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Dopamine asymmetry interacts with medication to affect cognition in Parkinson's disease
Abstract
Contradictory evidence exists regarding the nature and degree of impaired cognitive flexibility in PD. Dopaminergic medication may be expected to ameliorate such cognitive deficits, yet both medicated and unmedicated patients have been reported to perform more poorly than control subjects on tasks of cognitive flexibility, suggesting that such deficits may also be affected by other disease-related variables. The present study examined whether asymmetric dopamine deficiency (revealed by unilateral symptom onset) is related to the performance of spontaneous and reactive flexibility in PD, and the possible interaction of dopaminergic medication with such asymmetry. Thirty-five PD patients with mild motor symptoms and unilateral onset of PD (left-onset=14; right-onset=21) performed the Alternate Uses (AU) and intradimensional/extradimensional shift (IED) tasks. Interaction between side of onset and medication was observed for the number of errors in the AU task and number of reversal errors in the IED task. Significantly more AU errors were made by medicated patients with left-onset, as compared to all other participants. Conversely, medicated patients with right-onset made the most reversal errors. These results suggest that relatively early in the disease process when dopamine deficit in the less-affected hemisphere is mild, optimal dopaminergic medication (with respect to motor function) may involve over-medication of the less-affected hemisphere. Thus, AU errors may be the consequence of hyperdopaminergic state leading to impaired functioning of the left hemisphere, whereas increased reversal errors in right-onset PD patients receiving dopaminergic medication is related to impaired dopamine function in the right hemisphere.
... There is substantial evidence documenting the presence of mild cognitive deficits early in PD, although the underlying neuropathology remains controversial. Recent evidence suggests that cognitive impairment present in the early stages of PD cannot be fully explained by dopamine depletion alone (Hanna-Pladdy, Jones, Cabanban, Pahwa, & Lyons, 2013;Tomer, Aharon-Peretz, & Tsitrinbaum, 2007). In addition to dopamine, many other contributing factors to cognitive deficits in PD have been considered including structural changes in both cortical and subcortical regions, genetic variation in the COMT gene, amyloid plaques, alpha-synuclein, tau protein, and involvement of other neurotransmitter systems including GABA (Beyer, Janvin, Larsen, & Aarsland, 2007;Braak et al., 2003;Buongiorno, Compta, & Marti, 2011;Gomperts et al., 2013;Ibarretxe-Bilbao, Junque, Marti, & Tolosa, 2011;Luciana, Collins, & Depue, 1998). ...
... Other investigations have tried to explain the variability in cognitive presentation in PD through examination of patterns of cognitive dysfunction reflective of hemispheric asymmetries in dopamine depletion based on the side of motor symptom onset (Amick, Grace, & Chou, 2006;Katzen, Levin, & Weiner, 2006;Tomer et al., 2007;Verreyt et al., 2011). If asymmetric nigral cell loss implicated in asymmetric motor presentation is also responsible for cognitive deficits, then differential patterns of cognitive impairment based on hemispheric specialization could be evident. ...
... If asymmetric nigral cell loss implicated in asymmetric motor presentation is also responsible for cognitive deficits, then differential patterns of cognitive impairment based on hemispheric specialization could be evident. However, the literature has revealed a wide range of cognitive profiles based on motor symptom onset, in particular for patients in the early stages of the disease (Poletti et al., 2013;Tomer et al., 2007;Williams et al., 2007). In fact, contrary to other studies suggesting greater cognitive deficits with left hemisphere involvement, some studies have suggested there is greater cognitive impairment with right hemisphere involvement and after dopamine replacement for tasks mediated by the less affected side, suggesting a detrimental overdosing effect (Bentin, Silverberg, & Gordon, 1981;Tomer et al., 2007;Tomer, Levin, & Weiner, 1993). ...
Parkinson's disease (PD) is characterized by asymmetric motor symptom onset attributed to greater degeneration of dopamine neurons contralateral to the affected side. However, whether motor asymmetries predict cognitive profiles in PD, and to what extent dopamine influences cognition remains controversial. This study evaluated cognitive variability in PD by measuring differential response to dopamine replacement therapy (DRT) based on hemispheric asymmetries. The influence of DRT on cognition was evaluated in mild PD patients (n=36) with left or right motor onset symptoms. All subjects were evaluated on neuropsychological measures on and off DRT and compared to controls (n=42). PD patients were impaired in executive, memory and motor domains irrespective of side of motor onset, although patients with left hemisphere deficit displayed greater cognitive impairment. Patients with right hemisphere deficit responded to DRT with significant improvement in sensorimotor deficits, and with corresponding improvement in attention and verbal memory functions. Conversely, patients with greater left hemisphere dopamine deficiency did not improve in attentional functions and declined in verbal memory recall following DRT. These findings support the presence of extensive mild cognitive deficits in early PD not fully explained by dopamine depletion alone. The paradoxical effects of levodopa on verbal memory were predicted by extent of fine motor impairment and sensorimotor response to levodopa, which reflects extent of dopamine depletion. The findings are discussed with respect to factors influencing variable cognitive profiles in early PD, including hemispheric asymmetries and differential response to levodopa based on dopamine levels predicting amelioration or overdosing. (JINS, 2015, 21, 1-12).
... Although dopaminergic asymmetries are not consistently documented in the literature and seem to vary based on age, gender, species, and strain (for review, see [74]), numerous studies using methods of protein analyses in rodents have shown hemispheric distributions similar to the present results, greater levels of dopamine and its metabolites in the right NAc relative to the left [11,26,27,75]. It has been suggested that individual differences to natural rewards are a product of asymmetry in dopamine systems [76]. The present results support the notion that reward processes in the brain may be lateralized between cerebellocortico circuitry, which has considerable applications for disorders involving dysfunction of the subcortical dopamine functioning, disorders such as schizophrenia, Parkinson's, ADHD, and addiction [29][30][31]. ...
... In one study, patients whose motor symptoms began on the left side of the body performed more poorly on cognitive tests than those with right-side onset, leading to the conclusion that damage to right hemisphere dopamine plays a greater role in associated cognitive decline than left hemisphere depletion [79]. In the future, treatment for such symptoms may be optimal if applied differentially in each hemisphere [76]. Cerebellar-mediated dopamine pathways have previously been shown to exhibit plasticity and compensatory changes in the neural circuitry of rodent models of autism, providing a foundation for the cerebellum to develop unique connections between cerebral hemispheres [67]. ...
Cerebral and cerebellar hemispheres are known to be asymmetrical in structure and function, and previous literature supports that asymmetry extends to the neural dopamine systems. Using in vivo fixed potential amperometry with carbon fiber microelectrodes in anesthetized mice, the current study assessed hemispheric lateralization of stimulation-evoked dopamine in the nucleus accumbens (NAc) and the influence of the cerebellum in regulating this reward-associated pathway. Our results suggest that cerebellar output can modulate mesolimbic dopamine transmission, and this modulation contributes to asymmetrically lateralized dopamine release. Dopamine release did not differ between hemispheres when evoked by medial forebrain bundle (MFB) stimulation; however, dopamine release was significantly greater in the right NAc relative to the left when evoked by electrical stimulation of the cerebellar dentate nucleus (DN). Furthermore, cross-hemispheric talk between the left and right cerebellar DN does not seem to influence mesolimbic release given that lidocaine infused into the DN opposite to the stimulated DN did not alter release. These studies may provide a neurochemical mechanism for studies identifying the cerebellum as a relevant node for reward, motivational behavior, saliency, and inhibitory control. An increased understanding of the lateralization of dopaminergic systems may reveal novel targets for pharmacological interventions in neuropathology of the cerebellum and extending projections.
... Although dopaminergic asymmetries are not consistently documented in the literature and seem to vary based on age, gender, species, and strain [for review see 69], numerous studies using methods of protein analyses in rodents have shown hemispheric distributions similar to the present results, greater levels of dopamine and its metabolites in the right NAc relative to the left [11,26,70,71]. It has been suggested that individual differences to natural rewards are a product of asymmetry in dopamine systems [72]. The present results support the notion . ...
... In one study, patients whose motor symptoms began on the left side of the body performed more poorly on cognitive tests than those with right-side onset, leading to the conclusion that damage to right-hemisphere dopamine plays a greater role in associated cognitive decline than left-hemisphere depletion [75]. In the future, treatment for such symptoms may be optimal with if applied differentially in each hemisphere [72]. ...
Cerebral and cerebellar hemispheres are known to be asymmetrical in structure and function, and previous literature supports that asymmetry extends to the neural dopamine systems. Using in vivo fixed-potential amperometry with carbon-fiber microelectrodes in anesthetized mice, the current study assessed hemispheric lateralization of stimulation-evoked dopamine in the nucleus accumbens (NAc) and the influence of the cerebellum in regulating this reward-associated pathway. Our results suggest that cerebellar output can modulate mesolimbic dopamine transmission, and this modulation contributes to asymmetrically lateralized dopamine release. Dopamine release did not differ between hemispheres when evoked by medial forebrain bundle (MFB) stimulation; however, dopamine release was significantly greater in the right NAc relative to the left when evoked by electrical stimulation of the cerebellar dentate nucleus (DN). Furthermore, cross-hemispheric talk between the left and right cerebellar DN does not seem to influence mesolimbic release given that lidocaine infused into the DN opposite to the stimulated DN did not alter release. These studies may provide a neurochemical mechanism for studies identifying the cerebellum as a relevant node for reward, motivational behavior, saliency, and inhibitory control. An increased understanding of the lateralization of dopaminergic systems may reveal novel targets for pharmacological interventions in neuropathology of the cerebellum and extending projections.
