cortex (BA 24), neocortical areas (BA 32 and 8), as well as the SMA (BA 6). The physiological properties of relevant regions, and the functional consequences of their ablation have been explored in macaques. Okano & Tanji ( 1987)
18 and Halsband, Matsuzaka, & Tanji ( 1994) showed that more cells in the macaque SMA fire before spontaneous movements than before movements that are cued. Mushiake, Inase, & Tanji ( 1991) also showed that cells in the macaque SMA had a propensity to fire before motor movements that were internall y motivated, whereas cells in the lateral premotor cortex were biased to fire when movements were externally ( visually ) cued. These findings also suggest that the medial and lateral systems are not mutually exclusive and isolated, but rather that the medial system is preferentially active for internal generation (endoevoked) and the lateral system is preferentially active for external generation (exoevoked) ( Passingham, 1995) Activity in medial and lateral structures is not just correlated with internally and externally guided intention, but required for it Thaler et al. ( 1995 ) compared three groups of macaques with bilateral lesions to the preSMA/SMA, anterior cingulate cortex (ACC), or to lateral premotor cortex. These authors found that the groups with preSMA/SMA and ACC ( i.e. medial) lesions did not spontaneously initiate arm movements associated with a prelearned reward, but could move the arm to a cued sound. In contrast, macaques with lateral premotor lesions still produced some self initiated actions. Two R outes t o Action Evidence from Functional Neuroimaging i n Healthy Adults The use of functional neuroimaging in healthy human adults has also supported the existence of distinct exo and endo evoked systems. The lateralized readiness potential ( L RP) or bereitschaftspotential ( Kornhuber & Deecke, 1965) is a slow negative event related pot ential (ERP) over frontal, medial scalp sites 1.01.5 seconds before the onset of movement that originates from the SMA/preSMA. The waveform
19 has a greater amplitude for internally, freely selected movements than for predetermined, fixed movements, suggest ing the two are not equivalent ( Erdler et al., 2000; Jahanshahi et al., 1995) Crosson ( 2001) supported the existence of two intentional subsystems, and also demonstrated that their contributions are in balance for a given task, that is, not entirely internal ly or external ly motivated but rather lie along a continuum. These investigators performed functional magnetic resonance imaging (fMRI) of healthy adults during four language tasks that varied along a spectrum of internally versus externally prompted. In the most externally guided of the conditions, part icipants were asked to repeat words that they heard. In the most internally guided of the conditions, participants were asked to generate as many members of a given category as fast as possible. These investigators found a double dissociation between activity in the pre SMA, which increased proportionately with the degree of internal guidance, and activity along the inferior frontal sulcus (along lateral BA 6 and 8), which decreased proportionately with the degree of internal guidance. However, this pattern was not supported with activity in Brocas area, which suggests that the medial lateral distinction, while a well supported trend, is no t absolute. Functional neuroimaging has also shown differences in the activity of subcortical structures during internally versus externally guided movement. Gerardin et al. ( 2004) asked participants to (internally) select either thei r left or right thumb for a button press, and then to execute the button press. In a separate condition, participants were (externally) instructed which thumb to prepare and then execute. These authors found that activity in the caudate head and preSMA wa s associated with the (internal)
20 selection of movement, while the anterior putamen and SMA were associated with the preparation of an externally guided movement. The posterior putamen was associated with movement execution for both types of preparations. T his trend was also found by Jankowski et al. ( 2009 ) who showed that the caudate and anterior putamen wer e active in planning a novel sequence of finger movements, whereas the posterior putamen alone was active during the preparation of an overlearned finger movement sequence. The results of these studies suggest that exogenously and endogenous evoked intenti ons are associated with distinct functional anatomical profiles, not only cortically but also subcortically. This is consistent with the known anatomy and connectivity of subcortical regions with cortical regions For example, Alexander, Delong, & Strick ( 1986) showed distinct and noninterfacing cortical basal ganglia cortical loops Therefore, cortical regions that are preferentially associated with the exoevoked (lateral) or endoevoked (medial) subsystems of intention should also have distinct subcortical connections. Two Routes to Action Evidence from Clinical Populations Patients with utilization behavior and environmental dependency syndrome ( Lhermitte, Pillon, & Serdaru, 1986) demonstrate an inability to disengage from their immediate environment, presumably because the neural systems associated with their internal goals are dysfunctional, disconnected from, or overpowered by the neural systems associated with their relationship with their immediate environment. For example, these patients might sip from another persons cup, pull a fire alarm, or use a fire extinguisher that they encounter In short, their interaction with their immediate environment is disinhibited, but their disinhibition may not generalize to other types of behavior (e.g., interpersonal behavior).
21 Patients with akinetic mutism behave as described by the name of the disorder: they demonstrate an absence of spontaneous movement (akinesia) and speech (mutism). This often results from bilateral damage to the medial structures of the frontal lobe, most often the preSMA/SMA, anterio r cingulate cortex, and rostral cingulate zone ( K. M. Heilman & Watson, 1991) Additionally, patients with transc ortical motor aphasia (TCMA) demonstrate a lack of, or impaired spontaneous (i.e., endogenously generated) language ( K. M. Heilman & Valenstein, 2003) but remain comparatively able to repeat what they hear (i.e., external information). TCMA often results from unilateral damage to the lang uagedominant hemisphere in the medial frontal cortex which includes SMA ( Rubens, 1976) the left thalamus ( McFarling, Rothi, & Heilman, 1982) and the cortex that is superior to pars opercularis and pars triang ularis in the territory between the anterior cerebral artery and middle cerebral artery ( Masdeu, Schoene, & Funkenstein, 1978) The existence of the clinical syndromes described above provides evidence that there are dissociable systems mediating exogenously versus endogeno usly evoked behavior. The following section will extend this discussion to patients with Parkinsons disease, the population that will be studied in the present investigation. Parkinsons Disease Parkinsons disease is a progressive neurological illness that is associated with the death of dopamine producing neurons in the substantia nigra pars compacta (SNpc), which relates to the prominent motor symptoms of the disease: akinesia, resting tremor, bradykinesia, rigidity, and postural instability ( Jankovic, 2008) The nonmotor symptoms of PD include autonomic dysfunction, apathy and depression ( Kirsch Darrow, Marsiske, Okun, Bauer, & Bowers, 2011) and cognitive change most notably
22 characterized by executive dysfunction ( Barone et al., 20 11) Most PD patients develop symptoms in the 6th or 7th decade of life ( mean age at diagnosis is 70.5) ( Van Den Eeden, 2003) Many patients with PD first develop symptoms on one half of their body, corresponding with the asymmetri cal progression of the disease in the contralateral hemisphere of the brain ( Hoehn & Yahr, 1967 ) Functional disability in patients with PD is caused by bot h motor and cognitive difficulties. Cahn et al. ( 1998) showed that executive dysfunction (especially poor planning) related to difficulties with instrumental activities of daily living ADLs (e.g., paying bills), whereas finger speed and deftness related to bas ic activities of daily living (e.g., brushing teeth). Recently, freezing of gait (a phenomenon related to akinesia) was shown to be a strong predictor of healthrelated quality of life and specifically ADL completion ( Moore, Peretz, & Giladi, 2007) Caregivers also report that the patient needs help, guidance, or reminders to initiate activities. These reminders required by the patient are not solely the result of forgetting to do the activity, but also serve as external cues. In fact, patient and caregiver frustrations have prompted the development and marketing of commercially available products that provide external cues for mov ement, for example, glasses that project the image of a horizontal line for the patient to step over when he/she looks down ( McAuley, Daly, & Curtis, 2009) Another product includes a laser pointer on the tip of a walking cane to produce a visible line to step over. Parkinsons diseaserelated differences in end o evoked movement have been shown physiologically with the use of event related potentials (ERPs) and functional magnetic resonance imaging (fMRI). ERP studies have revealed that PD patients show
23 a reduction in the lateralized readiness potential that was described earlier ( Filipovic et al., 1997) that emanates from the preSMA/SMA region and precedes movement. Furthermore, whereas in healthy persons the waveform has a greater amplitude for internally, freely selected movements than for externally predetermined and fixed movements ( Erdler et al., 2000 ; Jahanshahi et al., 1995) patients with PD do not show this same amplitude disparity ( Praamstra, Cools, Stegeman, & Horstink, 1996) suggesting an attenuation of the endogenous movement system ( Praamstra, Stegeman, Cools, & Horstink, 1998) The use of fMRI has revealed that patients with PD show ed reduced activity during self initiated movements in the SMA, anterior cingulate, putamen, insular cortex, dorsolateral prefrontal cortex, and supramarginal gyrus. However, the PD groups did not differ from the healthy control group during externally guided actions ( Jahanshahi et al., 1995 ; Sabatini et al., 2000 ) The precise neural underpinning of kinesia paradoxica in PD is not known. Presumably, however, the disease preferentia lly affects the cortical and striatal component(s) associated with the endoevoked system. Dopamine replacement ( Buhmann et al., 2003; Haslinger et al., 2001) and deep brain stimulation of the subthalamic nucleus ( Grafton et al., 2006) ha ve been shown to increase activity in the SMA. Thus, decreased activity in the SMA in patients with PD appears to be related to dopaminerelated disruptions within the basal ganglia. Parkinsons diseaserelated effects on endoevoked movement have been sup ported with evidence from the classic Erikson flanker test ( Eriksen & Eriksen, 1974) This test shows participants a horizontal row of arrows, and asks participants to
24 respond with their right or left hands in the direction of the center arrow. On congruent trials, the center arrow points in the same direction as the surrounding ones. On incongruent trials, the center arrow points the opposite way, and participants slower reaction time for these trials is believed to reflect participants effort to suppress competing visual information. PD patients are more hindered by the incongruent flankers ( Praamstra et al., 1998) perhaps because patients internal drive (i.e., to resp ond to the center arrow) was weaker than their drive to attend and respond to other component of the environment (i.e., the flankers). This adherent, grasp behavior to external stimuli motivates our hypothesis for our second specific aim, relating to pat ients difficulty switching preparations and behaviors. Quantification of Akinesia The studies reviewed above provide some empirical support for what has classically been an anecdotal finding: that patients with PD have difficulty initiating movement based on their own volition (i.e., an endoevoked akinesia) Whereas caregivers report that this akinesia significantly impairs a persons functional independence and quality of life, no systematic research to date has documented th ese deficits. This documentat ion failure is in part due to the lack of a means of directly t esting for endoevoked movement This project aimed to do so by operationally defining endogenous preparation as the abilit y to reduce reaction time to an imperative stimulus with the availabil ity of advanced information (i.e., a cue) Preparing for a movement facilitates the initiation of that movement. For example, studies performed by Posner and colleagues ( Posner, 1980; Posner, Snyder, & Davidson, 1980) suggest that, when participants allocate attention to the location of a future imperative stimulus (e.g., in right versus left hemispace) he/she will respond more
25 rapidly when cued than when uncued. As an example, consid er a runner in the starting block before a race. Upon hearing the cue, take your mark the runners reaction time to the sound of the starting pistol is reduced because his exoevoked intentional system is engaged and priming his primary motor cortex to begin running. Now consider a race where there is a starting pistol but no cue. The runner could internally think, get ready, get set... and await the starting pistol. T here is evidence that healthy persons can benefit equally well from internal as from external cueing ( Fleming, Mars, Gladwin, & Haggard, 2009 ) presumably because their exoand endo evoked intention systems are equally capable. This analogy with the runner sets the stage for the present investigation with PD patients. This project was designed so that participants would see a midline imperative stimulus (colored letter L or R) and will respond (press a key) with the hand indicated by the letter. In the exoevoked condition, participants were valid ly cue d (midline white letter L or R) as to which hand (left or right) will be required to respond to an imperative stimulus (the white letter L or R fills with a color), also presented in the midline. In the endoevoked condition the participants saw a white letter C (i.e. choose) and internally selected either their right or left hand to prepare for a button push, and executed their choice when the white letter C turns a color (i.e., the imperative stimulus ) While the C is itself an exogenous cue, it prompts a choice, which on a spectrum of behavior between fully endogenous and exogenous, is more endogenous than the L or R (exogenous) conditions. Posners studies (summarized above) showed that individuals respond more rapidly to imperati ve stimuli when provided valid (i.e., correct) cues, but also included a small percent (20%) of invalid cues (i.e., miscues). Posner et al. ( 1980) reported that
