Penny Macdonald - Academia.edu (original) (raw)

Papers by Penny Macdonald

Frontiers in Human Neuroscience, Oct 2, 2014

Cognitive dysfunction is a feature of Parkinson's Disease (PD). Some cognitive functions are impa... more Cognitive dysfunction is a feature of Parkinson's Disease (PD). Some cognitive functions are impaired by dopaminergic medications prescribed to address the movement symptoms that typify PD. Learning appears to be the cognitive function most frequently worsened by dopaminergic therapy. However, this result could reflect either impairments in learning (i.e., acquisition of associations among stimuli, responses, and outcomes) or deficits in performance based on learning (e.g., selecting responses). We sought to clarify the specific effects of dopaminergic medication on (a) stimulus-response association learning from outcome feedback and (b) response selection based on learning, in PD. We tested 28 PD patients on and/or off dopaminergic medication along with 32 healthy, ageand education-matched controls. In Session 1, participants learned to associate abstract images with specific key-press responses through trial and error via outcome feedback. In Session 2, participants provided specific responses to abstract images learned in Session 1, without feedback, precluding new feedback-based learning. By separating Sessions 1 and 2 by 24 h, we could distinguish the effect of dopaminergic medication on (a) feedback-based learning and response selection processes in Session 1 as well as on (b) response selection processes when feedback-based learning could not occur in Session 2. Accuracy achieved at the end of Session 1 were comparable across groups. PD patients on medication learned stimulus-response associations more poorly than PD patients off medication and controls. Medication did not influence decision performance in Session 2. We confirm that dopaminergic therapy impairs feedback-based learning in PD, discounting an alternative explanation that warranted consideration.

Frontiers in Neurology, Aug 21, 2018

In Parkinson's disease (PD), cognitive functions mediated by brain regions innervated by ventral ... more In Parkinson's disease (PD), cognitive functions mediated by brain regions innervated by ventral tegmental area (VTA) worsen with dopamine replacement therapy, whereas processes relying on regions innervated by the substantia nigra pars compacta (SNc) improve. The SLC6A3 gene encodes the dopamine transporter (DAT). The common 9R polymorphism produces higher DAT concentrations and consequently lower baseline dopamine than SLC6A3 wildtype. Whether SLC6A3 genotype modulates the effect of dopaminergic therapy on cognition in PD is not known. We investigated the effect of dopaminergic therapy and SLC6A3 genotype on encoding and recall of abstract images using the Aggie Figures Learning Test in PD patients. Encoding depends upon brain regions innervated by the VTA, whereas recall is mediated by widespread brain regions, a number innervated by the SNc. We found that dopaminergic therapy worsened encoding of abstract images in 9R carriers only. In contrast, dopaminergic therapy improved recall of abstract images in all PD patients, irrespective of SLC6A3 genotype. Our findings suggest that 9R-carrier PD patients are more predisposed to dopamine overdose and medication-induced impairment of cognitive functions mediated by VTA-innervated brain regions. Interestingly, PD patients without the 9R polymorphism did not show such an impairment. SLC6A3 genotype does not modulate the dopaminergic therapy-induced improvement of functions mediated by SNc-innervated regions in PD patients.

$Research paper thumbnail of Social Symptoms of Parkinson\u27s Disease$

© 2020 Margaret T. M. Prenger et al. Parkinson\u27s disease (PD) is typically well recognized by ... more © 2020 Margaret T. M. Prenger et al. Parkinson\u27s disease (PD) is typically well recognized by its characteristic motor symptoms (e.g., bradykinesia, rigidity, and tremor). The cognitive symptoms of PD are increasingly being acknowledged by clinicians and researchers alike. However, PD also involves a host of emotional and communicative changes which can cause major disruptions to social functioning. These incude problems producing emotional facial expressions (i.e., facial masking) and emotional speech (i.e., dysarthria), as well as difficulties recognizing the verbal and nonverbal emotional cues of others. These social symptoms of PD can result in severe negative social consequences, including stigma, dehumanization, and loneliness, which might affect quality of life to an even greater extent than more well-recognized motor or cognitive symptoms. It is, therefore, imperative that researchers and clinicans become aware of these potential social symptoms and their negative effects...