... [5][6][7] Cognitive processes that are closely related with dopamine, such as cognitive flexibility and motivation, showed different deficits between right-onset and left-onset PD patients. 8 For example, left-onset PD patients with greater loss of dopamine in the right hemisphere had impaired cognitive flexibility. 5,8 Feedback-based associative learning, which involves learning through corrective feedback provided on each trial, has been correlated with striatal dopamine release 9 and function of the basal ganglia. ...
... 8 For example, left-onset PD patients with greater loss of dopamine in the right hemisphere had impaired cognitive flexibility. 5,8 Feedback-based associative learning, which involves learning through corrective feedback provided on each trial, has been correlated with striatal dopamine release 9 and function of the basal ganglia. 10,11 Previous studies have reported that feedback-based associative learning was impaired in PD patients. ...
Background and objectives:
Asymmetric onset of motor symptoms in PD can affect cognitive function. We examined whether motor-symptom laterality could affect feedback-based associative learning and explored its underlying neural mechanism by functional magnetic resonance imaging in PD patients.
Methods:
We recruited 63 early-stage medication-naïve PD patients (29 left-onset medication-naïve patients, 34 right-onset medication-naïve patients) and 38 matched normal controls. Subjects completed an acquired equivalence task (including acquisition, retention, and generalization) and resting-state functional magnetic resonance imaging scans. Learning accuracy and response time in each phase of the task were recorded for behavioral measures. Regional homogeneity was used to analyze resting-state functional magnetic resonance imaging data, with regional homogeneity lateralization to evaluate hemispheric functional asymmetry in the striatum.
Results:
Left-onset patients made significantly more errors in acquisition (feedback-based associative learning) than right-onset patients and normal controls, whereas right-onset patients performed as well as normal controls. There was no significant difference among these three groups in the accuracy of either retention or generalization phase. The three groups did not show significant differences in response time. In the left-onset group, there was an inverse relationship between acquisition errors and regional homogeneity in the right dorsal rostral putamen. There were no significant regional homogeneity changes in either the left or the right dorsal rostral putamen in right-onset patients when compared to controls.
Conclusions:
Motor-symptom laterality could affect feedback-based associative learning in PD, with left-onset medication-naïve patients being selectively impaired. Dysfunction in the right dorsal rostral putamen may underlie the observed deficit in associative learning in patients with left-sided onset.© 2016 International Parkinson and Movement Disorder Society.
... A survey of the literature suggests that learning, in various forms, is the cognitive function most commonly worsened by dopaminergic medication. Studies that have tested PD patients on relative to off medication have reported impairments in probabilistic associative (Torta et al., 2009;Jahanshahi et al., 2010), sequence (Feigin et al., 2003;Ghilardi et al., 2007;Seo et al., 2010;Tremblay et al., 2010), and stimulus-reward reversal learning (Swainson et al., 2000;Cools et al., 2002;Tomer et al., 2007;Graef et al., 2010;MacDonald et al., 2013a), as well as explicit abstract figure and list learning (MacDonald et al., 2013b), stimulus-stimulus facilitation , and learning from negative feedback (Frank et al., 2004). However, investigations often fail to separately assess the acquisition of associations among stimuli, responses, and outcomes, from processes of response selection that rely on these learned associations and that are used to measure new learning (McDonald and White, 1993;Jessup and O'doherty, 2011). ...
... These results support findings from previous studies in PD that report a medication-associated impairment in various forms of learning (Swainson et al., 2000;Cools et al., 2002;Feigin et al., 2003;Frank et al., 2004;Ghilardi et al., 2007;Tomer et al., 2007;Torta et al., 2009;Graef et al., 2010;Jahanshahi et al., 2010;Seo et al., 2010;Tremblay et al., 2010;but see Shiner et al., 2012Smittenaar et al., 2012). Whereas motor symptoms and some cognitive functions are improved by dopaminergic medication, other cognitive processes are actually worsened (Cools, 2006;MacDonald and Monchi, 2011). ...
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, age- and 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.
... Further support to the concept of denervation supersensitivity affecting functions other than motor in PD had been shown by Tomer et al. [29]. In their study, medicated PD patients demonstrated a decrease in specific cognitive functions related to the less affected hemisphere, for which medication dose was probably excessive [29]. ...
... Further support to the concept of denervation supersensitivity affecting functions other than motor in PD had been shown by Tomer et al. [29]. In their study, medicated PD patients demonstrated a decrease in specific cognitive functions related to the less affected hemisphere, for which medication dose was probably excessive [29]. Further support for asymmetry of brain function in PD patients, unrelated to pain, is based on the association between pathological gambling in medicated PD patients and resting state overactivity in a right hemisphere network [30]. ...
Background and purpose:
Reduced endogenous pain inhibition, as part of the degenerative process, is presumed to be the mechanism underlying the common presence of pain in patients with Parkinson's disease (PD). The present study aimed to assess an endogenous pain inhibitory system in PD using the conditioned pain modulation paradigm.
Methods:
Twenty-six predominantly unilateral PD patients and 19 controls underwent psychophysical pain assessment before and after patients' morning dopaminergic medication.
Results:
An unexpected increase in several parameters of pain perception for PD patients was found after dopaminergic medication (e.g. for 49°C noxious heat stimulation an increase from 70.6 ± 4.0 to 77.6 ± 4.0 on the numerical pain scale, P < 0.001). This increase was seen in patients with predominantly left-sided PD, regardless of the stimulated side (for 49°C noxious heat stimulation, predominantly left-sided PD patients, pain perception increased from 73.5 ± 6.8 to 85.0 ± 6.8, P < 0.001, whereas predominantly right-sided PD patients did not show a significant increase, 68.3 ± 6.8 to 70.4 ± 6.5, P = 0.777). Baseline efficiency of conditioned pain modulation inversely correlated with age at disease onset (r = -0.522; P = 0.009) and disease severity (Unified PD Rating Scale, r = 0.447; P = 0.032) but did not differ between patients and controls.
Conclusions:
Increased sensory response causing hyperalgesia occurs after dopaminergic medication in patients with predominantly left-sided PD.
... Dopamine supplementation in PD patients yielded reduced facilitation for consecutive, consistent stimulus-stimulus pairings in a selection task compared to normal implicit learning and hence facilitated responding when tested off medication [137]. Once stimulus-reward associations have been learned, reversing probabilities of stimulus-reward associations is also impaired for PD patients on dopamine replacement therapy [27, 32, 40, 104, 165–167]. Finally, dopamine therapy impaired learning from negative feedback [168]. ...
... Time estimation in the seconds but not millisecond range was impaired in patients on relative to off medication and healthy controls [155, 175]. Finally, impairment in generation tasks such as subject-ordered pointing [29] or production of alternate uses for common objects [167] have also been noted in PD patients on medication. ...
Cognitive abnormalities are a feature of Parkinson's disease (PD). Unlike motor symptoms that are clearly improved by dopaminergic therapy, the effect of dopamine replacement on cognition seems paradoxical. Some cognitive functions are improved whereas others are unaltered or even hindered. Our aim was to understand the effect of dopamine replacement therapy on various aspects of cognition. Whereas dorsal striatum receives dopamine input from the substantia nigra (SN), ventral striatum is innervated by dopamine-producing cells in the ventral tegmental area (VTA). In PD, degeneration of SN is substantially greater than cell loss in VTA and hence dopamine-deficiency is significantly greater in dorsal compared to ventral striatum. We suggest that dopamine supplementation improves functions mediated by dorsal striatum and impairs, or heightens to a pathological degree, operations ascribed to ventral striatum. We consider the extant literature in light of this principle. We also survey the effect of dopamine replacement on functional neuroimaging in PD relating the findings to this framework. This paper highlights the fact that currently, titration of therapy in PD is geared to optimizing dorsal striatum-mediated motor symptoms, at the expense of ventral striatum operations. Increased awareness of contrasting effects of dopamine replacement on dorsal versus ventral striatum functions will lead clinicians to survey a broader range of symptoms in determining optimal therapy, taking into account both those aspects of cognition that will be helped versus those that will be hindered by dopaminergic treatment.
... This suggests that a certain dopaminergic overdose may occur not only in the frontostriatal orbital circuit but, more generally, in the cerebral hemisphere less affected by the dopaminergic reduction. There is a possible asymmetry of the dopaminergic decrease between the two hemispheres that can affect patients with PD at the level of the general cognitive profile [84], the attention and executive functions [85], and memory [86], while many cognitive functions have asymmetric neural correlates. However, few studies have investigated the direct relationship between dopamine agonist therapy and cognitive functions. ...
The main histopathological hallmarks of Parkinson's disease (PD) are the degeneration of the dopaminergic neurons of the substantia nigra pars compacta and the loss of neuromelanin as a consequence of decreased dopamine synthesis. The destruction of the striatal dopaminergic pathway and blocking of striatal dopamine receptors cause motor deficits in humans and experimental animal models induced by some environmental agents. In addition, neuropsychiatric symptoms such as mood and anxiety disorders, hallucinations, psychosis, cognitive impairment, and dementia are common in PD. These alterations may precede the appearance of motor symptoms and are correlated with neurochemical and structural changes in the brain. This paper reviews the most crucial pathophysiology of neuropsychiatric alterations in PD. It is worth noting that PD patients have global task learning deficits, and cognitive functions are compromised in a way is associated with hypoactivation within the striatum, anterior cingulate cortex, and inferior frontal sulcus regions. An appropriate and extensive neuropsychological screening battery in PD must accurately assess at least five cognitive domains with some tests for each cognitive domain. This neuropsychological screening should consider the pathophysiological and clinical heterogeneity of cognitive dysfunction in PD.
... One of the many explanations for the motor asymmetry observed in these patients is the imbalance of dopamine levels between brain hemispheres [7,8]. However, dopamine imbalance has been shown to influence many non-motor symptoms of PD [9], including cognitive deficits [10,11]. ...