26 (independent of hand used) if the participant is correctly informed that the imperative stimulus will come in right hemispace, then the participant will have a more rapid reaction time than if there were no cue before this imperative stimulus. If, however, the subject is given a miscue (i.e., to left hemispace in this example), then when the imperative stimulus is presented in the unattended hemispace participants reaction times are longer than in the uncued condition. In the present study 20% of the cued trials were invalid, for example, if the participant viewed an exogenously provided L cue followed by a R imperative stimulus. This is to test participants ability to switch endogenous versus exogenous preparations. Indeed, it has been posited that patients akinesia results from difficulties terminating and switching behavior, rather than initiating behavior ( DeLong et al., 1984; Thach, 1978; Warabi, Fukushima, Olley, Chiba, & Yanagisawa, 2011) Patients Ability to Benefit from External Cues The use of reaction time as a dependent variable may seem problematic when studying a patient population with motor deficits A review of 26 reaction time studies with idiopathic, nondemented PD patients showed slowing on simple reaction time, and a review of 16 studies show ed variable effects on choice reaction time ( Gauntlett Gilbert & Brown, 1998) depending on the nature of the task However, even when their absolute motor speed is slower, PD patients are able to benefit (i.e. reduce their reaction time to an imperative stimulus) from advanced, externally guided information to the same degree as control participants ( K. M. Heilman, Bowers, Watson, & Greer, 1976; Jahanshahi, Brown, & Marsden, 1992; Stelmach, Worringham, & Strand, 1986; Willingham, Koroshetz, Treadwell, & Bennett, 1995)
27 A study by Bloxham, Mindel, & Frith ( 1984) is one exception to this trend. These authors used a verbal cue before a right or left hand button press: ready, ready right, or ready left. These cues occurred 200ms or 2000ms before the imperative stimulus. It is not clear why these authors did not show a cueing effect in the PD group. This study, however, differed from others in that they used verbal (e.g.,ready left) rather than visual cues (e.g., arrows). Despite the results of Bloxham et al. (1984), however, the preponderance of evidence suggests that patients with PD are slower but benefit from advanced, external information as well as control participants ( Gauntlett Gilbert & Brown, 1998) It was expected that the present study would support this finding with exogenous cues and contrast it with patients difficulty with endogenous cues. Stopping and Switching Motor Preparation Above it was discussed how patients with PD were tested for their ability to benefit (i.e., reduce their reaction time) with valid cueing. However, equally as important is the ability to disengage/switch motor preparations. The paucity of spontaneous movement (akinesia) that often accompanies PD may also be related to the difficulty that patients have disengaging from an earlier activity ( Warabi et al., 2011) For example, a patients seeming lack of motivation to brush his teeth may actually stem from difficulty disengaging from reading a book. This inability to disengage is visible in patients with PD when they demonstrate defective response inhibition ( Crucian et al., 2007) On the crossedresponse inhibition test, participants have their eyes closed and their hands resting on their lap. When the examiner touches one hand, patients lift the hand that was not touched. Patients with PD make many more errors than matched controls suggesting that exoevoked plans (i.e., engaging the stimulated hand) can overwhelm endoevoked plans (i.e.,
28 disengaging from the stimulus and raising the opposite hand). PD patients difficulty stopping/switching goal directed behavior can also be seen on formal cognitive tests, such as the Wisconsin Card Sort Test, where PD patients have been shown to demonstrate more perseverative errors ( Lezak, 2004) That is, when solving problems with changing solution algorithms, patients with PD remain stuck longer on the old algorithm. In the present study, some blocks of trials presented valid cues in isolati on, while others included 20% invalid trials. That is, the cue misdirect ed the participant from the action for which s/he prepared and required him/her to instead activation the neurons controlling the opposite hand. Similar to what has been shown by Posner ( 1980) it wa s predicted that the cost of disengaging/switc hing from the miscue would result in longer response latencies than in uncued trials. It wa s hypothesi zed that participants with PD will demonstrate a larger cost of switching (i.e., longer reaction time) because of the known diseaserelated difficulties disengaging from the environment (i.e., showing a neurobehavioral grasp) ( Drago et al., 2008) In the present study, during the blocks of trials that include invalid trials, the uncertainty of execution (i.e., because of the 20% possibility of having to switch) may have affected participants approach to the (80%) nonswitch (i.e., stay trials). Indeed, research with macaques suggested that there are specialized cells in the dorsolateral prefontal cortex (dlPFC) that are sensitive to the probability of action, not the action itself ( Quintana & Fuster 1999) It has not been studied if there is a PD related difference in the approach to uncertain movement. Parkinsons Disease and Mood Symptomatology It is common for patients with Parkinsons disease to experience changes in mood, most commonly depression and apathy. Although apathy is often an element of
29 depression, it occurs in isolation in approximately 29% of PD patients ( Kirsch Darrow et al., 2011) Estimates of the prevalence of depression in PD vary dramatically (between 2.7% and 90%); however, a recent m eta analysis concluded that clinically significant depressive features were present in approximately 35% of patients with PD, while 19% met formal DSM IV TR (citation) criteria for Major Depressive Disorder ( Reijnders, Ehrt, Weber, Aarsland, & Leentjens, 2008) These mood symptoms are conceptualized as not only psychological reactions to major neurological illness, but also a primary consequence of neurological and neurochemical change ( Leentjens, 2004) Because depression and apathy are so common in patients with PD, this study will not exclude patients with these symptoms. Rather, these experiences were quantified with self report measures Depression is known to contribute to functional limitations in PD ( Weintraub, Moberg, Duda, Katz, & Stern, 2004) In the present study it was hypothesized that while akinesia paradoxica may not be entirely distinct from mood symptoms, slow endogenous initiation will uniquely predict patients funct ional ability and caregiver burden, above and beyond the motor and mood symptoms of the disease. Influence of Healthy Aging The present study also included healthy young adult (YA) participants to clarify whether any significant findings in the PD group were due to a unique diseaserelated process, or rather an exaggerated phenomenon found in the course of (nonpathological) aging. We hypothesized the latter for several reasons. First, agerelated neurological change (e.g., atrophy) preferentially affects r egions important for endogenous movement, including the bilateral caudate nuclei, prefrontal white matter ( Raz et al., 2005) and perhaps the entire right cerebral hemisphere more than the left
30 ( Dolcos, Rice, & Cabeza, 2002) Secondly, one of the main pathophysiological underpinnings of PD, the loss of dopaminergic cells in the substantia nigra, is not an all or none phenomenon. Clinical symptoms of PD result when the substantia nigra has lost approximately 70% of its dopaminergic cells ( Goldberg, Haack, Lim, Janson, & Meshul, 2011) However, dopamine is also lost in the context of healthy aging as well, in fact, up to a 10% per decade loss of dopamine D1 and D2 receptors, which intricately relate to cognition for a review see Backman, Nyberg, Lindenberger, Li, & Farde ( 2006) Because it was hypothesized that endogenous movement is affected by age and not just by PD, it was expected that OA would show preferential difficulty (i.e. RT slowing) with endogenous initi ation and switching compared with the YA group. Summary Parkinsons disease is the second most common neurodegenerative disease and is associated with very significant emotional and financial costs to the patient, his or her family, and to the healthcare s ystem. One impairing but misunderstood feature of the disease is the reduction of spontaneous movement (akinesia), which reportedly results in functional impairment and increased burden to caregivers and the health care system. Individuals with PD often respond with better motor output to exogenous (external) stimuli than to endogenous motivation. Health professionals have discussed this phenomenon, termed kinesia paradoxica, as a curiosity of the disease, rather than a phenomenon deserving of rigorous clinical study. One reason for its lack of study is that there is not currently a way to objectively characterize an individuals degree of impairment. The present investigation used an innovative experimental paradigm that measured participants ability to reduce their reaction time to an imperative stimulus with the availability of advanced information (valid cues; stay trials), exogenous or
31 endogenous, as well as the cognitive cost (i.e., reaction time slowing) of invalid cues (switch trials). Analyses also targeted participants ability to benefit from valid cues in isolation versus with the possibility of having to switch. A healthy, young adult control group was included to clarify whether differences in evoked reaction time was a unique result of PD, or perhaps an exaggeration of a phenomenon that occurs with older age. Specific Aims, Hypotheses and Predictions: The present study had three specific aims: Aim 1: To investigate group differences in participants reaction time following exogenous versus endogenous valid cues (i.e., stay trials), which allows them to prepare for a movement. Hypothesis Prediction 1: Patients with idiopathic, Parkinsons disease, who do not have signs of dementia, would demonstrate faster reaction times following exogenous cues than endogenous cues relative to an older adult (OA) control group matched for age. Based on observation of patients with focal lesions, there may be two networks that help normal people prepare for movement, an allocentric network that may activate the lateral frontal lobes and a medial egocentric network. Observation of patients with PD who demonstrate kinesia paradoxica suggested that these patients have a greater impairment in the endogenous than exogenous action preparatory network. Thus, based on the known relationship between PD and preferential disruption of the endogenously evoked system, it is predicted that patients with PD will demonstrate slower reaction times in response to valid endogenous cues than from valid exogenous cues. Hypothesis Prediction 2: because nonpathological aging is associated with volume loss in structures that are important for endogenous initiation, as well as a decrease of dopaminergic neurons in the substantia nigra it is also predicted that the healthy older adult (OA) group, when compared to the younger adult (YA) group, would
32 demonstrate relatively slower reaction times foll owing endogenous cueing than exogenous cueing. To test these hypotheses, this study compared the reaction times of these three groups (PD, OA, YA) with valid exogenous and endogenous cued (stay) trials, with and without the possibility of switching. Ai m 2: To investigate the cognitive cost (i.e., reaction time slowing) of disengaging/switching motor preparations (switch trials). Hypothesis Prediction 1: Patients with PD have degeneration of the mesocortical dopaminergic network that supplies dopamine to the frontal lobe, as well as an impairment of their nigrostriatal dopamine system that supplies dopamine to the basal ganglia (e.g., caudate), which also has extensive connections with the frontal lobes. Thus, patients with PD may have frontal lobe dys function, and lesion studies have indicated that frontal lobe dysfunction can impair disengagement. Therefore, it was predicted that individuals with PD would demonstrate more difficulty disengaging (i.e., slower RTs) from invalid trials (miscues) than would OA participants. In addition, because the basal ganglia are more strongly implicated in endogenous movement, it is predicted that PD patients would have slower reaction times with endogenously evoked than with exogenously evoked preparations. Hypothesis Prediction 2: Because with aging there is a loss of dopaminergic neurons and frontal connectivity, we also predicted that the OA group would show more RT slowing than the young adult (YA) group. Aim 3: To examine the relationships between PD and OA part icipants exogenous and endogenous RTs (both stay and switch trials), functional impairments, and caregiver burden. Hypothesis Prediction: we predict that alterations of PD reaction
33 times (as discussed above) will predict self reported functional disabilit y and caregiver burden (slower RT=more disability).