Neurology, 2015

Objective/Background: We tested the prevalent contention that dorsal striatum (DS) mediates later... more Objective/Background: We tested the prevalent contention that dorsal striatum (DS) mediates later-stage stimulus-response learning when responses become automatic or habitual. Using functional magnetic resonance imaging, we examined striatal brain activity during later-stage stimulus-response learning, once performance accuracy was greater than 90[percnt]. Design/Methods: Seven males and seven females (mean age 22) learned to associate abstract images with left or right button-presses during an initial study phase. These pairings were reinforced by feedback in Session 1 and practiced without feedback in Session 2. Session 3 measured whether stimulus-response associations had achieved habit status. Results: DS activity correlated with stimulus-response events only during Blocks 1-3 of Session 1 when response times and accuracy suggested a level of deliberation in responding. No significant DS activity occurred for Blocks 4-12 or in Session 2 when responses times and accuracy had reac...

Parkinson’s disease (PD) is typically well-recognized by its characteristic motor symptoms (e.g.,... more Parkinson’s disease (PD) is typically well-recognized by its characteristic motor symptoms (e.g., bradykinesia, rigidity, and tremor). The cognitive symptoms of PD are increasingly being acknowledged by clinicians and researchers alike. However, PD also involves a host of emotional and communicative changes which can cause major disruptions to social functioning. These include problems producing emotional facial expressions (i.e., facial masking) and emotional speech (i.e., dysarthria), as well as difficulties recognizing the verbal and non-verbal emotional cues of others. These social symptoms of PD can result in severe negative social consequences, including stigma, dehumanization, and loneliness, which might affect quality of life to an even greater extent than more well-recognized motor or cognitive symptoms. It is therefore imperative that researchers and clinicians become aware of these potential social symptoms and their negative effects, in order to properly investigate and ...

Neurobiology of Aging, 2020

Processing regular patterns in auditory scenes is important for navigating complex environments. ... more Processing regular patterns in auditory scenes is important for navigating complex environments. Electroencephalography (EEG) studies find enhancement of sustained brain activity, correlating with the emergence of a regular pattern in sounds. How aging, aging-related diseases such as Parkinson's disease (PD), and treatment of PD affect this fundamental function remain unknown. We addressed this knowledge gap. Healthy younger and older adults, and PD patients listened to sounds that contained or were devoid of regular patterns. Healthy older adults and PD patients were tested twice-on and off dopaminergic medication in counterbalanced order. Regularity-evoked, sustained EEG activity was reduced in older, compared to younger adults. PD patients and older controls had comparable attenuation of the sustained response. Dopaminergic therapy further weakened the sustained response in both groups. These findings suggest that fundamental regularity processing is impacted by aging-related neural changes but not those underlying PD. The finding that dopaminergic therapy attenuates rather than improves the sustained response coheres with the dopamine overdose response and implicates brain regions receiving dopamine from the ventral tegmental area in regularity processing.

The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, 2017

Multiple system atrophy (MSA) is an incurable neurodegenerative illness in which progressive symp... more Multiple system atrophy (MSA) is an incurable neurodegenerative illness in which progressive symptoms, including stridor and acute laryngeal obstruction, occur. Advanced care planning and palliative care discussions in people living with MSA are not well defined. The aim of the present study is to evaluate advanced care planning and current practices in palliative care in MSA to identify opportunities for improving quality of care. The study is a retrospective chart review assessing the focus and timing of palliative care discussions in people living with MSA. Some 22 charts were reviewed. A total of 22 patients were included. The most common symptoms were parkinsonism, orthostatic hypotension, GI/GU dysfunction, ataxia and gait impairment. Six patients had stridor. Of the palliative care discussions that took place, the most common topics were diagnosis, symptoms or symptom management, and prognosis. In the majority of patients who died and who had a do-not-attempt-resuscitation or...