Background:
Parkinson's disease (PD) is characterized by a progressive loss of nigrostriatal dopaminergic neurons with impaired motor and non-motor symptoms. It has been suggested that motor asymmetry could be caused due to an imbalance in dopamine levels, as visualized by dopamine transporter single emission computed tomography test (DAT-SPECT), which might be related to indirect measures of neurodegeneration, evaluated by the Montreal Cognitive Assessment (MOCA) and α-synuclein levels in the cerebrospinal fluid (CSF). Therefore, this study aimed to understand the correlation between disease laterality, DAT-SPECT, cognition, and α-synuclein levels in PD.
Methods:
A total of 28 patients in the moderate-advanced stage of PD were subjected to neurological evaluation, TRODAT-1-SPECT/CT imaging, MOCA, and quantification of the levels of α-synuclein.
Results:
We found that α-synuclein in the CSF was correlated with global cognition (positive correlation, r2 = 0.3, p = 0.05) and DAT-SPECT concentration in the putamen (positive correlation, r2 = 0.4, p = 0.005), and striatum (positive correlation, r2 = 0.2, p = 0.03), thus working as a neurodegenerative biomarker. No other correlations were found between DAT-SPECT, CSF α-synuclein, and cognition, thus suggesting that they may be lost with disease progression.
Conclusions:
Our data highlight the importance of understanding the dysfunction of the dopaminergic system in the basal ganglia and its complex interactions in modulating cognition.
... In this regard, it has been reported that patients with right hemisphere deficits had greater motor and cognitive improvements after dopaminergic treatment. 6,37 Unlike prior investigations, 6,37 we did not find any significant interaction between dopaminergic hemispheric asymmetry and PD-replacement therapy despite our results showing a mild tendency for patients with PD-right to have a higher levodopa intake over time (P = 0.151), which would be aligned with a previous study. 6 The reasons for this inconsistent result may be complicated by the different staging of the disease across studies as well as the assessment of PD lateralization based on motor onset symptoms 6,37 rather than DAT imaging. ...
Background:
Asymmetric hemispheric loss of dopaminergic neurons is one of the characteristic features of Parkinson's disease (PD). However, it is still debated if right or left asymmetry differently affects cognitive and motor progression.
Objectives:
The objective of this study was to investigate, for the first time, the relevance of dopamine transporter (DAT) asymmetry on cognitive and motor manifestations at onset and at 4-year progression in drug-naïve PD.
Methods:
From the Parkinson's Progression Markers Initiative multicenter cohort, we identified 249 right-handed patients with PD with baseline asymmetry greater than 20% in putamen DAT binding at single-photon emission computed tomography. A predominant putamen asymmetry was found on the left in 143 patients (PD-left), and on the right side in 106 patients (PD-right); we compared them with 196 healthy controls. Patients were followed longitudinally (2-year and 4-year visits), examining their clinical, cognitive, and imaging data.
Results:
At baseline, the PD-left group showed worse performance on the Symbol Digit Modality Test, an attention and processing-speed test, and lower cerebrospinal fluid β-amyloid levels than the PD-right group. These differences were maintained at follow-up, declining over time in both groups. By contrast, the PD-right group showed greater motor impairment at baseline, which increased over 4 years. Striatal DAT binding decreased over time in both groups, but the PD-right group showed a steeper decline, particularly during the first 2-year follow-up. Putaminal asymmetry assessed at baseline was maintained over time.
Conclusions:
These findings suggest that hemispheric asymmetric dopaminergic denervation influences PD cognitive and motor performance as well as progression. Predominant right hemisphere nigrostriatal dopaminergic loss is associated with greater motor severity, whereas more pronounced left hemisphere denervation affects cognitive manifestations at onset and their progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
... Effects of PD and dopaminergic therapy on pattern and association learning are somewhat complex. The vast majority of studies, however, find that at the baseline, patients with PD perform sequence (Kwak et al., 2010) and association learning normally relative to age-matched controls (De Wit et al., 2011;Sharp et al., 2016) and this normal performance is actually worsened by dopaminergic therapy (Cools, 2001, 2006, Cools et al., 2003Feigin et al., 2003;Graef et al., 2010;Hiebert et al., 2014bHiebert et al., , 2019Jahanshahi et al., 2010;Levy-Gigi et al., 2019;MacDonald et al., , 2013Seo et al., 2010;Shohamy et al., 2004Shohamy et al., , 2006Swainson et al., 2000;Tomer et al., 2007;Torta et al., 2009;Tremblay et al., 2010;Vo et al., 2014; for reviews see; . Dopaminergic therapy also worsens association learning in healthy elderly (Vo et al., 2018;Breitenstein et al., 2006;Mehta et al., 2001;Santesso et al., 2009) and younger (Hiebert et al., 2014b;Vo et al., 2017Vo et al., , 2016 controls. ...
Processing regular patterns in auditory scenes is important for navigating complex environments. Electroencephalography 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 with dopaminergic therapy affect this fundamental function remain unknown. We addressed this knowledge gap. Healthy younger and older adults and patients with PD listened to sounds that contained or were devoid of regular patterns. Healthy older adults and patients with PD were tested twice-off and on dopaminergic medication, in counterbalanced order. Regularity-evoked, sustained electroencephalography activity was reduced in older, compared with younger adults. Patients with PD and older controls evidenced comparable attenuation of the sustained response. Dopaminergic therapy further weakened the sustained response in both older controls and patients with PD. These findings suggest that fundamental regularity processing is impacted by aging but not specifically by PD. The finding that dopaminergic therapy attenuates rather than improves the sustained response coheres with the dopamine overdose response and is in line with previous findings that regularity processing implicates brain regions receiving dopamine from the ventral tegmental area that is relatively spared in PD and normal aging.
... These researchers concluded that damage to right-hemisphere dopamine systems plays a greater role in associated cognitive decline than left-hemisphere depletion. Optimal treatment for these symptoms may involve administering different amounts of dopaminergic medication to each hemisphere (Tomer, Aharon-Peretz, & Tsitrinbaum, 2007). ...
Elucidating how dopamine neurons operate regularly in aspects of neurochemical release and in pathological systems is essential for understanding their role in behavior, drug treatment, and disease. Fixed-potential amperometry (FPA) combined with carbon fiber microelectrodes has proven to be effective at probing these dynamic microsystems and precisely describing the regulatory mechanisms that govern dopamine neurotransmission. To date, we have utilized FPA to: a) observe and quantify differences in the neurochemical profile of phasic dopamine release in major dopaminergic afferents including the striatum, nucleus accumbens (NAc), amygdala, and prefrontal cortex through stimulation of the medial forebrain bundle (MFB), b) provide evidence that differing behavioral processes in the brain emerge from spatial and temporal variations in the phasic response, and c) identify a pathway originating in the cerebellar dentate that projects to nigrostriatal and mesolimbic systems, solidifying the role of the cerebellum in higher cognitive functions and neuropathology related to dopamine dysfunction. These findings provide evidence that the cerebellum regulates dopamine release in the cerebrum, and previous literature has shown that dopaminergic systems in the bilateral cerebral hemispheres contribute asymmetrically to behavior, structure, and function. To determine whether asymmetrical lateralization in the dopaminergic system occurs at the level of the cerebellum, cerebrum, or both, FPA was used to examine asymmetry of dopamine release in the dentate nucleus (DN)-NAc and MFB-NAc pathways. We found significant differences in the amplitude of phasic dopamine release in the DN-NAc systems, but not the MFB-NAc pathways. Results from this study support the notion that reward processes in the brain may be lateralized between cerebrocerebellar networks, with greater phasic release occurring in projections from the left cerebellar DN to the right NAc. These studies may provide more detailed information about the relationship between the cerebrocerebellar networks and lateralization of the dopaminergic system as well as potentially reveal novel targets for pharmacological interventions in neuropathology of the cerebellum.
Chapter 2 has been published in the journal Synapse:
Holloway, Z. R., Freels, T. G., Comstock, J. F., Nolen, H. G., Sable, H. J., & Lester, D. B. (2018). Comparing phasic dopamine dynamics in the striatum, nucleus accumbens, amygdala, and medial prefrontal cortex. Synapse, 73(2), e22074. doi:10.1002/syn.22074 Copyright ©
... The lateralization of motor symptoms is associated with a more severe contralateral degeneration of dopaminergic neurons (Haaxma et al., 2010), which is in turn responsible for a hypodopaminergic state in the striatum and frontal regions (Marie et al., 1995;Mattay et al., 2002;Cheesman et al., 2005). The correlation between dopamine innervation and expression of cognitive capacities (Nieoullon, 2002) indicates that dopaminerelated asymmetry could impact on cognitive resources (Huber et al., 1989;St Clair et al., 1998;Tomer et al., 2007;Verreyt et al., 2011;Erro et al., 2013;Poletti et al., 2013;Pellicano et al., 2015). Different cross-sectional studies explored this topic both in drug naïve and medicated PD patients at different disease stages, yielding mixed results. ...
Background: Attention is crucial to voluntary perform actions in Parkinson’s disease (PD), allowing patients to bypass the impaired habitual motor control. The asymmetrical degeneration of the dopaminergic system could affect the attentional functions.
Objective: To investigate the relationship between the asymmetric dopaminergic degeneration and the attentional resources in Parkinsonian patients with right-side (RPD) and left-side (LPD) motor symptoms predominance.
Methods: 50 RPD, 50 LPD, and 34 healthy controls underwent visual (V), auditory (A), and multiple choices (MC) reaction time (RTs) tasks. For PD patients, these tasks were performed before and after a 4-week intensive, motor-cognitive rehabilitation treatment (MIRT). The effectiveness of treatment was evaluated assessing Unified Parkinson’s disease Rating Scale (UPDRS) III and Timed-up and Go Test (TUG).