34 CHAPTER 2 METHODS Participants There were three groups of participants: individuals with idiopathic Parkinsons disease (PD), healthy older adult control participants (OA) matched for age and education, and healthy young adult (YA) participants matched for education. Participants with i diopathic PD were diagnosed by a movement disorder specialist neurologist, with diagnoses based on Brain Bank Criteria (Hughes, Daniel, Kilford, & Lees, 1992). Participants in the PD and OA groups were recruited from a parent study and were offered a $20 g ift card for their participation. Participants in the YA group were recruited from the University of Florida (UF; Gainesville, FL) community. The UF Institutional Review Board approved this study and participants provided written informed consent in accord with the Declaration of Helsinki. Inclusion and Exclusion Criteria All participants had normal or correctedto normal vision. To avoid the possible confounding effects of hand dominance, all enrolled patients were also strongly right hand dominant, as det ermined by the Edinburg Handedness Inventory ( Oldfield, 1971) P articipants in the PD and OA groups were screened with the Dementia Rating Scale (DRS 2) ( Jurica, Leitten, & Mattis, 2001 ) and were not demented (total raw score > 130). PD patients had a Hoehn and Yahr scale score between 13, which indicated that they were physically independent, and were on their usual medication, which is reported in levodopaequivalent dosage (LED) ( Tomlinson et al., 2010) Exclusion criteria for all patients included: uncorrected vision or hearing impairments, history of deep brain stimulation (DBS) or ablation surgery history of neurological illness (other than PD) or
35 injury untreated psychiatric illness, medical diseases with organ failure (e.g., cardiac, pulmonary, kidney, liver) diagnosed learning disorder or symptoms of a learning disorder based on cognitive screening, an d current use of psychotropic drugs other than antidepressants. Procedure Computerized Test of Exogenous ly and Endogenously Evoked Movement Apparatus T he software, DirectRT ( Jarvis, 2004) was used to present the stimuli and collect the data. This software has a timing res olution of 1 millisecond (ms) and t he response timing is synchronized with the screen display so that timing always begins when the screen first begins to draw, which eliminates 1017 milliseconds of random error. For all conditions, participants sat approximately 18 inches away from a computer screen with their left and right index fingers rest ing on the left and right SHIFT key s on a standard computer keyboard. Block structure Participants completed 232 experimental trials that were organized into 5 blocks (0,1,2,3,4; Table 21 ). Block 0 contained only simple (i.e., not choice) reaction time trials, 8 trials in a row of one hand followed by 8 with the other hand (order counterbalanced across participants). Block 1 included uncued choice RT trials and exogenously cued trials without switch trials (i.e., all trials were stay trials), whereas Block 2 included uncued choice RT tri als and exogenously cued trials with 20% invalid trials (i.e., switch trials) This 80% 20% division was determined to be good split based on similar paradigms reported by others (e.g., Posner et al., 1984). Block 3 included
36 uncued choice RT trials and endogenous cued stay trials without switch trials, whereas Block 4 included endogenously cued stay and 20% switch trials Block 0 was always administered first. Blocks 1 and 2 (exogenously cued trials) were yoked in order (i.e., 2 always followed 1), and B locks 3 and 4 (endogenously cued trials) were yoked in order. However, the order of the cue types was counterbalanced across participants, so that half saw order 01 2 3 4, while the other half saw 03 4 1 2. The blocks comprised of only stay trials were s hown before the blocks with some switch trials in order to capture participants performance without the cognitive concern of potential switch, and also to strengthen participants trust in the cue. Before each block, the trial types included in that block were practiced for 8 trials total. Approximately every three minutes the participants were offered a brief rest and were asked to rate their level of fatigue and motivation on 7point Likert scales (higher=more fatigue, less motivation) The administrat ion of all trials took partic ipants approximately 45 minutes Trial s tructure Before the first trial of each block, and between subsequent trials, there was an interstimulus interval (ISI) of 4000 or 6000ms varied to avoid habituation and anticipation. For uncued choice RT trials, a large orange letter L or R served as the imperative stimulus that instructed the participant to press a computer key under his or her left or right index finger, respectively (Figure 2 1 ). Exogenously cued trials were similar in design to those used by Gerardin et al. ( 2004) : A white letter L or R was the cue to prepare for a left or right button press. The time that the cue was visible before the imperative stimulus, the stimulus onset asynchrony ( SOA; 1000, 2000, or 4000ms), was varied to avoid anticipation. The cue remained visible throughout the SOA until the
37 imperative stimulus so that the task did not tax spatial working memory, which may be affected in persons with Parkinsons disease ( Owen, Iddon, Hodges, Summers, & Robbins, 1997) Following the SOA, the white letter (cue) turned orange, which was the imperative stimulus for the participant to execute the prepared response. For switch tri als, the white letter turned blue, which was the imperative stimulus to execute the unprepared hand. For endogenously cued trials, the fixation cross was followed by a white letter C (i.e., choose) which alerted the participant to internally select and prepare either their right or left index finger for a key press. At the end of the SOA, the C turned orange, which was the imperative stimulus for participants to press their chosen key (stay trials). For switch trials, the C turned blue, which was the imperative stimulus for participants to execute their nonprepared hand. Following each endogenous switch trial, the program asked the participant whether he/she was successfully able to switch (Figure 21). The colors associated with stay and switch tri als, orange and blue, were counterbalanced across participants. The SOAs were 1000, 2000 or 4000ms for all trials because pilot data with healthy control participants (not shown) suggested that they required at least 1000ms for endogenous cueing. This is the approximate time course of the lateralized readiness potential ( Erdler et al., 2000) which is thought to mediate endogenous preparation ( Jahanshahi et al., 1995; Praamstra, Cools, et al., 1996; Praamstra, Meyer, Cools, Horstink, & Stegeman, 1996) Reaction time variables For all reaction time trials, outliers less than 100ms were excluded from analyses. Slow reaction times were not excluded because these may have been
38 reflective of akinesia, the target of the investigation. Outlying, extreme difference scores (>2SD for the respective group) were excluded and replaced with the group mean. Groups were compared (PD vs. OA; OA vs. YA) on the following variables: Simple RT Without Cues (Block 0), Choice RT Without Cues (combined trials from Blocks 14), Exogenous Valid Cues wit h Certainty (Block 1), Exogenous Valid Cues with Uncertainty (Block 2), Endogenous Valid Cues with Certainty (Block 3), Endogenous Valid Cues with Uncertainty (Block 4), Exogenous Invalid Cues (Switch Trials; Block 2), and Endogenous Invalid Cues (Switch T rials; Block 4). Differences between endogenous and exogenous cueing In addition to comparing the groups raw, absolute reaction time for each of the above conditions, three difference scores were computed to compare participants relative difficulty with endogenous versus exogenous cued reaction times as a percentage of the total speed. VALID CUES WITH CERTA INTY DIFFERENCE SCOR E. The following difference score was computed for each participant to compare his or her relative performance on exogenously versus endogenously cued stay trials without the possibility of switch. ( Block 3 endo stay trial mean ) ( Block 1 exo stay trial mean ) ( Block 3 endo stay trial mean ) + ( Block 1 exo stay trial mean ) 100 VALID CUES WITH UNCERTAINTY DIFFERENCE SCORE. The following variable was computed for each participant to compare his or her performance on exogenously versus endogenously cued stay trials with the possibility of switch: ( Block 4 endo stay trial mean ) ( Block 2 exo stay trial mean ) ( Block 4 endo stay trial mean ) + ( Block 2 e xo stay trial mean ) 100
39 The following variable was computed for each participant to compare his or her performance on exogenously versus endogenously cued switch trials: SWITCH (INVALID CUES) DIFFERENCE SCORE. The following variable was computed for each participant to compare his or her relative performance on exogenously versus endogenously incorrectly (invalid) cued switch trials: ( Block 4 endo switch trial mean ) ( Block 2 exo switch trial mean ) ( Block 4 endo switch trial mean ) + ( Block 2 exo switch trial mean ) 100 C ollection o f Motor, Mood, Cognitive, a nd Functional Impairment Variables Motor function and symptoms of disease severity The Unified Parkinsons Disease Rating Scale (UPDRS III) ( Fahn & Elton, 1987) was completed for individuals in both the PD and OA groups. This scale quantified t he type, number and severity of motor symptoms common to PD The scale was completed by trained raters, and checked by other trained raters who were blind to participant number or group. Two participants completed this scale on the same day as the other measures. For all others, the data were shared with the parent study and were current within 6 months of their RT data. Dependent variable (DV)=part III (motor severity). Mood symptoms The following mood measures were acquired from the OA and PD groups in order to quantify the sample and also because mood symptoms may relate to the same neural circuits as are important for endogenous initiation ( Leentjens, 2004) All participants completed these measures on the same day as their reaction time data were collected.
40 GERIATRIC DEPRESSION SCALE SHORT FORM. A measure of depression severity that deemphasizes somatic symptoms commonly experienced during older age and that may bias depression assessment ( Sheikh & Yesavage, 1986) DV= total raw score. APATHY INDEX. A self report inventory shown to be sensitive to reduced motivation and anhedonia ( Starkstein et al., 1992) and distinct from depression, in PD ( Kirsch Darrow et al., 2011) DV = total raw score. Functional m easures Two measures of activities of daily living (ADL) were administered to the OA and PD groups in order to examine the relationship between functional impairment and endogenously evoked RT responses on the experimental paradigm. All participants completed these measures on the same day as their RT data were collected. PARKINSONS DISEASE QUESTIONNAIRE (PDQ 39). A self report measure of symptoms common to PD in the domains of mobility, activities of daily living (ADL), emotional well being, stigma, social support, cognitive impairment, communication, and bodily discomfort. DV= PDQ 39 total score, which was included in a composite score, described below. MINIMUM DATA SET HOME CARE (MDS HC). A questionnaire of instrumental activities of daily living (IADLs). Th e MDS HC yielded two subscales, one that describes the participants independence completing IADLs and a second describing their difficulty in completing IADLs. In the present study the two MHS HC subscales and the PDQ 39 were added together to produce a f unctional impairment composite that was used in analyses.
41 ZARIT CAREGIVER BURDEN QUESTIONNAIRE. A measure of caregiver stress and burden ( Zarit, Reever, & BachPeterson, 1980) was completed by the participants spouse or significant other when avai lable. Neuropsychological measures This set of cognitive measures was administered in order to examine the groups estimated intelligence and to sample various executive functions that are affected by PD and/or may have overlapping neural circuitry as endogenous movement initiation and/or disengagement. WECHSLER TEST OF ADULT READING. A measure to assess premorbid intellect and assess similarities between groups ( D. Wechsler, 2001 ) DV = estimated Full Scale IQ This was not assessed on the same day as participants RT data, but was shared with parent study and current within six months. WISCONSIN CART SORT TEST (WCST). A test of concept learning and set shifting ( Heaton, 1981) DVs = Number of ca tegories learned, number of perseverative errors, failures to maintain set. STROOP COLOR WORD TEST. A test of cognitive control and inhibition ( Golden, 1978) DV=Color Word score. While the interference score may also be used, it is sensitive to basic processing speed, which may be impaired in patients with PD ( Hsieh, Chen, Wang, & Lai, 2008) WECHSLER ADULT INTELLIGENCE SCALE DIGIT SPAN SUBTEST. DVs=forward span and backward span, which measured participants basic auditory attention and verbal working memory ( David Wechsler, 2008) TRAIL MAKING TESTS A AND B. Tests of participants complex processing speed and rapid set shifting ability ( Reitan & Wolfson, 1985) DV=((Trail Making Test B)
42 (Trail Making Test A)), which is calculated to isolate the executiv e functioning component of the test. CONTROLLED ORAL WORD ASSOCIATION TEST. A measure of ideational fluency and generativity ( Benton, Hamsher, & Sivan, 1994 ) DVs=F,A,S total combined score and animal naming total score. FINGER TAPPING. A measure of finger speed with participants dominant (right) and nondominant hands for 10 trials each. DVs = dominant hand average score, nondominant average score. WECHSLER MEMORY SCALE, THIRD EDITION (WMS III) SPATIAL SPAN SUBTEST. A measure of participants nonverbal working memory ( David Wechsler, 1997) DVs= forward and backward span. Fo r all participants the phonemic fluency and digit span data were collected on the same day as their RT data. However, the other neuropsychological variables listed above were shared with the parent study and are current within 6 months. Three subjects part icipated in the presented study on the same day as their participation in the parent study and all data were collected on the same day. Statistical Analyses The analyses targeted the effects of Parkinsons disease by comparing the PD and the OA groups, and the effects of aging by comparing the OA and YA groups. Because the reaction time variables were strongly positively skewed, the (nonparametric), the MannWhitney U test (similar to an independent samples t test) was used to compare groups. For any of th e conditions and analyses described below, if a participants score exceeded two standard deviations of their groups mean, it was considered an outlier and replaced with the groups mean for that analysis
43 Effect of PD On Simple and Choice Reaction Time T o assess differences in basic perceptual motor speed, MannWhitney U tests analyzed group differences (PD vs. OA; OA vs, YA) in simple reaction times (Block 0) with each hand. MannWhitney U tests also compared group differences in uncued choice reaction t ime. Aim 1: Valid Cued ( Stay ) Trials This aim examined group responses to valid exogenous versus valid endogenous cues (stay trials), both with and without the possibility of switching, to examine if participants with idiopathic PD who are not demented can reduce their RT with cueing as well as age matched healthy participants and in addition to learn if OA can reduce their RT with cueing as well as YA. Four MannWhitney U tests were conducted for each comparison (PD vs. OA; OA vs. YA) to examine group differences in: (a) Exogenous Valid Cues with Certainty, (b) Exogenous Valid Cues with Uncertainty, (c) Endogenous Valid Cues with Certainty, (d) Endogenous Valid Cues with Uncertainty. Two MannWhitney U tests for each comparison then compared the groups (PD vs. OA; OA vs. YA) Difference Scores to examine relative RTs between endogenous and exogenous conditions: (a) Valid Cues With Certainty Difference Score, and (b) Valid Cues With Uncertainty Difference Score. Both stay difference scores were also correlated with relevant clinical and neuropsychological variables to identify overlap and to potentially clarify group differences. Each groups two stay difference scores were also statistically compared with MannWhitney U tests.