Abstracts of the 26th Annual Meeting of the GCMAS, 2021

Alzheimer's & Dementia, 2018

outcome measures were changes from baseline in the Vascular Dementia Assessment Scale-Cognitive S... more outcome measures were changes from baseline in the Vascular Dementia Assessment Scale-Cognitive Subscale(VADAS-cog) and neuropsychiatric Inventory(NPI) after 24 weeks treatment. The secondary outcomes were changes from baseline in the Clinician’s Interview-Based Impression of Change-Plus care Interview(CIBIC-plus),mini-mental state examination(MMSE), activity of daily living scale(ADL) ,clock drawing test(CDT), trail making test (TMT), hyperactivity of Liver Yang scale(HLY, a syndrome defined by traditional Chinese medicine). Results: The VADAS-cog showed a significant improvement in TZ and donepezil groups at the endpoint (mean change, 6.20(95% CI:5.31w7.09) in TZ group, 6.53(95% CI:5.63w7.4) in donepezil group, 3.47(95% CI:1.76w5.19) in placebo group, all p<0.001 for the comparison with placebo)(Figure 1).NPI showed modest improvement from baseline in TZ(-3.0364.84) and donepezil (-2.2165.45) compared to placebo(-0.3665.70) (P<0.001,P1⁄40.013 compared to placebo) (Figure 2).There was significant difference on the improvement percent of the CIBIC-plus between three groups( 73.71% in TZ group, 79.83% in donepezil group, 58.18% in placebo group, all p<0.001 compared with placebo) . There was no significant difference of TZ in the changes of VADAS-cog and CIBIC-plus from donepezil group. The HLY scale showed significant improvement in the TZ group than placebo group(P1⁄40.034). The change of HLY in the TZ group was significantly correlated to the changes of VADAS-cog(r1⁄40.16,p<0.001) and NPI(r1⁄40.24, p<0.001). No benefits obtained in the three groups on ADL, CDT, and TMT-B. The frequency of adverse events was no significant difference between three groups. Conclusions: In patients with mild to moderate VaD, TZ showed significant benefits with cognition, behavioral and psychological symptoms. TZ did not improve functional ability. NCT02453932. P1-067 AMBROXOL AS PHARMACOLOGICAL CHAPERONE TARGETING GBA1 AS A DISEASE MODIFYING TREATMENT FOR PARKINSON’S DISEASE DEMENTIA: A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL Stephen H. Pasternak, Carolina Silveira, Zhonghan Li, Robert Bartha, Michael Borrie, Jennie Wells, Penny MacDonald, Guangyoug Zou, Mary Jenkins, Elizabeth Finger, Mandar Jog, Tony Rupar, Rommel Tirona, Robarts Research Institute, London, ON, Canada; Western University, London, ON, Canada; Parkwood Institute, London, ON, Canada; Parkwood Institute, St Joseph’s Health Care Centre, London, ON, Canada. Contact e-mail: spasternak@robarts.ca

Parkinson's Disease, 2019

Freezing of gait (FOG) is experienced by a significant number of patients with Parkinson’s diseas... more Freezing of gait (FOG) is experienced by a significant number of patients with Parkinson’s disease (PD). The pathophysiology of this disabling motor symptom remains unclear, and there are no effective therapies. Anxiety has previously been posited as a contributing factor to gait freezing. There have been few studies directly investigating this topic, and a comprehensive literature review is lacking. The objective of this paper was to systematically review the evidence associating anxiety with the presence, severity, and progression of FOG in PD patients. The PubMed, EMBASE, and PsycINFO databases were searched up to September 19, 2018, for English-language, peer-reviewed articles that explored anxiety and FOG as outcome measures in a PD population base. Review articles, case reports, and articles that assessed gait disorders other than FOG were excluded, yielding a total of 26 articles in the final analysis. Of these 26 studies, 16 had a significant relationship between anxiety out...