Results: RTs did not differ between PD patients and healthy controls. Before MIRT, no differences between LPD and RPD patients were observed in RTs (p = 0.20), UPDRS III (p = 0.60), and TUG (p = 0.38). No differences in dopaminergic medication were found between groups (p = 0.44 and p = 0.66 before and after MIRT, respectively). After MIRT, LPD patients showed a significant reduction in MC RTs (p = 0.05), V RTs (p = 0.02), and MC-V RTs. A significant association between changes in RTs and improvements in UPDRS III and TUG was observed in LPD patients.
Conclusion: attention does not differ among RPD patients, LPD patients and healthy controls. Only LPD patients improved their performances on attentional tasks after MIRT. We argue that the increased early susceptibility of the left nigrostriatal system to degeneration affects differently the cognitive modifiability and the neuroplastic potential. Our results could provide insight into new therapeutic approaches, highlighting the importance to design different treatments for RPD patients and LPD patients.
... Reactive and spontaneous flexibility has been behaviourally and neurally dissociated in previous empirical work (e.g. Cools, Brouwer, De Jong, & Slooff, 2000;Parkin & Lawrence, 1994;Tomer et al., 2002Tomer et al., , 2007. An additional measure of cognitive flexibility is the Remote Associates Test (RAT; Mednick, 1962Mednick, , 1968, which tests the flexibility of one's semantic networks by assessing individuals' capacity to flexibly retrieve semantic associations between remote conceptual representations (Alexander, Hillier, Smith, Tivarus, & Beversdorf, 2007;Isen, 1990;Ishizuka, Hillier, & Beversdorf, 2007;Zmigrod & Zmigrod, 2016;Zmigrod, Zmigrod, & Hommel, 2015). ...
Cognitive flexibility is operationalized in the neuropsychological literature as the ability to shift between modes of thinking and adapt to novel or changing environments. Religious belief systems consist of strict rules and rituals that offer adherents certainty, consistency, and stability. Consequently, we hypothesized that religious adherence and practice of repetitive religious rituals may be related to the persistence versus flexibility of one’s cognition. The present study investigated the extent to which tendencies towards cognitive flexibility versus persistence are related to three facets of religious life: religious affiliation, religious practice, and religious upbringing. In a large sample (N = 744), we found that religious disbelief was related to cognitive flexibility across three independent behavioural measures: the Wisconsin Card Sorting Test, Remote Associates Test, and Alternative Uses Test. Furthermore, lower frequency of religious service attendance was related to cognitive flexibility. When analysing participants’ religious upbringing in relation to their current religious affiliation, it was manifest that current affiliation was more influential than religious upbringing in all the measured facets of cognitive flexibility. The findings indicate that religious affiliation and engagement may shape and be shaped by cognitive control styles towards flexibility versus persistence, highlighting the tight links between flexibility of thought and religious ideologies.
... Thus, DRT would be detrimental on subsets of cognitive functions mediating learning activities based on the integration of environment feedback with ongoing behavior. This dichotomy is somehow consistent with previous observations that DRT improves cognitive functions mediated by the dorsal striatum, such as selective attention, category judgment, time estimation, visual-spatial processing, implicit and explicit retrieval, set shifting and task switching [37] [39] [40] [51] but impairs functions mediated by the ventral striatum such as implicit and explicit learning, impulsivity, reversal learning and orienting to stimuli [52] [53] [54]. These neuropsychological findings parallel the different pathological involvement of the dorsal and ventral striatum in PD. ...
Cognitive impairment is a frequent non-motorsymptom of Parkinson’s disease (PD). In early disease stage, this takes the features of dysexecutive syndrome, and is mostly dependent on derangement of frontostriatal circuitries. In advanced stages, worsening of dysexecutive symptoms is accompanied by disorientation and memory deficit leading to dementia in 30% of cases, due to multiple neurotransmitter derangement. Dysexecutive symptoms in the early stages of PD may benefit from dopamine replacement therapy (DRT). Conversely, severe cognitive symptoms in more advanced stages are frequently aggravated by DRT. In particular, pulsatile stimulation of dopaminergic receptors by orally administered levodopa (LD) plays a significant negative role on cognitive and neuropsychiatric symptoms in advanced PD. The introduction of a gel of LD-carbidopa for continuous intestinal administration (LCIG) allows marked stabilization of plasma LD concentrations and provides benefit on motor fluctuations and dyskinesia of significantly greater magnitude than conventional oral administration in advanced PD patients. The results from several preliminary studies suggest that efficacy of LCGI on motor symptoms may be accompanied by good tolerability and potential benefit on several non-motor symptoms, including cognitive impairment. Future studies with longer observation period and larger cohorts are advised to confirm these preliminary observations.
... In contrast, medication appears to worsen those cognitive functions mediated by VTAinnervated brain regions, presumably due to dopamine overdose of these dopamine-replete areas [2,[4][5][6][7]. Investigations in PD on versus off medication have found impairments in probabilistic associative [10,11], sequence [12][13][14][15], stimulus-reward and reversal learning [1,[16][17][18][19][20], as well as explicit abstract figure and list learning [21] , stimulus-stimulus facilita- tion [2], and learning from negative feedback [3]. Consistent with the dopamine overdose hypothesis, these learning functions have been shown empirically to correlate with [2,[22][23][24][25]or depend upon [26,27] VTA-innervated brain regions. ...
... It has been suggested that DA treatment causes brain regions that are normally less affected by the loss of DA neurons to experience a "DA overdose" which then disrupts the cognitive functions they perform (Cools and D'Esposito 2011). Interestingly, DA treatment in PD patients with asymmetric loss of DA neurons between hemispheres resulted in separate cognitive deficits, suggesting distinct effects caused by DA overdosing of the left or the RH (Tomer et al. 2007). Additionally, deep-brain stimulation (DBS) of the left subthalamic nucleus, a procedure known to mimic enhanced DA function in the LH (Palminteri et al. 2013), negatively influenced creativity in one artist suffering from PD. Specifically, DBS caused a reduced appreciation of the quality of another artist's paintings and lower scores on a divergent thinking task (Drago et al. 2009b), as well as a significant reduction in the quality and creative style of the artist's own paintings (Drago et al. 2009a). ...
The idea that creativity resides in the right cerebral hemisphere is persistent in popular science, but has been widely frowned upon by the scientific community due to little empirical support. Yet, creativity is believed to rely on the ability to combine remote concepts into novel and useful ideas, an ability which would depend on associative processing in the right hemisphere. Moreover, associative processing is modulated by dopamine, and asymmetries in dopamine functionality between hemispheres may imbalance the expression of their implemented cognitive functions. Here, by uniting these largely disconnected concepts, we hypothesize that relatively less dopamine function in the right hemisphere boosts creativity by releasing constraining effects of dopamine on remote associations. Indeed, participants with reduced neural responses in the dopaminergic system of the right hemisphere (estimated by functional MRI in a reward task with positive and negative feedback), displayed higher creativity (estimated by convergent and divergent tasks), and increased associative processing in the right hemisphere (estimated by a lateralized lexical decision task). Our findings offer unprecedented empirical support for a crucial and specific contribution of the right hemisphere to creativity. More importantly our study provides a comprehensive view on potential determinants of human creativity, namely dopamine-related activity and associative processing.
... Motor deficit asymmetry in individuals with PD correlates with their substantia nigra volumes and is associated with poorer spatial memory [5]. DA deficiency in the right hemisphere corresponded mainly to left-side disturbances of motor function and vice versa [12]. Next step was made to test the hypothesis about possible relations between incentive motivation in healthy volunteers and asymmetry of D 2 receptor distribution in striatum [9]. ...
Parkinson's disease (PD) is a common neurodegenerative disease which is characterized by a progressive degeneration of dopaminergic neurons in the midbrain. A most reliable mechanism causing the apoptosis in dopaminergic structures of the brain during aging and Parkinson's disease is the activation of oxidative stress. Until now, effective means for the prevention of dopaminergic neurons degeneration and for the retention of damaged neurons functioning is still lacking. A promising way to slacken the pace of degenerative processes during aging and PD could be the adaptation to intermittent hypoxia. Such adaptation strengthens dopamine (DA) synthesis and release at peripheral chemoreceptors in carotid bodies and activates tyrosine hydroxylase - a rate-limiting enzyme for catecholamine synthesis. In this chapter, we examined three groups of rats: adult, old, and old rats with experimental DA deficiency. It was revealed that there was an asymmetry of dopamine distribution between the right and left striatum of adult rats. Prevalent quantity of dopamine was concentrated in right hemisphere. During aging DA, production decreased in the examined structures mainly in right hemisphere of the striatum, so its distribution asymmetry diminished. In PD animals, this decrease was much more expressed and led to practically total abolishment of quantitative difference between right and left hemispheres. Two-week course of intermittent hypoxia training (IHT, five cycles of 15-min exposures to 12% O2 followed by 15-min room air breathing per day) increased dopamine synthesis in old and experimental PD animals, especially in the right striatum, restored partially the asymmetry of DA distribution between brain hemispheres. IHT also decreased the intensity of lipid peroxidation. Increased plasma antioxidant activity positively correlated with increased DA concentration in the striatum. Therefore, IHT could serve as a good perspective means for the deceleration of aging and prevention/treatment of Parkinson's disease.
... Dopamine supplementation yielded reduced facilitation for consecutive, consistent stimulusstimulus pairings in a selection task compared to normal facilitation when PD patients were tested off medication [4]. Once stimulus-reward associations have been learned, reversing these associations is also performed more poorly for PD patients on dopamine replacement therapy [6,[77][78][79][80][81][82][83]. Dopamine therapy has been shown to impair learning from negative feedback [84]. ...