44 Aim 2: Invalid Cued ( Switch ) Trials This aim investigated the cognitive cost (i.e., reaction time slowing) of disengaging/switching motor preparations to examine if patients with PD are equivalent to age matched healthy participants and to learn if OA performed differently than YA> Two pairs of MannWhitney U tests were conducted to examine group differences (PD vs. OA; OA vs. YA) in (a) Exogenous Invalid Cues (Switch Trials), and (b) Endogenous Invalid Cues (Switch Trials). A set of MannWhitney tests also compared group differenc es in the Switch (Invalid Cues) Difference Score. The Switch Difference Score was also correlated with relevant clinical and neuropsychological variables to identify overlap and to potentially clarify group differences. Errors and Omissions An error was de fined as an incorrect response, for example, pressing the left key rather than the right key, or failing to switch on invalid trials. The number of errors committed by each group was compared with Kruskal Wallis ANOVAs for each trial type. Significant omnibus findings were followed with MannWhitney U tests. Participants were encouraged to use each hand some of the time on endogenous trials. However, despite the instructions, not every participant engaged each hand with each trial type. The groups were compared with Kruskal Wallis ANOVAs for the number of absent responses demonstrated for each block and trial type. Significant omnibus findings were followed with MannWhitney U tests. Comparison of Fatigue and Motivation Ratings Approximately every three minutes during the reaction time trials participants were offered brief breaks and were asked to self rate their level of motivation and fatigue on 7point Likert scales. (higher = more fatigued, less motiv ated). Groups mean
45 ratings per block were compared with Kruskal Wallis ANOVAs. When significant group differences were found, follow up analyses with the MannWhitney test were implemented. Aim 3: Functional Impairment and Caregiver Burden This aim invest igated the relationship between participants endogenous reaction times and functional impairment and caregiver burden. Two hierarchical multiple regressions were conducted to predict functional impairment and caregiver burden in the PD and OA groups independent of general speed, diseaserelated motor symptoms, and mood symptoms. Functional impairment was defined as a functional composite score equal to the sum of the PDQ 39, the MDS HC Independence subscale, and the MDS HC Difficulty subscale. Caregiver bu rden was defined as the total score on the Zarit Caregiver Burden questionnaire. The first block of each regression controlled for symptoms of depression (GDS total score) and motor symptom severity (UPDRS part III). The second block of each regression inc luded participants mean cued reaction time score across trials (to control for overall speed), as well as the three difference scores.
46 Table 21. Blocks and t rials Block Trials Types Number of Trials Presentation 0 Uncued L & R 8, 8 One hand in a row, then the other 1 Uncued L & R Exo L Stay; Exo R Stay 8,8 24, 24 Randomized 2 Uncued L & R Exo L Stay; Exo R Stay Exo L R Switch; Exo R L Switch 8, 8 16 6,6 Randomized 3 Uncued L & R Endo Stay 8,8 16 Randomized 4 Uncued L & R Endo Stay Endo Switch 8,8 48 12 Randomized 232 Trials Note. Exo=exogenously cued, Endo=endogenously evoked, L=left handed response, R=right handed response, Stay=valid trial, Switch=invalid trial.
47 Figure 21. Experimental Stimuli. A) An uncued trial. B) A n exogenously cued trials. For both of these examples, there is a left (L) imperative stimul us, but there were also right (R) imperative stimuli. C) A n endogenously cued trial. Endogenous stay trials ended with the imperative stimulus, but the switch tr ials had an additional component that asked participants about their switch. The imperative stimuli were filled orange (stay) or blue (switch; colors counterbalanced), but are shown here in gray.
48 CHAPTER 3 RESULTS Demographic, Clinical, and Neuropsychological Variables PD participants were equivalent to the OA participants with regard to age, and all three groups (PD, OA, YA) were similar in education (Table 31). All participants were strongly right hand dominant. PD patients were different from OA participants in expected, diseaserelated signs and symptoms: they reported a higher levodopa equivalent dosage, more symptoms of apathy and depression (AS, GDS), more functional difficulty (PDQ 39, MDS HC), their caregivers reported more burden, and demonstrated more severe motor symptoms (UPDRS). On neuropsychological tests PD participants trended towards having achieved fewer categories on the WCST, had more failures to maintain set, named fewer items on the semantic fluency test, and recalled f ewer items on the backwards spatial span. Effect Of Parkinsons Disease and Aging on Simple and Choice Reaction Time Participants simple reaction times were captured in Block 0 and their uncued choice reaction times were assessed in Blocks 14 (Table 32) The groups were compared (PD vs. OA; OA vs. YA) with Mann Whitney U tests (Table 33). The PD group was equivalent to the OA group for both simple ( p =.104) and uncued choice RT ( p =.143). The OA group was slower than the YA group for both simple ( p <.001) and uncued choice RT ( p <.001). Aim 1: Stay trials This aim investigated group differences (PD vs. OA; OA vs. YA) in reaction time following valid endogenous than exogenous cues (stay trials), both with and without the
49 possibility of switching. Group means and standard deviations are presented in Table 3 2, and are analyzed as shown in Table 33. Valid Cues with Certainty MannWhitney U tests revealed that the PD and OA groups were equivalent for both exogenously cued ( p =.558) and endogenously cued ( p =.223) valid cues with certainty (Table 32). The Valid Cues With Certainty Difference Score was equivalent between the PD and OA groups ( p =.354)(Figure 31), and was correlated with advanced age (r=.386) and slower tapping with the nondominant (left) hand ( r = .352) (Figure 3 2). The YA group was significantly faster than the OA group for both exogenously cued ( p =.003) and endogenously cued ( p <.001) valid cues with certainty. However, the Valid Cues with Certainty Difference Score revealed that older adults trended towards being relatively slower ( p =.067) on endogenous trials than exogenous trials. Valid Trials with Uncertainty PD and OA participants were equivalent on valid trials with uncertainty, both exogenously cued ( p =.807) and endogenously cued ( p =.354). T he groups were also equivalent on the Valid Cued with Uncertainty Difference Score ( p =.626), and it correlated with a worse neuropsychological performance, including poorer nonverbal working memory on the WMS III Spatial Span subtest (backward span r = .45 2), slower tapping with the right (dominant) hand ( r =.344), and two variables on the Wisconsin Card Sorting Test: fewer categories achieved ( r = .600) and more perseverative errors ( r =.424) (Figure 32).
50 YA participants were faster than OA for all valid trial with uncertainty, both exogenously cued ( p <.001) and endogenously cued ( p <.001). The Valid Cues with Uncertainty Difference Score was equivalent between the OA and YA groups ( p =.138). Aim 2: Switch Trials This aim examined the cognitive cost (i.e., s lower reaction time) of switching endogenous and exogenous preparation. Three PD participants were outliers and their scores were replaced with the group mean for this analysis. PD and OA participants were equivalent on the invalid cued (switch) trials, both with exogenous cues ( p =.845) and endogenous cues ( p =.166). However, the Switch Difference Score revealed that the PD participants were significantly slower on endogenous switch trials than exogenous switch trial ( p =.003). The Switch Difference Score was also correlated ( p <.05) with a higher Zarit Caregiver Burden score ( r = .434), more functional difficulty on the composite score ( r = .424), worse semantic fluency ( r = .462), slower tapping with both the dominant (right) ( r = .392), and nondominant hands ( r = .419), and several variables from the Wisconsin Card Sorting Test: fewer categories achieved ( r = .639), more perseverate errors ( r =.514), and more failures to maintain set ( r =.466). There were statistical trends ( p < .10) towards a larger difference score correlating with advanced age ( r = .274), and larger score (worse performance) on Trail Making Tests B minus A ( r =.380). The YA group was faster than the OA group for both kinds of switch trials, both exogenously cued ( p =.026) and endogenously cued ( p =.011). However, the Switch Difference Score was equivalent ( p =.727) between the two groups.
51 Errors and Omissions MannWhitney U tests compared group error rates (i.e., incorrect responses) and omissions (e.g., failure t o select each hand on endogenous trials) for each trial type. There were no group differences (PD vs. OA; OA vs. YA) for any trial type in the number of errors (all p endogenous trial type except the block 4 switch trials, where the PD group had significantly more omissions than the OA group ( U =55.00, p =.033). Fatigue and Motivation The groups were equivalent in their reported fatigue for all blocks except for block 4 where the PD group reported significantly more fatigue than the OA group ( U =35.00, p =.021). The OA and YA groups fatigue was equivalent for all blocks. The PD and OA groups, and the OA and YA groups, were equivalent in their reported motivation for all blocks. Aim 3: Functional Imp airment a nd Caregiver Burden This aim related difference scores to functional impairment and caregiver burden in the OA and PD groups (Table 34). All PD and OA participants completed functional measures and significant others of 21 participants (PD n=10; OA n=11) completed the Zarit Caregiver Burden questionnaire. After accounting for motor symptom severity (UPDRS, part III) and depressive symptoms (GDS), the Switch Difference score emerged as a significant predictor her score = more impairment), independent of the two Stay Difference Scores and overall speed (mean uncued choice RT). The Switch Difference Score was also a significant independent predictor of caregiver burden en) after accounting for the same
52 variables. The Stay (with switch) Difference Score was also a significant predictor of .505), but with the opposite magnitude; a smaller difference score predicted more burden.
53 Table 31 Participant mood, clinical, and neuropsychological c haracteristics Young Adult Older Adult Parkinsons Disease Mean SD Mean SD Mean SD p= n 14 15 12 Age (years) 27.07 5.09 69.21 4.23 68.58 5.50 PD=OA Sex 5m 9f 14m 1f 10m 2f Education (years) 18.36 1.34 18.14 1.46 16.58 2.94 note a DRS 2 Total Score 139.71 5.62 139.45 3.39 .888 AS Total Score 6.78 2.86 10.75 4.81 .023 GDS Total Score 1.00 1.30 6.50 8.62 .050 MDS HC Independence Score 7.43 8.96 18.36 17.95 .058 MDS HC Difficulty Score 0.14 0.36 5.91 8.08 .040 PDQ 39 Total Score 5.07 3.67 28.45 31.47 .034 Functional Composite Score 12.13 11.04 48.33 52.62 .038 Zarit Caregiver Total Score 6.64 6.52 21.30 19.74 .047 UPDRS part III (motor severity) 6.00 5.39 19.33 9.38 <.001 Levodopa Equiv. Dose (mg/day) 862.08 461.55 Years with Symptoms 8.92 3.40 Hoehn & Yahr Stage Stage1 n =4, Stage2 n =5, Stage3 n =3 Hemibody of Symptom Onset Right n =8 Left n =4 Neuropsychological Variables WTAR Estimated IQ 113.50 4.91 110.50 5.58 .163 WCST Categories 5.57 0.94 4.00 2.41 .052 WCST Perseverative Errors (# errors) 13.14 9.84 20.67 15.56 .166 WCST Failure to Maintain Set 0.72 0.91 1.83 1.40 .029 Trails B Trails A (seconds) 37.60 21.08 58.73 44.74 .154 Stroop Color Word (total) 38.78 7.31 36.58 9.09 .508 Digit Span Forward (max. span) 7.27 1.03 7.17 1.27 .827 Digit Span Backward (max. span) 5.47 1.06 4.83 0.49 .113 Phonemic Fluency (F,A,S) Total 44.13 10.32 38.42 10.26 .164 Semantic (Animal) Fluency 23.00 3.98 19.42 4.17 .033 Tapping: Dominant (Right) Hand 47.75 6.22 45.43 7.06 .381 Tapping: Non Dominant (Left) Hand 42.61 6.03 39.51 9.89 .357 Spatial Span Forward (max. span) 7.00 1.69 6.00 1.54 .121 Spatial Span Backward (max. span) 8.13 1.64 6.75 1.76 .048 Note. aParticipants education was compared with a oneway ANOVA that revealed a trend, F (2,37)=3.00, p =.062, towards YA participants being more educated than PD participants ( p =.073). The PD and OA groups were equivalent ( p = .115), as were the YA and OA groups ( p = .689).