$Research paper thumbnail of {"__content__"=>" Polymorphism Predisposes to Dopamine Overdose in Parkinson's Disease.", "i"=>{"__content__"=>"SLC6A3"}}$

Frontiers in neurology, 2018

In Parkinson's disease (PD), cognitive functions mediated by brain regions innervated by vent... more In Parkinson's disease (PD), cognitive functions mediated by brain regions innervated by ventral tegmental area (VTA) worsen with dopamine replacement therapy, whereas processes relying on regions innervated by the substantia nigra pars compacta (SNc) improve. The gene encodes the dopamine transporter (DAT). The common 9R polymorphism produces higher DAT concentrations and consequently lower baseline dopamine than wildtype. Whether genotype modulates the effect of dopaminergic therapy on cognition in PD is not known. We investigated the effect of dopaminergic therapy and genotype on encoding and recall of abstract images using the Aggie Figures Learning Test in PD patients. Encoding depends upon brain regions innervated by the VTA, whereas recall is mediated by widespread brain regions, a number innervated by the SNc. We found that dopaminergic therapy worsened encoding of abstract images in 9R carriers only. In contrast, dopaminergic therapy improved recall of abstract images i...

NeuroImage: Clinical, 2018

Parkinson's disease (PD) is a progressive neurological disorder that has no reliable biomarkers. ... more Parkinson's disease (PD) is a progressive neurological disorder that has no reliable biomarkers. The aim of this study was to explore the potential of semi-automated sub-regional analysis of the striatum with magnetic resonance imaging (MRI) to distinguish PD patients from controls (i.e., as a diagnostic biomarker) and to compare PD patients at different stages of disease. With 3 Tesla MRI, diffusion-and T1-weighted scans were obtained on two occasions in 24 PD patients and 18 age-matched, healthy controls. PD patients completed one session on and the other session off dopaminergic medication. The striatum was parcellated into seven functionally disparate sub-regions. The segmentation was guided by reciprocal connections to distinct cortical regions. Volume, surface-based morphometry, and integrity of white matter connections were calculated for each striatal sub-region. Test-retest reliability of our volume, morphometry, and white matter integrity measures across scans was high, with correlations ranging from r = 0.452, p < 0.05 and r = 0.985, p < 0.001. Global measures of striatum such as total striatum, nucleus accumbens, caudate nuclei, and putamen were not significantly different between PD patients and controls, indicating poor sensitivity of these measures, which average across subregions that are functionally heterogeneous and differentially affected by PD, to act as diagnostic biomarkers. Further, these measures did not correlate significantly with disease severity, challenging their potential to serve as progression biomarkers. In contrast, a) decreased volume and b) inward surface displacement of caudal-motor striatumethe region first and most dopamine depleted in PDedistinguished PD patients from controls. Integrity of white matter cortico-striatal connections in caudal-motor and adjacent striatal sub-regions (i.e., executive and temporal striatum) was reduced for PD patients relative to controls. Finally, volume of limbic striatum, the only striatal sub-region innervated by the later-degenerating ventral tegmental area in PD, was reduced in later-stage compared to early stage PD patients a potential progression biomarker. Segmenting striatum based on distinct cortical connectivity provided highly sensitive MRI measures for diagnosing and staging PD.