Increasingly memory deficits are recognized in Parkinson's disease (PD). In PD, the dopamine-producing cells of the substantia nigra (SN) are significantly degenerated whereas those in the ventral tegmental area (VTA) are relatively spared. Dopamine-replacement medication improves cognitive processes that implicate the SN-innervated dorsal striatum but is thought to impair those that depend upon the VTA-supplied ventral striatum, limbic and prefrontal cortices. Our aim was to examine memory encoding and retrieval in PD and how they are affected by dopamine replacement. Twenty-nine PD patients performed the Rey Auditory Verbal Learning Test (RAVLT) and a non-verbal analogue, the Aggie Figures Learning Test (AFLT), both on and off dopaminergic medications. Twenty-seven, age-matched controls also performed these memory tests twice and their data were analyzed to correspond to the ON-OFF order of the PD patients to whom they were matched. We contrasted measures that emphasized with those that accentuated retrieval and investigated the effect of PD and dopamine-replacement on these processes separately. For PD patients relative to controls, encoding performance was normal in the off state and was impaired on dopaminergic medication. Retrieval was impaired off medication and improved by dopamine repletion. This pattern of findings suggests that VTA-innervated brain regions such as ventral striatum, limbic and prefrontal cortices are implicated in encoding, whereas the SN-supplied dorsal striatum mediates retrieval. Understanding this pattern of spared functions and deficits in PD, and the effect of dopamine replacement on these distinct memory processes, should prompt closer scrutiny of patients' cognitive complaints to inform titration of dopamine replacement dosages along with motor symptoms.
... Some evidences resulting from studies assessing patients on-and off-medication or comparing treated and untreated patients have suggested that the negative effect on cognitive performance in early PD might reflect over-medication of the less affected dopaminergic projections to cortex [28,29]. Interestingly, the direct dopaminergic projection to the prefrontal cortex seems to be hyperactive early in the course of the disease [30,31], presumably as a compensatory mechanism. ...
... Positron emission tomography (PET) has revealed reduced blood flow in the globus [35], the caudate, and the dorsolateral frontal cortex of PD patients compared to controls in response to activation with the Tower of London task [36], which is improved by levodopa [37]. In the very early stages of PD, dopaminomimetics may, however, lead to executive dysfunction; for example, reversal errors may be related to the hyperdopaminergic state of the relatively intact hemisphere resulting from dopaminergic replacement therapy in patients with early PD and unilateral motor symptom onset [38]. Executive deficits have also been linked to cholinergic deficits observed on functional neuroimaging [39]. ...
Movement disorders fall into two broad categories: hypokinetic and hyperkinetic. Hypokinetic disorders involve a paucity of
voluntary movement and are exemplified by Parkinson’s disease and related parkinsonian disorders such as progressive supranuclear
palsy and multiple system atrophy; in contrast, hyperkinetic disorders are characterized by excessive involuntary movements,
a classic example of which is Huntington’s disease (HD). These disorders all involve basal ganglia and/or cerebellum, and
the cortical–basal ganglionic–thalamic–cortical pathophysiologies of the various disorders have been well described [1]. Motor
neuron disorders are not classified as movement disorders. These disorders are grouped into upper and lower motor neuron disorders.
Upper motor neuron disease is characterized by signs such as weakness, increased muscle tone, and hyperreflexia, whereas lower
motor neuron disease is characterized by weakness, loss of reflexes, loss of muscle tone, fasciculations, and muscular atrophy.
Although patients afflicted by motor neuron disease may have difficulty moving limbs due to weakness (for example, brushing
their teeth due to upper extremity proximal weakness), they do not have a movement disorder per se. The best known motor neuron
disease is amyotrophic sclerosis (ALS) or Lou Gehrig’s disease. This chapter describes the more important movement and motor
neuron disorders, specifically Parkinson’s disease, progressive supranuclear palsy, essential tremor, Huntington’s disease,
and ALS and highlights the pathophysiology and neurobehavioral features of each condition.
... The striatum is highly asymmetric. In Parkinson's disease patients exhibiting unilateral motor symptom onset, preservative errors on the WCST have been associated with left-onset Parkinson's disease (Tomer, Aharon-Peretz, & Tsitrinbaum, 2007), suggesting that dopaminergic activity in the right hemisphere plays a larger role in set-shifting (Tomer, Levin, & Weiner, 1993). Other studies also observed greater right frontal cortex activity during set-shifting (Aron, Robbins, & Poldrack, 2004;Swainson et al., 2003). ...
Cognitive flexibility or the ability to change behavior in response to external cues is conceptualized as two processes: one for shifting between perceptual features of objects and another for shifting between the abstract rules governing the selection of these objects. Object and rule shifts are believed to engage distinct anatomical structures and functional processes. Dopamine activity has been associated with cognitive flexibility, but patients with dopaminergic deficits are not impaired on all tasks assessing cognitive flexibility, suggesting that dopamine may have different roles in the shifting of objects and rules. The goals of this study were to identify brain regions supporting object and rule shifts and to examine the role of dopamine in modulating these two forms of cognitive flexibility. Sixteen young, healthy volunteers underwent fMRI while performing a set-shift task designed to differentiate shifting between object features from shifting between abstract task rules. Participants also underwent PET with 6-[¹⁸F]-fluoro-l-m-tyrosine (FMT), a radiotracer measuring dopamine synthesis capacity. Shifts of abstract rules were not associated with activation in any brain region, and FMT uptake did not correlate with rule shift performance. Shifting between object features deactivated the medial PFC and the posterior cingulate and activated the lateral PFC, posterior parietal areas, and the striatum. FMT signal in the striatum correlated negatively with object shift performance and deactivation in the medial PFC, a component of the default mode network, suggesting that dopamine influences object shifts via modulation of activity in the default mode network.
... It is also important to consider that PD patients frequently present with asymmetric motor symptoms, suggesting that in the early phases of the disease the dopamine depletion often involves one hemisphere more than the other. The neuropsychological study of how dopamine asymmetries impact cognitive functioning is at an early stage and its findings are still controversial [39,61,99]. Considering dopamine asymmetries in PD and asymmetries in the neural correlates of some ToM processes, as shown by lesion studies (for example, the role of the right ventromedial prefrontal cortex in the detection of faux pas in social situations [94]), we suggest that future research should compare performances of different subgroups (left motor onset, right motor onset, bilateral motor onset) of PD patients in tasks of social cognition and ToM. ...
The ability to infer other people's mental states (i.e. Theory of Mind, ToM) is a major topic of interest in various neurological and psychiatric disorders. However, it is only recently that there has been an assessment of cognitive and affective components of ToM ability in neurodegenerative disorders. In this review, we examine studies investigating the ToM ability in Parkinson's disease (PD). Taken together, these studies provide preliminary evidence that ToM difficulties may occur in PD patients. In particular, these difficulties principally involve the cognitive component of ToM in the early stages of the disease. The spatio-temporal progression of dopamine depletion supports the hypothesis that the affective component may only be affected in the advanced stages of the disease. The relationships between executive functioning, dopaminergic therapies, and ToM in PD as well as the relationships between frontostriatal circuits and ToM processing are discussed.
... This asymmetry influences the therapeutic effects of dopaminergic drugs on motor symptoms, which are better improved in PD patients with right hemibody onset (Foster et al., 2009). The dopamine depletion asymmetry is also an influence, even if empirical findings are preliminary and partially different, probably due to the tasks adopted for the cognitive assessment (Cooper et al., 2009; Katzen et al., 2006; Tomer, Aharon-Peretz, & Tsitrinbaum, 2007 ). The dopamine depletion asymmetry also suggests that, in early stages of PD, the treatment with l-dopa could overdose not only the orbital frontostriatal circuit (Cools, 2006) but also the brain hemisphere less affected by the dopamine depletion. ...
Cognitive impairments are common in patients with Parkinson's disease (PD) from the early stages. Recent studies reported that medicated PD patients have poor performances, with respect to age-matched healthy controls, in a decision-making task like the Iowa Gambling Task (IGT), which detects the ability to alter choice behavior in response to fluctuations in reward contingencies. The IGT principally activates functions related to the orbitofrontal cortex, which plays a crucial role in the generation of outcome expectancies and processing of rewards. The analysis of IGT performances of PD patients is of particular interest because PD represents a good clinical model to study reward processing when its neural bases are affected by a neuropathology or are overdosed by dopaminergic therapies. As a matter of fact, either PD-related neuropathology in advanced stages of the disease or the dopamine replacement therapy from earlier stages of PD may affect the functioning of the orbitofrontal cortex. Three causal hypotheses on a dysfunctional decision making in PD patients, as assessed by IGT, are discussed. Finally, the possible relation between the phenomenon of decision-making impairment and impulse control disorders, a psychiatric complication observed with increasing frequency in PD patients, is discussed.
... Rule shifting is determined either through the number of errors made on this phase, the number of trials required before the participant reaches criterion, or the percentage of participants who reach criterion. Each of these methods indicate rule shifting impairment in PD (Downes et al., 1989;Gauntlett-Gilbert, Roberts & Brown, 1999;Lange et al., 1992;Slabosz et al, 2006;Tomer, Aharon-Peretz, & Tsitrinbaum, 2007). ...
Measures of explicit rule-based category learning are commonly used in neuropsychological evaluation of individuals with Parkinson's disease (PD) and the pattern of PD performance on these measures tends to be highly varied. We review the neuropsychological literature to clarify the manner in which PD affects the component processes of rule-based category learning and work to identify and resolve discrepancies within this literature. In particular, we address the manner in which PD and its common treatments affect the processes of rule generation, maintenance, shifting and selection. We then integrate the neuropsychological research with relevant neuroimaging and computational modeling evidence to clarify the neurobiological impact of PD on each process. Current evidence indicates that neurochemical changes associated with PD primarily disrupt rule shifting, and may disturb feedback-mediated learning processes that guide rule selection. Although surgical and pharmacological therapies remediate this deficit, it appears that the same treatments may contribute to impaired rule generation, maintenance and selection processes. These data emphasize the importance of distinguishing between the impact of PD and its common treatments when considering the neuropsychological profile of the disease.