54 Table 32 Reaction time: Group means and standard deviations Parkinsons Disease Older Adults Younger Adults Mean SD Mean SD Mean SD Simple RT Without Cues 509.37 51.74 546.16 76.74 398.88 37.12 Choice RT Without Cues 1022.16 250.09 907.47 186.91 653.19 61.56 Exo Stay Trials with Certainty 697.21 374.27 552.57 153.11 425.59 49.18 Exo Stay Trials with Uncertainty 770.34 172.71 761.31 203.81 533.06 50.18 Endo Stay Trials with Certainty 775.57 313.14 628.50 213.49 417.91 39.98 Endo Stay Trials with Uncertainty 1206.41 938.86 870.63 314.20 542.97 63.28 Exo Switch Trials 900.68 273.57 915.23 344.55 649.55 96.52 Endo Switch Trials 1360.19 756.23 1085.86 619.09 637.97 85.29 Stay Trial w/ Certainty Diff. Score 10.89 12.87 4.15 8.69 0.93 5.88 Stay Trial w/ Uncertainty Diff. Score 12.41 20.56 3.46 7.75 0.81 5.01 Switch Trial Diff. Score 19.30 16.28 1.05 8.57 0.70 10.82
55 Table 33. Group comparisons PD vs. OA OA vs. YA U= p= U= p= Simple RT Without Cues 57.0 .104 7.0 <.001 Choice RT Without Cues 60.0 .143 5.0 <.001 Exo Stay Trials with Certainty 78.0 .558 38.0 .003 Exo Stay Trials with Uncertainty 85.0 .807 12.0 <.001 Endo Stay Trials with Certainty 65.0 .223 9.0 <.001 Endo Stay Trials with Uncertainty 71.0 .354 4.0 <.001 Exo Switch Trials 86.0 .845 54.0 .026 Endo Switch Trials 50.0 .166 42.0 .011 Stay Trial w/ Certainty Diff. Score 71.0 .354 63.0 .067 Stay Trial w/ Uncertainty Diff. Score 80.0 .626 71.0 .138 Switch Trial Diff. Score 29.0 .003 97.0 .727
56 Figure 31. Valid trials with certainty difference scores. Difference s core =((endoexo)/(endo+exo))*100. +p<.10 *p<.05. Error bars represent the 95% confidence interval of the mean.
57 Figure 32. Correlations between PD and OA participants difference scores and select clinical, demographic, mood, and neuropsychological variables. Statistical trends (p<.10) and significant findings (p<.05) are shaded.
58 Figure 33. Valid trials with uncertainty difference scores Difference s core=((endoexo) / (endo+exo))*100. Error bars represent the 95% confidence interval of the mean.
59 Figure 34. Invalid cues (switch trials) difference s core s. Difference score = ((endoexo) / (endo+exo))*100. Error bars represent the 95% confidence interval of the mean.
60 Figure 35. Fatigue and m otivation. A) Fatigue ratings. B) Motivation ratings. Par ticipants rated these feelings on a 7point Likert scale (higher number = more fatigue; less motivation) approximately every 3 minutes during the RT trials. Participant responses are presented above as averages within each block.
61 Table 34. Hierarchical multiple regression analysis predicting functional impairment and caregiver burden Functional Impairment Caregiver Burden Predictor R 2 R 2 Step 1 .460*** .453** UPDRS, Part III .115 .102 GDS .602** .606* Step 2 .213* .280* Mean Uncued Choice RT .354* .147 Stay (without switch) Difference Score .009 .007 Stay (with switch) Difference Score .245 .505* Switch Difference Score .395* .630** Total R 2 .673** .733** n 27 21 Note. p <.05 ** p <.01 ***p <.001
62 CHAPTER 4 DISCUSSION Parkinsons Patients Compared to Matched Older Adult Controls These results indicate that there were several major significant differences between the PD and OA groups. In regard to simple reaction times we found that our subjects with PD were not different than the OA. This result is in conflict with prior studies which suggest that patients with PD have slowed reaction times to uncued stimuli The reason for this difference between this current study and earlier studies is not known. While we considered that this might be related to these participants being on medications, the study by Jahanshahi et al. (1992) did not reveal that medication had a dramatic effect on reaction times. Because kinesia paradoxica is often as sociated with PD, we expected that when compared to the normal OA participants, the subjects with PD, in the trials where there was no switch or even a possibility of a switch (Valid Cues With Certainty), the participants with PD would show a relatively gr eater reduction with of RT with valid exogenous than endogenous cues. However, the difference between the reaction times with exogenous versus endogenous cues was not significantly greater for the participants with PD than the OA group. The failure to find differences between the PD subjects and the normal OA may be the related to the same reason the participants with PD did not have slowed simple reaction times. Their normal reaction times suggest that the participants with PD did not have a defective abil ity to endogenously upregulate their sensory attention and action intentional system in preparation for the reaction time stimulus.
63 With the knowledge that there may be a switch, it was possible that the participants would not prepare the motor systems i ndicated by the cue with the same intensity as when there is no possibility of a switch, since with intense engagement there may be a delay in disengagement. Thus, this project also examined group differences in stay trials presented in the context of 20% invalid (i.e., switch) trials. Again, however, there were no differences between the PD and OA groups. The PD group demonstrated great variability on these trials, and perhaps their variability is meaningful. The variability may suggest that some participants with PD more strongly neurologically/ actionintentionally "invested" in their selected movement despite the possibility of having to switch, whereas others may not have wanted to "gamble" on this investment. This investment strategy may have been strategic or may have reflected underlying neurologically based differences in action uncertainty. For example, Fiorillo, Tobler & Schultz (2003) showed that the certainty of action execution correlated with phasic dopamine activity in the ventral midbrain of monkeys. Unfortunately, the present study did not ask participants if they were explicitly using a strategy, but future research might address disease related neurocognitive investment in uncertainty. As mentioned, there is strong evidence that patients with PD often have evidence of frontal subcortical dysfunction. Because one of the major deficits associated with dysfunction in these networks is a reduced ability to disengage, the second aim of this study was to investigate the cost (i.e., reaction time slowing) of discontinuing the preparation for a specific action and initiating a different action (stopping and switching, which we termed switch trials). Because patients with PD may have frontal subcortical dysfunction with a deficit in disengagement, the prediction was that PD patients would
64 demonstrate more difficulty (i.e. have relatively slower reaction times) when switching endogenously than exogenously evoked preparations, whereas control participants would have more equal disengagement. This hypothesis was supported; PD participants demonstrated dramatically slower endogenous than exogenous switch RTs. Furthermore, during the trial block with endogenous switch trials, PD patients reported significantly more fatigue and neglected to select each response hand at a greater rate than other groups. These findings cannot be explained as artifacts of block order because some participant saw this block third, whereas others saw this block last, and may instead be additional signs that the PD group found t hese trials more difficult. The third aim was to examine the relationship between PD and OA participants difference scores and functional impairment and caregiver burden. The first hypothesis was that larger difference scores (i.e., slower endogenous than exogenous RT) would predict self reported functional disability and caregiver burden (slower RT=more disability), independent of overall speed, diseaserelated motor symptoms, and mood symptoms. This hypothesis was supported; the difference scores were s ignificantly related to impairment, and the switch difference score was a significant independent predictor, suggesting that slower endogenous switch reaction time is related to more functional impairment. The second hypothesis was that OA and PD participants endogenous RTs would predict the severity of caregiver burden (higher difference score=more burden), independent of overall speed, diseaserelated motor symptoms, and mood symptoms. The Switch Difference Score and Valid Cues with Uncertainty Differenc e scores emerged as significant individual predictors, such that greater burden was predicted by a larger Switch Difference Score and a smaller Valid Cues with
65 Uncertainty Difference Score. The Switch Difference Score was related to caregiver burden as hypothesized, but the Valid Cues With Uncertainty Difference Score was not anticipated. Future research is needed to clarify exactly which patient behaviors lead to impairment and/or caregiver burden. Possible Mechanisms of Differences Associated with Parkinsons Disease The classic model of basal ganglia functions may help explain the results of this study. In this model, the cortex projects to the basal ganglia, which refine the signal to noise ratio of the information, and the cerebral cortex then receives the refined information via the thalamus. The basal ganglia refine the signal by three distinct, nonoverlapping pathways that converge on the globus pallidus pars interna (GPi), which inhibits projections from the thalamus to the cortex. The direct pathway, which inhibits the GPi (thus releasing the thalamus), facilitates thalamocortical transmission, while the indirect and hyperdirect pathways inhibit thalamocortical transmission by activating the GPi. In healthy persons, these three loops work in concert to improve the signal to noise ratio of cortical processing by facilitating and enhancing the intended action or cognitive activity while suppressing related or alternative actions or cognitive activities (Mink, 1996). Nambu, Tokuno, & Takada (200 2) described the temporal sequence of the three pathways as they relate to voluntary movement: the hyperdirect pathway first suppresses extensive areas of the thalamus and cerebral cortex that are related to both the selected motor program and other comp eting programs a reset of sorts Then, another corollary signal through the direct pathway disinhibits only the selected motor program. Finally, the third corollary signal through the indirect pathway inhibits competing motor programs.
66 In Parkinsons disease, dopamine depletion leads to increased activity in the indirect pathway and reduced activity in the direct pathway, resulting in excessive GPi inhibition of the thalamus. For example, Nambu (2005) writes: when a voluntary movement is about to be initiated by cortical mechanisms, signals through the hyperdirect and indirect pathways expand and suppress larger areas of the thalamus and cortex than in the normal state, and a signal through the direct pathway is reduced. Thus, smaller areas of the thalamus and cortex are disinhibited for a shorter period of time than in the normal state, and not only the unwanted motor program, but also the selected motor program, cannot be released, resulting in akinesia of Parkinsons disease (p. IV/3). This model of the basal ganglia in action selection may help explain the results of the current study. Applied to our experimental paradigm, we hypothesize that the hyperdirect pathway first inhibited both possible actions (left and right index finger move ment), the direct pathway then disinhibited the target behavior, either the endogenously selected one or the exogenously specified one, depending on the trial. The indirect pathway then suppressed the alternative, unselected movement. One of our major f indings is that PD patients on medication demonstrated a relatively slower reaction time for endogenous than exogenous switch trials, whereas older and younger adult control participants showed equivalent endogenous and exogenous switch reaction times. Previous research has postulated that the akinesia associated with Parkinsons disease may stem from a failure to terminate and disengage from a previous behavior, rather than a primary deficit initiating a new behavior (DeLong et al., 1984), and this hypothesis has received some recent research
67 support (Warabi et al., 2011). The classic basal ganglia model of PD can explain this phenomenon by the over inhibition of related, alternative behaviors by the hyperdirect and indirect pathways. For example, a patient with PD might walk down a hallway and then freeze when turning around because the action programs associated with turning were over inhibited while walking, and then take more time to engage. In the paradigm presented here, the basal ganglia model of PD would predict that PD patients would require more time to switch to an unselected behavior because it was over inhibited by the indirect pathway. Our results add to the literature by showing that switching endogenously selected actions required significantly more time than switching exogenously selected action. Endogenously evoked behaviors rely more heavily of frontal subcortical networks than exogenously evoked behaviors; therefore, basal ganglia frontal dysfunction may impair disengagement from this end ogenous preparatory state more than the exogenous preparatory state. The relatively slower endogenous switching exhibited by the PD participants was correlated with cognitive perseveration and impersistence (i.e., failures to maintain set) on the Wisconsin Card Sorting Test (WCST), as well as fewer items generated on a semantic fluency test. These are deficits that are often associated with frontal subcortical (basal ganglionic) dysfunction. These frontal subcortical networks are critical for mediating the process of intention, which includes the selection and preparation of goal oriented action (Crosson, Benjamin, & Levy, 2007), the persistence of action until the goal is completed, the ability to inhibit actions that are not goal oriented, and the ability to terminate an action once the goal is completed. Failures of this system can induce akinesia (or hypokinesia), impersistence, defective response inhibition and perseveration (Crucian et al., 2007;
68 Heilman & Watson, 1991). The finding that the participant s with PD had impaired ability to disengage from incorrect preparation may be considered an example of defective response inhibition. Younger Versus Older Participants The OA group was globally slower than the YA group for all RT conditions. Additionally, there was a trend by which older adults had a larger Valid Cues with Certainty Difference Score. This suggests that they were relatively slower with endogenous movement initiation than exogenous movement initiation. Overall, combined with the PD groups results, these findings suggest that whereas there is a relative slowing of endogenously versus exogenously initiated movement with aging, the presence of PD did not influence this relative slowing to endogenous cueing. It was also predicted that in the swit ch trials the healthy older adult (OA) group would show more RT slowing than the young adult (YA) group. This hypothesis, however, was not supported; the OA and YA control groups' difference scores were equivalent to each other and to zero, which reflect ed equal reaction time with exogenous and endogenous switch trials. Overall, together with PD groups data, these results suggest that the relative ability to switch endogenously prepared movements is not influenced by age, but strongly impacted by Parkinsons disease and/or Parkinsons disease medication. Possible Mechanisms Associated with Age Related Differences Our data revealed that older age was associated with slower execution of endogenously selected movements than those that are exogenously selected.. Applying the basal ganglia model presented above, this agerelated relative slowing of endogenously cued reaction time may reflect poorer signal to noise resolution from