Parkinson's Disease, 2018

Difficulty with emotion recognition is increasingly being recognized as a symptom of Parkinson’s ... more Difficulty with emotion recognition is increasingly being recognized as a symptom of Parkinson’s disease. Most research into this area contends that progressive cognitive decline accompanying the disease is to be blamed. However, facial mimicry (i.e., the involuntary congruent activation of facial expression muscles upon viewing a particular facial expression) might also play a role and has been relatively understudied in this clinical population. In healthy participants, facial mimicry has been shown to improve recognition of observed emotions, a phenomenon described by embodied simulation theory. Due to motor disturbances, Parkinson’s disease patients frequently show reduced emotional expressiveness, which translates into reduced mimicry. Therefore, it is likely that facial mimicry problems in Parkinson’s disease contribute at least partly to the emotional recognition deficits that these patients experience and might greatly influence their social cognition abilities and quality o...

NeuroImage, 2019

Learning associations between stimuli and responses is essential to everyday life. Dorsal striatu... more Learning associations between stimuli and responses is essential to everyday life. Dorsal striatum (DS) has long been implicated in stimulus-response learning, though recent results challenge this contention. We have proposed that discrepant ndings arise because stimulus-response learning methodology generally confounds learning and fi response selection processes. In 19 patients with Parkinson's disease (PD) and 18 age-matched controls, we found that dopaminergic therapy the ef ciency of stimulus-response learning, with corresponding decreased fi attenuation of ventral striatum (VS) activation. In contrast, exogenous dopamine response selection accuracy related improved to DS BOLD signal. Contrasts PD patients and controls fully support these within-subject pat-enhanced between terns. These double dissociations in terms of behaviour and neural activity related to VS and DS in PD and in response to dopaminergic therapy, strongly refute the view that DS mediates stimulus-response learning through feedback. Our ndings integrate with a growing literature favouring a role for DS in decision making rather than fi learning, and unite two literature that have been evolving independently.

International journal of geriatric psychiatry, 2018

Values are reported as means (±SEM). BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory ... more Values are reported as means (±SEM). BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory II; SAS, Starkstein Apathy Scale. *P < .05. Dopaminergic medications, such as L‐3,4‐dihydroxyphenylalanine (levodopa), are a mainstay of treatment in Parkinson's disease (PD), a neurodegenerative movement disorder with prominent cognitive and psychiatric symptoms. Recently, dopaminergic medications have been proposed as a possible treatment for mood disorders, depression in particular. PD patients are characterized by marked degeneration of dopaminergic neurons. The possibility that dopaminergic deficits contribute to high rates of depression, anxiety, and apathy in PD has been considered. Previous findings for potential mood‐enhancing effects of levodopa in PD were largely inconsistent. Whether levodopa is effective in mood, anxiety, or apathy remains unclear. The aim of the present study was to test the potential for levodopa to affect mood, anxiety, and apathy independent of pathophysiological processes related to PD. We administered a single dose of levodopa/carbidopa 100/25 mg to 24 healthy older adults (Mage ± SEM = 66.13 ± 1.30 years; 11 males, 13 females). Participants had no history of neurological or psychiatric illnesses, including alcohol or substance abuse problems, and had no contraindications to levocarb. Written informed consent was obtained prior to beginning the experiment in accordance with the Declaration of Helsinki. This study was approved by the Health Sciences Research Ethics Board of the University of Western Ontario. Across two testing sessions separated by a week, participants were assessed once after receiving levodopa/carbidopa 100/25 mg and once after receiving the equivalent volume of placebo, in counterbalanced order across individuals. Both drug and placebo were administered orally in identical capsules to maintain double‐ blindedness. After 45 minutes, to allow for enhanced plasma dopamine levels, standardized and validated self‐report psychiatric rating measures were administered. These included the Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Starkstein Apathy Scale (SAS). For each psychiatric measure, we performed 2 × 2 mixed ANOVAs withOrder (L/P vs P/L) as the between‐subject factor and Session (levodopa vs placebo) as the within‐subject variable. Higher scores on our measures indicated greater self‐reported ratings of depression, anxiety, and apathy, respectively. Our analyses revealed a significantmain effect of Session for BDI scores [F(1,22) = 6.699, MSE = 1.008, P = .017, ηp = 0.223] but not for BAI or SAS (both F values < 1). Participants reported lower BDI scores when treated with levodopa compared to placebo (Table 1). There was no main effect of Order for any measure (all F values < 1). There was a marginally significant Order × Session interaction effect for BDI [F(1,22) = 4.053, MSE = 1.008, P = .056] but