... However , their elevated scores were within the normal range and most likely reflect inflation due to the somatic items of the questionnaire which are affected as part of the physical symptoms of PD. Previous studies have shown that the interpretability and significance of PD patient performance depends critically on the specific characteristics of any given patient sample, including age (Aarsland, Tandberg, Larsen, & Cummings, 1996 ), gender distribution (Kaasinen et al., 2001), predominant motor symptom type (Zetusky, Jankovic, & Pirozzolo, 1985), laterality (Cheesman et al., 2005; Tomer, Aharon-Peretz, & Tsitrinbaum, 2007) and subtype (Graham & Sagar, 1999; Lewis, Foltynie, et al., 2005) which may be linked to particular genetic polymorphisms (Foltynie, Sawcer, Brayne, & Barker, 2002; Williams-Gray, Hampshire, Barker, & Owen, 2008). While the effects of disease severity have been previously addressed (Owen et al., 1992Owen et al., , 1993), the present study is the first to relate severity-dependent task switching deficits to a parametric disease measure, namely total UPDRS score, although Hoehn & Yahr stage was not sensitive to differences between patients. ...
This study sought to disambiguate the impact of Parkinson's disease (PD) on cognitive control as indexed by task set switching, by addressing discrepancies in the literature pertaining to disease severity and paradigm heterogeneity. A task set is governed by a rule that determines how relevant stimuli (stimulus set) map onto specific responses (response set). Task set switching may entail reconfiguration in either or both of these components. Although previous studies have shown that PD patients are impaired at switching between stimuli, in the present study not all patients were impaired at switching entire task sets, that is, both stimulus and response sets: compared with controls, patients with unilateral signs (Hoehn & Yahr Stage I) demonstrated intact switching, even following withdrawal from dopaminergic medication, while bilaterally affected Stage II patients were impaired. The parametric measure of Unified Parkinson's Disease Rating Scale (UPDRS) score predicted increasing switch costs within the patient group. These findings suggest that switching entire task sets may be a function of extrastriatal, possibly non-dopaminergic pathology which increases as the disease progresses.
... We hypothesize that overall increased NoGo signals in the BG prevented non-medicated patients from updating information into WM, causing deficits across all performance phases. Along the same lines, Cools et al. (2006) found that medicated, but not unmedicated, PD patients were impaired at probabilistic reversal learning (also see Tomer, Aharon-Peretz, & Tsitrinbaum, 2007 for similar results). According to our models, this is possibly due to impairment in NoGo learning since reversal learning requires suppressing a habitual response as well as selecting another response (Frank, 2005). ...
Parkinson's disease (PD) patients exhibit cognitive deficits, including reinforcement learning, working memory (WM) and set shifting. Computational models of the basal ganglia-frontal system posit similar mechanisms for these deficits in terms of reduced dynamic range of striatal dopamine (DA) signals in both medicated and non-medicated states. Here, we report results from the first study that tests PD patients on and off dopaminergic medications in a modified version of the AX continuous performance (AX-CPT) working memory task, consisting of three performance phases and one phase requiring WM associations to be learned via reinforcement feedback. Patients generally showed impairments relative to controls. Medicated patients showed deficits specifically when having to ignore distracting stimuli during the delay. Our models suggest that this impairment is due to medication causing excessive WM updating by enhancing striatal "Go" signals that facilitate such updating, while concurrently suppressing "NoGo" signals. In contrast, patients off medication showed deficits consistent with an overall reduction in striatal DA and associated Go updating signals. Supporting this dichotomy, patients on and off medication both showed attentional shifting deficits, but for different reasons. Deficits in non-medicated patients were consistent with an inability to update the new attentional set, whereas those in medicated patients were evident when having to ignore distractors that had previously been task relevant. Finally, in the feedback-based WM phase, medicated patients were better than unmedicated patients, suggesting a key role of striatal DA in using feedback to update information into WM. These results lend further insight into the role of basal ganglia dopamine in WM and broadly support predictions from neurocomputational models.
... Parkinson's disease (PD) typically has an asymmetric onset of motor symptoms (tremor, bradykinesia, rigidity), and this asymmetry, which persists throughout the disease, 1 may reflect asymmetrical nigrostriatal dysfunction. 2 Lateralized cognitive deficits, 3,4 in contrast, are postulated to reflect an asymmetrically decreased cortical dopaminergic tone. 5 Brain atrophy and ventricular enlargement consequent to neurodegenerative cell loss is associated with cognitive deficits in PD. 6,7 The extent to which lateral ventricular enlargement and asymmetries relate to motor symptom asymmetries is unknown, but such a relationship might reasonably be hypothesized, given that the lateral ventricles are surrounded by basal ganglia and downstream structures (thalamus and frontal lobe) affected by PD. ...
Parkinson's disease (PD) typically manifests with asymmetric motor symptom onset. Ventricular enlargement, a nonspecific measure of brain atrophy, has been associated with cognitive decline in PD, but not with motor symptom asymmetry. Asymmetrical ventricular enlargement on magnetic resonance images was explored in a monozygotic twin pair discordant for PD and in nine healthy monozygotic twin pairs. The left-right lateral ventricular volumetric difference of the PD-twin was greater than that of his twin and all other healthy twins, with the larger ventricle observed contralateral to the more symptomatic side. Moreover, the lateral ventricle asymmetry difference between twin pairs was significantly higher for the discordant PD-twin pair than for the healthy twin pairs. This is the first report to suggest the presence of asymmetrical ventricular enlargement in PD, findings that may be worthy of further study.
... Other limitations include the relatively small sample size and the possibility that PD medications could have influenced behavior. The relationship between dopaminergic medication and cognition is complex (for review, see Cools, 2006) and a recent study has shown that dopaminergic medication may interact with asymmetry to influence cognitive function in PD (Tomer, Aharon-Peretz, & Tsitrinbaum, 2007). Nevertheless, our cognitive findings did not differ according to medication status. ...
Studies suggest motor deficit asymmetry may help predict the pattern of cognitive impairment in individuals with Parkinson disease (PD). We tested this hypothesis using a highly validated and sensitive spatial memory task, spatial delayed response (SDR), and clinical and neuroimaging measures of PD asymmetry. We predicted SDR performance would be more impaired by PD-related changes in the right side of the brain than in the left. PD (n=35) and control (n=28) participants performed the SDR task. PD participants either had worse motor deficits on the right (RPD) or left (LPD) side of the body. Some participants also had magnetic resonance imaging for measurement of their substantia nigra (SN) volumes. The LPD group performed worse on the SDR task than the RPD and control groups. Right SN volume accounted for a unique and significant portion of the variance in SDR error, with smaller volume predicting poorer performance. In conclusion, left motor dysfunction and smaller right SN volume are associated with poorer spatial memory.
... In addition, there are at present no precise guidelines about which tests would be used to ascertain MCI, or about which of the multitudinous scores yielded by many tests would have to fall 1.5 standard deviations below the normative mean. Fifth, performance on neuropsychological tests can be affected by dopaminergic medications used to treat PD (Cools 2006), and especially in early PD, when one hemisphere may be preferentially affected by disease, overmedication of the relatively intact hemisphere can affect test performance (Tomer et al. 2007), making identification of MCI difficult. Sixth, depression (which is common in PD) can exacerbate cognitive impairment Tröster et al 1995) and in practice it is difficult to distinguish with a single neuropsychological assessment whether cognitive impairment in PD reflects depression or MCI. ...
Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are neurodegenerative conditions sharing a disorder of alpha-synuclein metabolism. Temporal differences in the emergence of symptoms and clinical features warrant the continued clinical distinction between DLB and PDD. While DLB and PDD groups' neuropsychological profiles often differ from those in Alzheimer's disease (AD), the diagnostic sensitivity, specificity, and predictive values of these profiles remain largely unknown. PDD and DLB neuropsychological profiles share sufficient similarity to resist accurate and reliable differentiation. Although heterogeneous cognitive changes (predominantly in memory and executive function) may manifest earlier and more frequently than previously appreciated in Parkinson's disease (PD), and executive deficits may be harbingers of dementia, the enthusiasm to uncritically extend the concept of mild cognitive impairment (MCI) to PD should be tempered. Instead, future research might strive to identify the precise neuropsychological characteristics of the prodromal stages of PD, PDD, and DLB which, in conjunction with other potential biomarkers, facilitate early and accurate diagnosis, and the definition of neuroprotective, neurorestorative, and symptomatic treatment endpoints.
Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by motor symptoms that initially manifest unilaterally. Whilst some studies indicate that right-side onset is associated with greater symptom severity, others report no differences between right-side and left-side onset patients. The present meta-analysis was thus designed to reconcile inconsistencies in the literature and determine whether side of onset affects PD symptom severity. Following the PRISMA guidelines 1013 studies were initially identified in database and grey literature searches; following title and abstract, and full text, screening 34 studies met the stringent inclusion criteria (n = 2210). Results of the random-effects meta-analysis indicated no difference in symptom severity between PD patients with left-side (n = 1104) and right-side (n = 1106) onset. As such, the meta-analysis suggests that the side of onset should not be used to predict symptom trajectory or to formulate prognoses for PD patients. The current meta-analysis was the first to focus on the relationship between the side of onset and symptom severity in PD. However, the studies included were limited by the common exclusion of left-handed participants. Future research would benefit from exploring other factors that may influence symptom severity and disease progression in PD, such as asymmetric loss of nigrostriatal dopaminergic neurons.