69 inefficient resetting by the hyperdirect pathway, or by poor signal enhanceme nt by the direct pathway. Indeed, the functioning of the direct pathway is strongly mediated by dopamine D1 receptors (Onn, West, & Grace, 2000; West & Grace, 2002), which are progressively lost with age (Corts, Camps, Gueye, Probst, & Palacios, 1989; Rinne, Lnnberg, & Marjamki, 1990) with notable cognitive correlates (Backman, Lindenberger, Li, & Nyberg, 2010; Backman et al., 2006). Implications The results of this study suggest that PD patients have greater difficulty with internally than externally guided responses. This is not a new idea (Brown & Marsden, 1988; Jahanshahi et al., 1995), but the present study is one of few behavioral paradigms that test this hypothesis. Specifically, the current results support the hypothesis that Parkinsons akinesia stems from inefficient stopping and switching of endogenously motivated action (Warabi et al., 2011). This coheres with the recent finding that PD patients difficulties with activities of daily living stem from errors of commission (e.g., perseverating on one step of an action), rather than omission (e.g., failing to perform a step)(Giovannetti et al., 2012). Some research has addressed compensation strategies for endogenous akinesia, for example, by providing external cues to prompt the initiation of movement (Donovan et al., 2011; McAuley et al., 2009). However, the current research suggests that perhaps compensation strategies should instead address the termination and switching of movement. Limitations A major limitation of the study was the inability t o distinguish between effects of Parkinson's disease versus the effects of medication. Future research should investigate participants on versus off dopamine replacement medication. Dopamine
70 agonists, while often highly effective in reducing the motor symptoms of PD, may have a more nuanced relationship with endogenous behavior than supposed. For example, a recent study found that deep brain stimulation of the subthalamic nucleus (a structure in the indirect and hyperdirect pathways) was effective in reduci ng patients perseverative motor behavior, but levodopa was not (Herzog et al., 2009). A second major limitation was that the comparisons between young and older adults were cross sectional, so inferences about the role of aging need support from longitudi nal data. The groups were successfully matched on a number of important attributes, but also differed on some. The YA group had a higher proportion of female participants than the other groups. This may have influenced their reaction times, as some sex dif ferences in RT have been reported (Der & Deary, 2006; Silverman, 2006). Although the PD group trended towards being less educated than the other groups, their estimated premorbid IQ was equivalent. On traditional neuropsychological testing, the PD group showed expected differences in domains that are typically affected by the disease (e.g., executive functioning)(Barone et al., 2011). The PD group also reported more symptoms of apathy than the OA group. This is not surprising given that apathy is a core feature of PD related mood disturbances (KirschDarrow et al., 2011). It is not likely that this introduced a reaction time confound, and in fact may be highly related to the diseaserelated differences we were addressing in this study. Whereas the present paradigm targeted PD related lack of initiation of movement, apathy may be conceptualized as a lack of initiation of emotion, and sometimes occurs with damage to the same neuroanatomical areas that are important for endogenous movement (Levy & Dubois, 2006). Another potential limitation was a lack of representativeness of
71 participants; thus, our results may not be generalizable. All groups were well educated, medically healthy, of similar socioeconomic and ethnic/racial backgrounds, and socially familiar with research participation. The PD participants were in the early stages of the disease, generally independent, and well controlled on medication. Regarding the logistical/methodological limitations of the study, participants may have been influenced by thei r participation in another study. All PD and OA participants were recruited from another study, and some participants were approached during their day of participation in the other study. For those who were not able to participate on a separate day, they c ompleted testing on the same day as their participation in the other study. The two studies shared common data so as to reduce burden and not create practice effects, but participants may have felt fatigued nonetheless. Fortunately, however, there were not systematic betweengroup differences in reported fatigue or motivation. Relatedly, because data elements were shared between the two studies, some participants non reaction time data were collected up to 6 months prior. Neuropsychological tests that were common to the two studies were not readministered by the current study so as not to introduce practice effects for the other study. The age of the nonRT data were equal between the OA and PD groups, but this still likely introduced some degree of error into our analyses. No participant reported or demonstrated any physical difficulty completing the tasks. However, future studies may have to provide accommodations (e.g., larger response buttons) for PD patients with more severe tremors or dyskinesia. Let ters (Left, Right, Choose) were used as the cues and imperative stimuli for the reaction time trials. This has been done by others (Gerardin et al., 2004), and was
72 implemented here to optimize the equivalence between all trial types. However, future resear ch is needed to ensure that these are equivalent with stimuli used by other studies (e.g., arrows). Future D irections The present study is one of few that have experimentally measured endogenously cued RT in patients with PD and has introduced several areas deserving of further inquiry. First, the role of dopaminergic medication. Although dopaminergic medication often reduces akinesia in PD patients, its relationship with endogenous movement needs to be explored. Second, future research may clarify whether there are sub processes involved in the switch trials. The current paradigm may have actually required two separate processes: stopping the initial preparation and then switching. The stop signal task (Aron, Fletcher, Bullmore, Sahakian, & Robbins, 2003) targets the neural processes involved in stopping the execution of an exogenously initiated behavior, and is highly related to functioning of the subthalamic nucleus (Aron & Poldrack, 2006), a structure included in the hyperdirect and indirect basal gangli a pathways. Future research may modify the stop signal task to also measure participants ability to stop an endogenously selected behavior. Third, future research may relate endogenous reaction times to observed akinetic behavior, for example, freezing of gait. Fourth, it would be beneficial to clarify the role of stimulus onset asynchrony (SOA) the time that the participant has to prepare for the imperative stimulus. In the present study the SOAs were equal between the exogenous and endogenous trials to maintain equivalency. However, there is evidence that these two processes may have different time courses; whereas exogenous processes may take 50500ms (Bloxham et al., 1984), endogenous processes may take 10001500ms
73 (Praamstra, Meyer, et al., 1996). Furthermore, because the different basal ganglia loops are active at different times, different SOAs may emphasize the specific contribution of each (Copland, 2003; Seiss & Praamstra, 2004). Fifth, future research might apply this paradigm to patients with m ore advanced disease who are less independent. Sixth, The current results suggested that PD participants have different responses to stay trials when the outcome was certain versus when there was a 20% chance of having to switch. However, the direction of this relationship was different than in a previous investigation (Hocherman, Moont, & Schwartz, 2004). Future research might systematically investigate participants' willingness to "invest" in a cue as a function of switch probability, and whether PD patients have different thresholds for investing. Seventh, future research might address withinpatient changes before and after deep brain stimulation (DBS) surgery. This procedure is effective in reducing akinesia (Brown et al., 1999), improving motoric inhibition (van den Wildenberg et al., 2006) by altering functioning of the indirect and/or hyperdirect pathways, and has been shown to increase activity in the SMA (Grafton et al., 2006). Thus, it may improve patients endogenous movement. Finally, to better understand individual differences and to refine the paradigm, future research may consider the use of functional neuroimaging to target when and in which trials important structures and networks are active. Summary and C onclusion This study addressed whether non demented, medicated patients with idiopathic PD are different from control participants (both young and agematched) in their ability to initiate and switch endogenously evoked movement compared to exogenous movements. Patients with PD were equivalent to age matched controls in their relative ability to initiate an endogenously selected behavior. However, they were relatively
74 much slower than controls in switching an endogenously selected behavior, and this related to poorer neuropsychological perform ance, greater functional difficulty, and caregiver burden. These findings may be explained by the classic basal ganglia model of Parkinsons disease, and suggests that patients akinesia may result from difficulty stopping and switching, rather than initiating, endogenous behavior. This has implications for compensation strategies. However, the relationship between dopaminergic medication and endogenously motivated behavior needs to be clarified.
75 REFERENCES Akkal, D., Dum, R. P., & Str ick, P. L. (2007). Supplementary motor area and presupplementary motor area: targets of basal ganglia and cerebellar output. Journal of Neuroscience, 27(40), 1065910673. doi: 10.1523/JNEUROSCI.313407.2007 Alexander, G. E., DeLong, M. R., & Strick, P. L. (1986). Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annual Review of Neuroscience, 9, 357 381. doi: 10.1146/annurev.ne.09.030186.002041 Aron, A. R., Fletcher, P. C., Bullmore, E. T., Sahakian, B. J., & Robbins, T. W. (2003). Stop signal inhibition disrupted by damage to right inferior frontal gyrus in humans. Nature Neuroscience, 6(2), 115 116. doi: 10.1038/nn1003 Aron, A. R., & Poldrack, R. A. (2006). Cortical and subcortical contributions to S top signal response inhibition: role of the subthalamic nucleus. Journal of Neuroscience, 26(9), 24242433. doi: 10.1523/JNEUROSCI.468205.2006 Backman, L., Lindenberger, U., Li, S. C., & Nyberg, L. (2010). Linking cognitive aging to alterations in dopamin e neurotransmitter functioning: recent data and future avenues. Neuroscience & Biobehavioral Reviews, 34(5), 670 677. doi: 10.1016/j.neubiorev.2009.12.008 Backman, L., Nyberg, L., Lindenberger, U., Li, S. C., & Farde, L. (2006). The correlative triad among aging, dopamine, and cognition: current status and future prospects. Neuroscience & Biobehavioral Reviews, 30(6), 791 807. doi: 10.1016/j.neubiorev.2006.06.005 Barbas, H., & Pandya, D. N. (1989). Architecture and intrinsic connections of the prefrontal cortex in the rhesus monkey. Journal of Comparative Neurology, 286(3), 353375. doi: 10.1002/cne.902860306 Barone, P., Aarsland, D., Burn, D., Emre, M., Kulisevsky, J., & Weintraub, D. (2011). Cognitive impairment in nondemented Parkinson's disease. Movement Disorders, 26(14), 2483 2495. doi: 10.1002/mds.23919 Benton, A. L., Hamsher, K. D., & Sivan, A. B. (1994). Multilingual aphasia examination: manual of instructions Iowa City, IA: AJA Associates. Bloxham, C. A., Mindel, T. A., & Frith, C. D. (1984). Initi ation and execution of predictable and unpredictable movements in Parkinson's disease. Brain, 107 ( Pt 2) 371 384. Brass, M., & Haggard, P. (2008). The what, when, whether model of intentional action. Neuroscientist, 14(4), 319325. doi: 10.1177/1073858408317417
76 Brodmann, K. (1909). Vergleichende Lokalisationslehre der Grosshirnrinde. Leipzig: Johann Ambrosius Bart. Brown, R., Dowsey, P. L., Brown, P., Jahanshahi, M., Pollak, P., Benabid, A., . Rothwell, J. (1999). Impact of deep brain stimulation on upper limb akinesia in Parkinson's disease. Annals of Neurology, 45 (4), 473488. Brown, R., & Marsden, C. (1988). Internal versus external cues and the control of attention in Parkinson's disease. Brain, 111 (2), 323 345. Buhmann, C., Glauche, V., Sturenburg, H. J., Oechsner, M., Weiller, C., & Buchel, C. (2003). Pharmacologically modulated fMRI --cortical responsiveness to levodopa in drug naive hemiparkinsonian patients. Brain, 126(2), 451461. Bush, G., Luu, P., & Posner, M. I. (2000). Cognitive and emotional influences in anterior cingulate cortex. Trends in Cognitive Science, 4(6), 215 222. Cahn, D. A., Sullivan, E. V., Shear, P. K., Pfefferbaum, A., Heit, G., & Silverberg, G. (1998). Differential contributions of cognitive and motor component processes to physical and instrumental activities of daily living in Parkinsons disease. Archives of Clinical Neuropsychology, 13(7), 575583. Cavada, C., & GoldmanRakic, P. S. (1989). Posterior parietal cortex in rhesus monkey: II. Evidence for segregated corticocortical networks linking sensory and limbic areas with the frontal lobe. Journal of Comparative Neurology, 287(4), 422445. doi: 10.1002/cne.902870403 Cohen, M. L., Burtis, B., Kwon, J. C., Williamson, J., & Heilman, K. M. (2010). Action intentional spatial bias in a patient with posterior cortical atrophy. Neurocase, 16(6), 529 534. doi: 10.1080/13554794.2010.487 827 Copland, D. (2003). The basal ganglia and semantic engagement: Potential insights from semantic priming in individuals with subcortical vascular lesions, Parkinson's disease, and cortical lesions. Journal of the International Neuropsychological Society 9 (7), 10411052. Corts, R., Camps, M., Gueye, B., Probst, A., & Palacios, J. (1989). Dopamine receptors in human brain: autoradiographic distribution of D1and D2 sites in Parkinson syndrome of different etiology. Brain research, 483(1), 30 38. Crosson B., Benjamin, M., & Levy, I. (2007). Role of the basal ganglia in language and semantics: supporting cast. In J. Hart & M. A. Kraut (Eds.), Neural Basis of Semantic Memory (pp. 219243). Cambridge, UK: Cambridge University Press. Crosson, B., Sadek, J. R ., Maron, L., Gokcay, D., Mohr, C. M., Auerbach, E. J., . Briggs, R. W. (2001). Relative shift in activity from medial to lateral frontal cortex during internally versus externally guided word generation. Journal of Cognitive Neuroscience, 13(2), 272 2 83.