Frontiers in human neuroscience, 2017

Parkinson's disease (PD) is characterized by resting tremor, rigidity and bradykinesia. Dopam... more Parkinson's disease (PD) is characterized by resting tremor, rigidity and bradykinesia. Dopaminergic medications such as L-dopa treat these motor symptoms, but can have complex effects on cognition. Impulse control is an essential cognitive function. Impulsivity is multifaceted in nature. Motor impulsivity involves the inability to withhold pre-potent, automatic, erroneous responses. In contrast, cognitive impulsivity refers to improper risk-reward assessment guiding behavior. Informed by our previous research, we anticipated that dopaminergic therapy would decrease motor impulsivity though it is well known to enhance cognitive impulsivity. We employed the Go/No-go paradigm to assess motor impulsivity in PD. Patients with PD were tested using a Go/No-go task on and off their normal dopaminergic medication. Participants completed cognitive, mood, and physiological measures. PD patients on medication had a significantly higher proportion of Go trial Timeouts (i.e., trials in which...

eNeuro

In the double-step paradigm, healthy human participants automatically correct reaching movements ... more In the double-step paradigm, healthy human participants automatically correct reaching movements when targets are displaced. Motor deficits are prominent in Parkinson's disease (PD) patients. In the lone investigation of online motor correction in PD using the double-step task, a recent study found that PD patients performed unconscious adjustments appropriately but seemed impaired for consciously-perceived modifications. Conscious perception of target movement was achieved by linking displacement to movement onset. PD-related bradykinesia disproportionately prolonged preparatory phases for movements to original target locations for patients, potentially accounting for deficits. Eliminating this confound in a double-step task, we evaluated the effect of conscious awareness of trajectory change on online motor corrections in PD. On and off dopaminergic therapy, PD patients (n = 14) and healthy controls (n = 14) reached to peripheral visual targets that remained stationary or unex...

Human Brain Mapping, 2017

We investigated a controversy regarding the role of the dorsal striatum (DS) in deliberate decisi... more We investigated a controversy regarding the role of the dorsal striatum (DS) in deliberate decision-making versus late-stage, stimulus-response learning to the point of automatization. Participants learned to associate abstract images with right or left button presses explicitly before strengthening these associations through stimulus-response trials with (i.e., Session 1) and without (i.e., Session 2) feedback. In Session 1, trials were divided into response-selection and feedback events to separately assess decision versus learning processes. Session 3 evaluated stimulus-response automaticity using a location Stroop task. DS activity correlated with response-selection and not feedback events in Phase 1 (i.e., Blocks 1-3), Session 1. Longer response times (RTs), lower accuracy, and greater intertrial variability characterized Phase 1, suggesting deliberation. DS activity extinguished in Phase 2 (i.e., Blocks 4-12), Session 1, once RTs, response variability, and accuracy stabilized, though stimulus-response automatization continued. This was signaled by persisting improvements in RT and accuracy into Session 2. Distraction between Sessions 1 and 2 briefly reintroduced response uncertainty, and correspondingly, significant DS activity reappeared in Block 1 of Session 2 only. Once stimulus-response associations were again refamiliarized and deliberation unnecessary, DS activation disappeared for Blocks 2-8, Session 2. Interference from previously learned right or left button responses with incongruent location judgments in a location Stroop task provided evidence that automaticity of stimulus-specific button-press responses had developed by the end of Session 2. These results suggest that DS mediates decision making and not late-stage learning, reconciling two, independently evolving and well-supported literatures that implicate DS in different cognitive functions.