This book proposes a new integrative framework for understanding and promoting creatively adaptive thinking. The mind is not only cognition, narrowly construed, but is deeply intermeshed with action, perception, and emotion. This means that optimal mental agility is realized at the dynamic intersection of environment, brain, and mind. Building on empirical research from the behavioral and brain sciences, from developmental and social psychology, and from neuropsychology, psychopathology, and allied disciplines, this book argues that understanding our agile minds requires that we go beyond dichotomous classifications of cognition as intuitive versus deliberate. When we are optimally creatively adaptive, we are able to adroitly move across not only a wide range of levels of cognitive control, but also across multiple levels of detail. Neither abstraction nor specificity, neither controlled nor automatic processes alone are what is needed. Contextually sensitive variation is essential, including rapidly intermixed modes of cognitive control, if we are to realize our fullest capacities for insightful innovation, fluent improvisation, and flexible thinking.
Abstract
Parkinson's disease (PD), a neurodegenerative disease, has been traditionally defined by its characteristic motor symptoms. Non-motor symptoms, including mood disorder, psychosis, sleep disturbance, autonomic dysfunction, and cognitive impairment, have being recently recognized as symptoms of PD. Cognitive impairment or dementia is one of the critical symptoms during the advanced stages of PD and is associated with increased disability and reduced quality of life of both patients and caregivers. The point prevalence of dementia in PD is about 30%, and its incidence rate in PD patients is 4-6 times higher than that in age-matched controls. The term mild cognitive impairment (MCI) has been adopted to describe the potential prodromal stage of dementia in PD, which has been gaining increasing attention. Several studies have reported the clinical features, epidemiology, biomarkers, and neuropathology of MCI in PD; however, neither the precise definitions nor the employed criteria were consistent across these studies. Recently, the Movement Disorder Society Task Force proposed new diagnostic criteria for MCI in PD to allow clinicians to identify PD patients with increased risk of dementia. Further studies are needed to validate the proposed criteria in daily clinical practice.
In Parkinson's disease (PD), abnormalities of speech rate have been observed in spontaneous speech, reading tasks and syllable repetition tasks. Impaired temporal speech patterns have been contributed to dysfunctional basal ganglia circuits, but little is known about a possible differential role of right and left basal ganglia concerning speech production, although neurodegeneration in PD typically follows an asymmetrical pattern. The aim of our study was to reveal a possible influence of lateralized basal ganglia dysfunction on speech timing in PD.
60 patients with PD (30 with predominant symptoms on the left-side PD_L and 30 with predominant symptoms on the right side PD_R) and 40 healthy controls were tested. Participants had to repeat a single syllable in a self chosen steady pace. Additionally, the participants performed a reading task in order to measure speaking rate related to connected speech.
Syllable repetition showed a significant instability in both PD groups as compared to controls. However, the PD_L group performed in a much higher pace with further significant pace acceleration in the course of the syllable repetition task. This pattern showed a further correlation to axial motor symptoms. No correlations were seen between parameters of syllable repetition and the reading task.
Lateralization of basal ganglia dysfunction in PD seems to differentially impact the stability of spontaneous syllable repetition pace. Our data suggest a crucial role of the right basal ganglia in the maintenance of isochronous speech rhythms at least in patients with additional axial motor symptoms.
At disease onset, patients with Parkinson's disease (PD) typically report one side of the body to be more affected than the other. Previous studies have reported that this motor symptom asymmetry is associated with asymmetric dopaminergic degeneration in the brain. Research on the cognitive repercussions of this asymmetric degeneration has yielded inconsistent results. Here, we review studies that reported on the cognitive performance of patients with left-sided (LPD) or right-sided (RPD) motor symptom predominance. We present evidence that patients with RPD typically experience problems with language-related tasks and verbal memory, whereas patients with LPD more often perform worse on tasks of spatial attention, visuospatial orienting and memory and mental imagery. In general, no differences were found between both groups on tasks measuring attention and executive function. The association between motor asymmetry and cognitive performance indicates that PD does not lead to one typical cognitive profile. The effect of symptom laterality on the cognitive complaints should be considered in the assessment and treatment of each individual patient.
To examine the influence of bilateral motor behaviors on flexibility performance, two studies were conducted. Previous research has shown that when performing unilateral motor behavior that activates the affective and motivational systems of approach versus avoidance (arm flexion vs. extension), it is the congruence between laterality and motor activation that determines flexibility-rigidity functioning (Cretenet & Dru, 2009). When bilateral motor behaviors were performed, a mechanism of embodiment was revealed. It showed that the flexibility scores were determined by the match between the respective qualities of congruence of each of the unilateral motor behaviors performed. These results bring to light an overall embodied mechanism associated with the compatibility of the cognitive impact(s) of each motor behavior performed.
The present study examined how asymmetrical motor symptomatology helps predict the pattern of perceptual judgements of body-scaled aperture width in lateralised Parkinson's disease (PD). Eleven patients with PD predominantly affecting the left side of their body (LPD), 16 patients with PD predominantly affecting their right side (RPD), and 16 healthy controls made forced-choice judgements about whether or not they would fit without turning their shoulders through a life-sized schematic doorway shown on a large screen. Whereas control and LPD groups made accurate estimations of body-scaled aperture width, RPD patients significantly underestimated aperture width relative to their body, perceiving doorways on average that were 12% narrower than their bodies as wide enough to allow them to pass through without rotation. Across all patients, estimates of body-scaled aperture width correlated with ratio of right-to-left symptom severity. These perceptual errors may indicate a mismatch between the neural representation of external space and that of body size in PD.
Cognitive impairment exists in Parkinson's disease (PD) as a transitional state between cognitively intact and demented PD patients. It seems to be a risk factor for the development of dementia in PD, but the precise criteria and unfavorable cognitive profile of mild cognitive impairment in PD (MCI-PD) have not yet been established. The concept may turn to be different from that in Alzheimer's disease since we search for those already diagnosed PD patients who are at risk of developing dementia. In addition, clinical variables specific for PD also play role. Importantly, MCI possesses a metabolic basis in PD. Various biomarkers particularly including neuropsychological testing and the brain imaging hold promise in identification of MCI-PD patients with unfavorable prognoses. Well-designed longitudinal studies in MCI-PD cohorts are needed to assess the sensitivity and specificity of the PD-MCI designation as far as dementia development is concerned.
We sought to establish whether patients with Parkinson's disease (PD) exhibit change in religiosity as a function of disease progression and asymmetry, medication regimens, mood dysfunction, sex, and age.
We assessed both controlled (conscious reflection) and automatic (semantic priming) modes of religiosity. In the main study, self-reported religiosity, cognitive, and clinical measures were assessed in 71 patients with midstage PD and 75 age-matched controls with non-neurological chronic health conditions. To understand a potential mechanism associated with change in religiosity in PD patients, we supplemented the findings with pilot investigations. The pilot included 21 PD patients and utilized a different self-report measure than that of the main study and assessed automatic activation of religious concepts both on and off levodopa.
The main study results demonstrated that PD patients consistently scored lower in five of six dimensions of religiosity. Multivariate linear regression demonstrated that self-reported religiosity was related to disease stage, asymmetry, and male gender. Results are discussed in the context of other neurologic correlates of religiosity. The pilot study on religious concept activation suggested that the mechanism is organic and hemisphere dependent. On/off drug testing confirmed these findings to be independent of medication effects. Gain/decay semantic modeling suggested that right and left forebrain pathways selectively mediated the time constant of gain and decay, respectively, for religious concepts.
PD patients exhibit significant differences in both controlled and automatic access to religious concepts with mid/late-stage, male, left-onset patients most impaired in access to religious cognition. The findings indicate that aspects of religious/spiritual cognition appear related to specific cerebral structures.
This study examined the contribution of executive functions to arrangement problem-solving performance in Parkinson's disease (PD), with a particular focus on self-directed cognitive flexibility. PD patients and healthy age-matched adults completed a battery of neuropsychological measures of executive function and a series of anagram puzzles, some of which were modified to include graphemic cues designed to prime potential solutions. PD patients were less successful than healthy controls (HC) at resolving the anagram puzzles, but when a cue accompanied the anagram stimulus, PD patients performed normally. Anagram performance was associated with measures of verbal fluency and inhibition; no association emerged with working memory or set shifting ability. These data suggest that subjects with PD may have difficulty sufficiently inhibiting their automatic response to the experimental stimulus in order to generate the novel arrangements required to produce a successful response. Such deficits might be remediated through the use of environmental cues designed to support strategy generation.
This study examined the effects of depletion of dopamine from the caudate nucleus of the common marmoset (Callithrix jacchus), on tasks sensitive to prefrontal damage (attentional set-shifting and spatial delayed response). There was a marked impairment in performance on the spatial delayed response task, but performance on the attentional set-shifting task was relatively preserved except for an impairment in re-engagement of a previously relevant perceptual dimension. This pattern of impairment is distinct from that seen after excitotoxic lesions of the prefrontal cortex and in patients with Parkinson's disease. Though it is not possible to identify specific cognitive functions that are independent of dopaminergic modulation of the caudate nucleus, due to the partial nature of the lesion, the results do provide insight into those cognitive processes that appear most dependent on caudate dopamine.