77 Crucian, G. P., Heilman, K., Junco, E., Maraist, M., Owens, W. E., Foote, K. D., & Okun, M. S. (2007). The crossed response inhibition task in Parkinson's disease: disinhibition hyperkinesia. Neurocase, 13(3), 158164. doi: 10.1080/13554790701448184 D eLong, M., Alexander, G., Georgopoulos, A., Crutcher, M., Mitchell, S., & Richardson, R. (1984). Role of basal ganglia in limb movements. Human Neurobiology, 2(4), 235244. Der, G., & Deary, I. J. (2006). Age and sex differences in reaction time in adulth ood: results from the United Kingdom Health and Lifestyle Survey. Psychology and Aging, 21(1), 62. Dolcos, F., Rice, H. J., & Cabeza, R. (2002). Hemispheric asymmetry and aging: right hemisphere decline or asymmetry reduction. Neuroscience and Biobehavior al Reviews, 26(7), 819 826. Donovan, S., Lim, C., Diaz, N., Browner, N., Rose, P., Sudarsky, L. R., . Simon, D. K. (2011). Laserlight cues for gait freezing in Parkinson's disease: an openlabel study. Parkinsonism & Related Disorders, 17(4), 240 245. doi: 10.1016/j.parkreldis.2010.08.010 Dorsey, E. R., Constantinescu, R., Thompson, J. P., Biglan, K. M., Holloway, R. G., Kieburtz, K., . Tanner, C. M. (2007). Projected number of people with Parkinson disease in the most populous nations, 2005 throug h 2030. Neurology, 68(5), 384 386. doi: 10.1212/01.wnl.0000247740.47667.03 Drachman, D. A. (2005). Do we have brain to spare? Neurology, 64(12), 20042005. doi: 10.1212/01.WNL.0000166914.38327.BB Drago, V., Foster, P. S., Skidmore, F. M., Kluger, B., Antoniello, D., & Heilman, K. M. (2008). Attentional grasp in Parkinson disease. Cognitive and Behavioral Neurology, 21(3), 138 142. doi: 10.1097/WNN.0b013e3181864a35 Dum, R. P., & Strick, P. L. (1991) The origin of corticospinal projections from the premotor areas in the frontal lobe. Journal of Neuroscience, 11(3), 667 689. Erdler, M., Beisteiner, R., Mayer, D., Kaindl, T., Edward, V., Windischberger, C., . Deecke, L. (2000). Supplementary motor area activation preceding voluntary movement is detectable with a wholescalp magnetoencephalography system. Neuroimage, 11(6), 697 707. doi: 10.1006/nimg.2000.0579 Eriksen, B. A., & Eriksen, C. W. (1974). Effects of noise letters upon the identification of a target letter in a nonsearch task. Attention, Perception, & Psychophysics, 16(1), 143149. Fahn, S., & Elton, R. (1987). Unified Parkinson's disease rating scale. Recent Developments in Parkinson's Disease, 11, 153 163.
78 Filipovic, S. R., Covickovic Sternic, N., Radovic, V. M., Dragasevic, N., Stojanovic Svetel, M., & Kostic, V. S. (1997). Correlation between Bereitschaftspotential and reaction time measurements in patients with Parkinson's disease. Measuring the impaired supplementary motor area function? Journal of the Neurological Sciences, 147(2), 177 183. Fiorillo, C. D., Tobler, P. N., & Schultz, W. (2003). Discrete coding of reward probability and uncertainty by dopamine neurons. Science, 299(5614), 18981902. doi: 10.1126/science.1077349 Fleming, S. M., Mars, R. B., Gladwin, T. E., & Haggard, P. (2009). When the brain changes its mind: flexibility of action selection in instructed and free choices. Cerebral Cortex, 19(10), 2352 2360. doi: 10.1093/cercor/bhn252 Frith C. D., & Done, D. J. (1986). Routes to action in reaction time tasks. Psychological Research, 48(3), 169 177. GauntlettGilbert, J., & Brown, V. J. (1998). Reaction time deficits and Parkinson's disease. Neuroscience and Biobehavioral Reviews, 22(6), 86 5 881. Gerardin, E., Pochon, J. B., Poline, J. B., Tremblay, L., Van de Moortele, P. F., Levy, R., . Lehericy, S. (2004). Distinct striatal regions support movement selection, preparation and execution. Neuroreport, 15(15), 23272331. Giovannetti, T. Britnell, P., Brennan, L., Siderowf, A., Grossman, M., Libon, D. J., . Seidel, G. A. (2012). Everyday action impairment in Parkinson's disease dementia. Journal of the International Neuropsychological Society, 18(5), 787 798. doi: 10.1017/S135561771200046X Goldberg, G. (1985). Supplementary motor area structure and function: Review and hypothesis. Behavioral and Brain Sciences, 8 (4), 567588. Goldberg, Haack, A. K., Lim, N. S., Janson, O. K., & Meshul, C. K. (2011). Dopaminergic and behavioral correl ates of progressive lesioning of the nigrostriatal pathway with 1methyl 4 phenyl 1,2,3,6tetrahydropyridine. Neuroscience, 180, 256 271. doi: 10.1016/j.neuroscience.2011.02.027 Golden, C. J. (1978). Stroop Color and Word Test: A Manual for Clinical and Ex perimental Uses Los Angeles: Western Psychological Services. GoldmanRakic, P. S., Selemon, L. D., & Schwartz, M. L. (1984). Dual pathways connecting the dorsolateral prefrontal cortex with the hippocampal formation and parahippocampal cortex in the rhesus monkey. Neuroscience, 12(3), 719743. Grafton, S. T., Turner, R. S., Desmurget, M., Bakay, R., Delong, M., Vitek, J., & Crutcher, M. (2006). Normalizing motor related brain activity: subthalamic nucleus stimulation in Parkinson disease. Neurology, 66(8), 11921199. doi: 10.1212/01.wnl.0000214237.58321.c3
79 Haggard, P. (2008). Human volition: towards a neuroscience of will. Nature Reviews Neuroscience, 9(12), 934 946. doi: 10.1038/nrn2497 Hallett, M. (2007). Volitional control of movement: the physiology of free will. Clinical Neurophysiology, 118(6), 11791192. doi: 10.1016/j.clinph.2007.03.019 Halsband, U., Matsuzaka, Y., & Tanji, J. (1994). Neuronal activity in the primate supplementary, presupplementary and premotor cortex during externally and internal ly instructed sequential movements. Neuroscience Research, 20(2), 149155. Haslinger, B., Erhard, P., Kampfe, N., Boecker, H., Rummeny, E., Schwaiger, M., . Ceballos Baumann, A. O. (2001). Event related functional magnetic resonance imaging in Parkins on's disease before and after levodopa. Brain, 124 (3), 558 570. Heaton, R. K. (1981). A manual for the Wisconsin card sorting test Odessa: Western Psycological Services. Heilman, K. M., Bowers, D., Watson, R. T., & Greer, M. (1976). Reaction times in Par kinson disease. Archives of Neurology, 33 (2), 139140. Heilman, K. M., & Valenstein, E. (Eds.). (2003). Clinical Neuropsychology (Fourth ed.). Oxford, UK: Oxford University Press. Heilman, K. M., & Watson, R. T. (1991). Intentional motor disorders. In H. S. Levin, H. M. Eisenberg & A. L. Benton (Eds.), Frontal Lobe Function and Dysfunction. Oxford: Oxford University Press. Heilman, K. M., Watson, R. T., & Valenstein, E. (1993). Neglect and related disorders. Clinical Neuropsychology, 3, 279 336. Herzog, J., Moller, B., Witt, K., Pinsker, M. O., Deuschl, G., & Volkmann, J. (2009). Influence of subthalamic deep brain stimulation versus levodopa on motor perseverations in Parkinson's disease. Movement Disorders, 24(8), 12061210. doi: 10.1002/mds.22568 Hocherman, S., Moont, R., & Schwartz, M. (2004). Response selection and execution in patients with Parkinson's disease. Cognitive Brain Research, 19(1), 40 51. doi: 10.1016/j.cogbrainres.2003.11.001 Hoehn, M. M., & Yahr, M. D. (1967). Parkinsonism: onset, progression and mortality. Neurology, 17(5), 427 442. Hsieh, Y. H., Chen, K.J., Wang, C.C., & Lai, C. L. (2008). Cognitive and motor components of response speed in the stroop test in Parkinson's disease patient s. The Kaohsiung Journal of Medical Sciences, 24(4), 197 203.
80 Hughes, A. J., Daniel, S. E., Kilford, L., & Lees, A. J. (1992). Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinicopathological study of 100 cases. Journal of Neurology, Neurosurgery, and Psychiatry, 55(3), 181 184. Jahanshahi, M., Brown, R. G., & Marsden, C. D. (1992). Simple and choice reaction time and the use of advance information for motor preparation in Parkinson's disease. Brain, 115(2), 539564. Jahanshahi, M ., Jenkins, I. H., Brown, R. G., Marsden, C. D., Passingham, R. E., & Brooks, D. J. (1995). Self initiated versus externally triggered movements. I. An investigation using measurement of regional cerebral blood flow with PET and movement related potentials in normal and Parkinson's disease subjects. Brain, 118(4), 913933. James, W. (2010). The principles of psychology (Vol. 2): Digireads.com. Jankovic, J. (2008). Parkinson's disease: clinical features and diagnosis. Journal of Neurology, Neurosurgery, and Psychiatry, 79 (4), 368376. doi: 10.1136/jnnp.2007.131045 Jankowski, J., Scheef, L., Huppe, C., & Boecker, H. (2009). Distinct striatal regions for planning and executing novel and automated movement sequences. Neuroimage, 44(4), 13691379. doi: 10.1016/j .neuroimage.2008.10.059 Jarvis, W. (2004). DirectRT. New York, NY: Empirisoft Corp Jurica, P. J., Leitten, C. L., & Mattis, S. (2001). Dementia Rating Scale2 (DRS 2) Manual Odessa, FL: Psychological Assessment Resources. Kirsch Darrow, L., Marsiske, M. Okun, M. S., Bauer, R. M., & Bowers, D. (2011). Apathy and Depression: Separate Factors in Parkinson's Disease. Journal of the International Neuropsychological Society, 17(6), 10581066. doi: 10.1017/s1355617711001068 Kornhuber, H. H., & Deecke, L. (1965). Changes in the brain potential in voluntary movements and passive movements in man: Readiness potential and reafferent potentials. Pflgers Archiv fr die gesamte Physiologie des Menschen und der Tiere, 284, 1 17. Krieghoff, V., Waszak, F., Prinz, W., & Brass, M. (2011). Neural and behavioral correlates of intentional actions. Neuropsychologia, 49(5), 767 776. doi: 10.1016/j.neuropsychologia.2011.01.025 Knzle, H. (1978). An autoradiographic analysis of the efferent connections from premotor and adjacent prefrontal regions (Areas 6 and 9) in Macaca fascicularis. Brain, Behavior, and Evolution, 15 189 209.
81 Leentjens, A. F. (2004). Depression in Parkinson's disease: conceptual issues and clinical challenges. Journal of Geriatric Psychiatry and Neurology, 17 (3), 120126. doi: 10.1177/0891988704267456 Leichnetz, G. R. (1986). Afferent and efferent connections of the dorsolateral precentral gyrus (area 4, hand/arm region) in the macaque monkey, with comparisons to area 8. Journal of Comparative Neurology, 25 4 (4), 460 492. doi: 10.1002/cne.902540403 Levy, R., & Dubois, B. (2006). Apathy and the functional anatomy of the prefrontal cortex basal ganglia circuits. Cerebral Cortex, 16(7), 916 928. doi: 10.1093/cercor/bhj043 Lezak, M. D. (2004). Neuropsychological Assessment (Fourth ed.). New York: Oxford University Press. Lhermitte, F., Pillon, B., & Serdaru, M. (1986). Human autonomy and the frontal lobes. Part I: Imitation and utilization behavior: a neuropsychological study of 75 patients. Annals of Neurology, 19 (4), 326 334. doi: 10.1002/ana.410190404 Lu, M. T., Preston, J. B., & Strick, P. L. (1994). Interconnections between the prefrontal cortex and the premotor areas in the frontal lobe. Journal of Comparative Neurology, 341(3), 375 392. doi: 10.1002/cne.903410308 Luppino, G., Matelli, M., Camarda, R., & Rizzolatti, G. (1993). Corticocortical connections of area F3 (SMA proper) and area F6 (preSMA) in the macaque monkey. Journal of Comparative Neurology, 338(1), 114140. doi: 10.1002/cne.903380109 Luppino, G. Matelli, M., & Rizzolatti, G. (1990). Cortico cortical connections of two electrophysiologically identified arm representations in the mesial agranular frontal cortex. Experimental Brain Research, 82(1), 214 218. Masdeu, J. C., Schoene, W. C., & Funkens tein, H. (1978). Aphasia following infarction of the left supplementary motor area: a clinicopathologic study. Neurology, 28(12), 12201223. McAuley, J. H., Daly, P. M., & Curtis, C. R. (2009). A preliminary investigation of a novel design of visual cue glasses that aid gait in Parkinson's disease. Clinical Rehabilitation, 23(8), 687 695. doi: 10.1177/0269215509104170 McFarling, D., Rothi, L. J., & Heilman, K. M. (1982). Tr anscortical aphasia from ischaemic infarcts of the thalamus: a report of two cases. Journal of Neurology, Neurosurgery, and Psychiatry, 45(2), 107 112. Mink, J. W. (1996). The basal ganglia: focused selection and inhibition of competing motor programs. Pr ogress in Neurobiology, 50(4), 381 425.
82 Moore, O., Peretz, C., & Giladi, N. (2007). Freezing of gait affects quality of life of peoples with Parkinson's disease beyond its relationships with mobility and gait. Movement Disorders, 22(15), 21922195. doi: 10.1002/mds.21659 Mufson, E. J., & Pandya, D. N. (1984). Some observations on the course and composition of the cingulum bundle in the rhesus monkey. Journal of Comparative Neurology, 225(1), 31 43. doi: 10.1002/cne.902250105 Mushiake, H., Inase, M., & Tanj i, J. (1991). Neuronal activity in the primate premotor, supplementary, and precentral motor cortex during visually guided and internally determined sequential movements. Journal of Neurophysiology, 66(3), 705718. Nachev, P., Rees, G., Parton, A., Kennar d, C., & Husain, M. (2005). Volition and conflict in human medial frontal cortex. Current Biology, 15(2), 122 128. doi: 10.1016/j.cub.2005.01.006 Nambu, A. (2005). A new approach to understand the pathophysiology of Parkinson's disease. Journal of Neurology, 252 Suppl 4, IV1 IV4. doi: 10.1007/s00415005 4002y Nambu, A., Tokuno, H., & Takada, M. (2002). Functional significance of the corticosubthalamopallidal" hyperdirect" pathway. Neuroscience research, 43(2), 111 117. O'Brien, J. A., Ward, A., Michels, S., Tzivelekis, S., & Brandt, N. (2009). Economic burden associated with Parkinson's disease. Drug Benefit Trends, 21(6), 179 190. Obeso, J. A., Marin, C., Rodriguez Oroz, C., Blesa, J., Benitez Temino, B., MenaSegovia, J., . Olanow, C. W. (2008). T he basal ganglia in Parkinson's disease: current concepts and unexplained observations. Annals of Neurology, 64, S30 46. doi: 10.1002/ana.21481 Okano, K., & Tanji, J. (1987). Neuronal activities in the primate motor fields of the agranular frontal cortex preceding visually triggered and self paced movement. Experimental Brain Research, 66(1), 155166. Olanow, C. W., Stern, M. B., & Sethi, K. (2009). The scientific and clinical basis for the treatment of Parkinson disease (2009). Neurology, 72 (21 Suppl 4), S1 136. doi: 10.1212/WNL.0b013e3181a1d44c Oldfield, R. C. (1971). The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia, 9(1), 97 113. Onn, S.P., West, A. R., & Grace, A. A. (2000). Dopamine mediated regulation of striatal neuronal and network interactions. Trends in Neurosciences, 23, S48 S56.
83 Owen, A. M., Iddon, J. L., Hodges, J. R., Summers, B. A., & Robbins, T. W. (1997). Spatial and nonspatial working memory at different stages of Parkinson's disease. Neuropsychologia, 35 (4), 519532. Passingham, R. E. (1995). The Frontal Lobes and Voluntary Action Oxford: Oxford University Press. Picard, N., & Strick, P. L. (1996). Motor areas of the medial wall: a review of their location and functional activation. Cerebral Cortex, 6 (3), 342353. Pockett, S., Banks, W. P., & Gallagher, S. (Eds.). (2006). Does Consciousness Cause Behavior? Cambridge: MIT Press. Posner, M. I. (1980). Orienting of attention. Quarterly Journal of Experimental Psychology, 32 (1), 3 25. Posner, M. I., Sn yder, C. R., & Davidson, B. J. (1980). Attention and the detection of signals. Journal of Experimental Psychology, 109(2), 160174. Praamstra, P., Cools, A. R., Stegeman, D. F., & Horstink, M. W. (1996). Movement related potential measures of different mo des of movement selection in Parkinson's disease. Journal of the Neurological Sciences, 140(1 2), 6774. Praamstra, P., Meyer, A. S., Cools, A. R., Horstink, M. W., & Stegeman, D. F. (1996). Movement preparation in Parkinson's disease: Time course and distribution of movement related potentials in a movement precueing task. Brain, 119 (5), 16891704. Praamstra, P., Stegeman, D. F., Cools, A. R., & Horstink, M. W. (199 8). Reliance on external cues for movement initiation in Parkinson's disease. Evidence from movement related potentials. Brain, 121(1), 167177. Quintana, J., & Fuster, J. M. (1999). From perception to action: temporal integrative functions of prefrontal and parietal neurons. Cerebral Cortex, 9(3), 213221. Raz, N., Lindenberger, U., Rodrigue, K. M., Kennedy, K. M., Head, D., Williamson, A., . Acker, J. D. (2005). Regional brain changes in aging healthy adults: general trends, individual differences and modifiers. Cerebral Cortex, 15(11), 16761689. doi: 10.1093/cercor/bhi044 Reijnders, J. S., Ehrt, U., Weber, W. E., Aarsland, D., & Leentjens, A. F. (2008). A systematic review of prevalence studies of depression in Parkinson's disease. Movement Disorders, 23 (2), 183 189; quiz 313. doi: 10.1002/mds.21803 Reitan, R. M., & Wolfson, D. (1985). The HalsteadReitan neuropsychological test battery: Theory and clinical interpretation. Tucson: Neuropsychology Press.
84 Rinne, J. O., Lnnberg, P., & Marjamki, P. (1990). Agedependent decline in human brain dopamine D1 and D2 receptors. Brain Research, 508(2), 349 352. Rubens, A. B. (1976). Transcortical motor aphasia. Studies in Neurolinguistics, 1, 293 306. Sabatini, U., Boulanouar, K., Fabre, N. Martin, F., Carel, C., Colonnese, C., . Rascol, O. (2000). Cortical motor reorganization in akinetic patients with Parkinson's disease: a functional MRI study. Brain, 123(2), 394 403. Sanides, F. (1964). The cytomyeloarchitecture of the human front al lobe and Its relation to phylogenetic differentiation of the cerebral cortex. Journal fur Hirnforschung, 47, 269282. Seiss, E., & Praamstra, P. (2004). The basal ganglia and inhibitory mechanisms in response selection: evidence from subliminal priming of motor responses in Parkinsons disease. Brain, 127(2), 330 339. Selemon, L. D., & GoldmanRakic, P. S. (1988). Common cortical and subcortical targets of the dorsolateral prefrontal and posterior parietal cortices in the rhesus monkey: evidence for a distributed neural network subserving spatially guided behavior. Journal of Neuroscience, 8(11), 40494068. Seltzer, B., & Pandya, D. N. (1984). Further observations on parietotemporal connections in the rhesus monkey. Experimental Brain Research, 55(2), 301 312. Seltzer, B., & Pandya, D. N. (1989). Frontal lobe connections of the superior temporal sulcus in the rhesus monkey. Journal of Comparative Neurology, 281(1), 97 113. doi: 10.1002/cne.902810108 Sheikh, J. I., & Yesavage, J. A. (1986). Geriatric D epression Scale (GDS): Recent evidence and development of a shorter version. In T. L. Brink (Ed.), Clinical Gerontology: A Guide to Assessment and Intervention (pp. 165173). New York: The Haworth Press, Inc. Silverman, I. W. (2006). Sex differences in sim ple visual reaction time: A historical meta analysis. Sex Roles, 54(1 2), 57 68. Starkstein, S. E., Mayberg, H. S., Prezosi, T. J., Andrezejewski, P., Leiguarda, R., & Robinson, R. G. (1992). Reliability, validity, and clinical correlates of apathy in Par kinson's disease. Journal of Neuropsychiatry, 4(2), 134139. Stelmach, G. E., Worringham, C. J., & Strand, E. A. (1986). Movement preparation in Parkinson's disease: The use of advance information. Brain, 109 (6), 11791194.
85 Thach, W. (1978). Correlation of neural discharge with pattern and force of muscular activity, joint position, and direction of intended next movement in motor cortex and cerebellum. Journal of Neurophysiology, 41(3), 654 676. Thaler, D., Chen, Y. C., Nixon, P. D., Stern, C. E., & Pas singham, R. E. (1995). The functions of the medial premotor cortex. I: Simple learned movements. Experimental Brain Research, 102(3), 445 460. Tomlinson, C. L., Stowe, R., Patel, S., Rick, C., Gray, R., & Clarke, C. E. (2010). Systematic review of levodopa dose equivalency reporting in Parkinson's disease. Movement Disorders, 25(15), 26492653. doi: 10.1002/mds.23429 Van Den Eeden, S. K. (2003). Incidence of Parkinson's disease: Variation by age, gender, and race/ethnicity. American Journal of Epidemiology 157 (11), 10151022. van den Wildenberg, W. P., van Boxtel, G. J., van der Molen, M. W., Bosch, D. A., Speelman, J. D., & Brunia, C. H. (2006). Stimulation of the subthalamic region facilitates the selection and inhibition of motor responses in Parkinson's disease. Journal of Cognitive Neuroscience, 18(4), 626 636. Vogt, B. A., & Pandya, D. N. (1987). Cingulate cortex of the rhesus monkey: II. Cortical afferents. Journal of Comparative Neurology, 262(2), 271 289. doi: 10.1002/cne.902620208 Warabi, T., Fukushima, K., Olley, P. M., Chiba, S., & Yanagisawa, N. (2011). Difficulty in terminating the preceding movement/posture explains the impaired initiation of new movements in Parkinson's disease. Neuroscience Letters, 496(2), 8489. doi: 10.1016/j.neulet.2011.04.001 Wechsler, D. (1997). WMS III: Wechsler memory scale administration and scoring manual San Antonio, TX: Psychological Corporation. Wechsler, D. (2001). Wechsler Test of Adult Reading: WTAR San Antonio, TX: Harcourt Assessment. Wechs ler, D. (2008). Wechsler Adult Intelligence Scale 4th Edition (WAIS IV) : Harcourt Assessment, San Antonio, TX. Weintraub, D., Moberg, P. J., Duda, J. E., Katz, I. R., & Stern, M. B. (2004). Effect of psychiatric and other nonmotor symptoms on disability in Parkinson's disease. Journal of the American Geriatrics Society, 52(5), 784 788. doi: 10.1111/j.15325415.2004.52219.x West, A. R., & Grace, A. A. (2002). Opposite Influences of Endogenous Dopamine D1 and D2 Receptor Activation on Activity States and El ectrophysiological Properties of Striatal Neurons: Studies CombiningIn Vivo Intracellular Recordings and Reverse Microdialysis. The Journal of Neuroscience, 22(1), 294 304.
86 Wiesendanger, M., & Wiesendanger, R. (1984). The supplementary motor area in light of recent investigations. Experimental Brain Research, 2, 382 392. Willingham, D. B., Koroshetz, W. J., Treadwell, J. R., & Bennett, J. P. (1995). Comparison of Huntington's and Parkinson's disease patients' use of advanced information. Neuropsychology, 9 (1), 39 46. Zarit, S. H., Reever, K. E., & Bach Peterson, J. (1980). Relatives of the impaired elderly: correlates of feelings of burden. Gerontologist, 20(6), 649 655.
87 BIOGRAPHICAL SKETCH Matthew Cohen was born in Newark, DE and obtained his Bachelor of Arts degree in psychology from the University of Delaware. He obtained his Master of Science degree and Ph.D from the University of Florida in clinical psychology with an emphasis in neurops ychology. His dissertation studied movement initiation in patients with Parkinsons disease. He completed his predoctoral internship at the Baltimore VA Medical Center and in September, 2013 he started a twoyear postdoctoral fellowship at the Johns Hopkins School of Medicine (Baltimore, MD).