Twelve patients with focal damage of the frontal cortex and 12 patients with mild, medicated, early stage Parkinson's disease switched between letter- and digit=naming tasks on every second trial of a task-switching paradigm. Compared with age- and IQ-matched control performance, patients with left-sided, but not right-sided, frontal damage exhibited markedly increased time costs associated with these predictable switches only when there was a general incidence of interference or 'crosstalk' between the tasks, and particularly so when the available task cues were relatively weak and arbitrary. The same patients also showed evidence of an increased sensitivity to the facilitatory and inhibitory effects of previous processing, when required to switch between tasks. Both groups of patients (with left- or right-sided frontal damage) exhibited slow, disorganized performance early in practice. In contrast to these frontal effects, the Parkinson's disease patients showed little indication of larger time costs of task switches but they did show progressive increases in the error costs, while age- and IQ-matched control subjects showed reductions. We propose that while both left and right frontal cortical areas are involved in the organization of cognitive and motor processes in situations involving novel task demands, only the left frontal cortex is involved in the dynamic reconfiguring between already-established task-sets, and specifically, that it is the site of an executive mechanism responsible for the modulation of exogenous task-set activity. Finally, dopaminergic transmission, along the nigrostriatal pathway, may be implicated in sustaining various cognitive and motor processes over prolonged periods, including the operation of those executive control mechanisms that accomplish reconfiguring between task-sets.
Groups of patients with idiopathic Parkinson's disease, either medicated or unmedicated, were compared with matched groups of normal controls on a computerized battery previously shown to be sensitive to frontal lobe dysfunction, including tests of planning, spatial working memory and attentional set-shifting. In a series of problems based on the ‘Tower of London’ test, medicated patients with Parkinson's disease were shown to be impaired in the amount of time spent thinking about (planning) the solution to each problem. Additionally, an impairment in terms of the accuracy of the solution produced on this test was only evident in those patients with more severe clinical symptoms and was accompanied by deficits in an associated test of spatial short-term memory. Medicated patients with both mild and severe clinical symptoms were also impaired on a related test of spatial working memory. In contrast, a group of patients who were unmedicated and ‘early in the course’ of the disease were unimpaired in all three of these tests. However, all three Parkinson's disease groups were impaired in the test of attentional set-shifting ability, although unimpaired in a test of pattern recognition which is insensitive to frontal lobe damage.
These data are compared with those previously published from a group of young neurosurgical patients with localized excisions of the frontal lobes and are discussed in terms of the specific nature of the cognitive deficit at different stages of Parkinson's diseas.
A group of ten patients with idiopathic Parkinson's disease (PD) was tested on a series of automated tests of learning, memory, planning and attention whilst either on or off L-dopa medication. Controlled withdrawal of L-dopa interfered with aspects of performance on three of the tests that had previously been shown to be sensitive to frontal lobe dysfunction; a spatial working memory task, the Tower of London planning test, and a visual discrimination paradigm that also included intra- and extra-dimensional shift tests of selective attention. More specifically, errors were increased in the spatial working memory test, and both the accuracy and latency of thinking were impaired. Thinking time was significantly slowed following L-dopa withdrawal, even though the possible contaminating effects on motor slowing were fully controlled by a yoked control procedure. Nine out of ten patients reached a further stage of the visual discrimination, set-shifting paradigm when on, rather than off, L-dopa medication. Spatial span was also impaired off medication, but there were no effects of L-dopa withdrawal on tests of pattern and spatial recognition memory, simultaneous and delayed matching to sample or visuospatial conditional associative learning. Comparisons with a large control group confirmed previous findings that PD is associated with deficits on the majority of these tests. The results are discussed in terms of the fronto-striatal, dopamine dependent nature of some of the cognitive deficits found in PD, but the apparent dopamine-independent nature of deficits in other aspects of cognitive functioning, notably in tests of visual recognition memory and associative learning.
Many forms of psychopathology in higher animals and humans include the production of maladaptive, repetitive behaviour. Behaviour which is both repetitive and excessive in amount can be described as stereotyped whereas behaviour which represents a restriction of behavioural possibilities without excessive production can be described as perseverative. Both types of repetition can result from pathology in the neural mechanisms which control either the production of motor output or the organisation of behaviour at a higher level. A number of forms of repetitive behaviour can be induced environmentally. Confinement in adulthood results in a functional disorder which rapidly dissipates when normal conditions are restored but confinement in infancy may have a permanent effect on the organism's ability to interact in a flexible and creative way with its environment. The permanence of these disorders suggests that the environment can affect the way in which the nervous system develops.
The two hemispheres are functionally different in ways not adequately captured by the classic distinction between linguistic and nonlinguistic processes. The right hemisphere is critical for processing novel cognitive situations. The left hemisphere is key to the processes mediated by well-routinized representations and strategies. The left frontal systems appear to be critical for the cognitive selection driven by the content of working memory and for context-dependent behavior, the right frontal systems for cognitive selection driven by the external environment and for context-independent behavior. The crucial role of the right hemisphere in processing cognitively novel situations underscores the importance of the right frontal systems in task orientation and in the assembly of novel cognitive strategies.
The effects of 6-hydroxydopamine lesions of the prefrontal cortex in monkeys were investigated on two cognitive tests of prefrontal function, spatial delayed response, and attentional set shifting. The latter test provided a componential analysis of the Wisconsin Card Sort Test, a commonly used clinical test of frontal lobe function in man. Acquisition of a visual compound discrimination requiring a shift of attention from one dimension to another (extradimensional shift), for example, shapes to lines, was significantly improved. This enhancement was behaviorally specific in that there were no effects on acquisition of a discrimination that required the continued maintenance of an attentional set toward one particular dimension (intradimensional shift), nor any effects on a series of visual or spatial discrimination reversals that involved the repeated shifting of responding between two exemplars from the same dimension. In contrast, spatial delayed response performance was impaired, in agreement with previous results. Neurochemical measures showed a marked depletion of dopamine limited to the prefrontal cortex and a smaller loss of prefrontal noradrenaline. This was accompanied by a long-term adaptive change in the striatum such that extracellular dopamine in the caudate nucleus, as measured by in vivo microdialysis, was elevated in response to potassium stimulation as long as 18 months postsurgery. It is proposed that attentional set shifting is mediated by a balanced interaction between prefrontal and striatal dopamine, and that elevated dopamine contributes to the improvement in attentional set-shifting ability. This interpretation is consistent with the impairment in attentional set-shifting ability observed in patients with Parkinson's disease or with damage to the frontal lobes using the same test as used here for infrahuman primates.
Attentional set-shifting and discrimination reversal are sensitive to prefrontal damage in the marmoset in a manner qualitatively similar to that seen in man and Old World monkeys, respectively (Dias et al., 1996b). Preliminary findings have demonstrated that although lateral but not orbital prefrontal cortex is the critical locus in shifting an attentional set between perceptual dimensions, orbital but not lateral prefrontal cortex is the critical locus in reversing a stimulus–reward association within a particular perceptual dimension (Dias et al., 1996a). The present study presents this analysis in full and extends the results in three main ways by demonstrating that (1) mechanisms of inhibitory control and “on-line” processing are independent within the prefrontal cortex, (2) impairments in inhibitory control induced by prefrontal damage are restricted to novel situations, and (3) those prefrontal areas involved in the suppression of previously established response sets are not involved in the acquisition of such response sets.
These findings suggest that inhibitory control is a general process that operates across functionally distinct regions within the prefrontal cortex. Although damage to lateral prefrontal cortex causes a loss of inhibitory control in attentional selection, damage to orbitofrontal cortex causes a loss of inhibitory control in affective processing. These findings provide an explanation for the apparent discrepancy between human and nonhuman primate studies in which disinhibition as measured on the Wisconsin Card Sort Test is associated with dorsolateral prefrontal damage, whereas disinhibition as measured on discrimination reversal is associated with orbitofrontal damage.
Previous research suggests that lexical and semantic verbal fluency are differentially sensitive to the effects of cortical and subcortical dementias, but little is known about action fluency performance in dementias. The present study compared lexical, semantic, and action fluency in groups of patients with Parkinson's disease (PD) with and without dementia and an elderly control group. Findings revealed an interaction between fluency type and subject group. Although the demented PD (PDD) group performed significantly more poorly than their non-demented counterparts and normal controls on all three fluency tasks, a disproportionate disparity in scores was noted on the action fluency task. The findings suggest that action fluency may be particularly sensitive to PD-associated dementia and may be an early indicator of the conversion from PD to PDD. As reported elsewhere, PD without dementia was not associated with significant impairment on any of the fluency tasks.
When humans retrieve learned stimulus-response associations in a stereotyped manner the necessary brain structures may differ from those required when the same associations must be retrieved and adapted to new circumstances. We tested this hypothesis by means of tasks that resembled those employed in monkeys, using positron emission tomography (PET). Stimuli consisted of abstract two-dimensional shapes. Stereotyped retrieval of learned stimulus-response associations was studied by the use of a concurrent discrimination task with fixed pairing. This was contrasted with conditions requiring retrieval and adaptation of learned associations: forced-choice recognition, response reversal and concurrent discrimination with random pairing. Visuomotor control, passive viewing and fixation conditions were also included. During concurrent discrimination with fixed pairing, the left lower precentral gyrus and rostral anterior cingulate demonstrated higher blood flow levels in comparison with recognition, concurrent discrimination with random pairing, and to a lesser degree, response reversal. In the left lower precentral gyrus these blood flow levels were also higher in comparison with control conditions. Conversely, during recognition, concurrent discrimination with random pairing and reversal, a single region within the right inferior frontal gyrus demonstrated higher blood flow levels in comparison with concurrent discrimination with fixed pairing and control conditions. This right inferior frontal gyrus activation did not depend on the need for active familiarity judgements or response inhibition. To conclude, the left lower precentral gyrus is more active during stereotyped retrieval of learned stimulus-response associations and the right inferior prefrontal cortex is more active when a learned stimulus-response association must be retrieved and adapted to new circumstances.
Few detailed clinico-pathological correlations of Parkinson's disease have been published. The pathological findings in 100 patients diagnosed prospectively by a group of consultant neurologists as having idiopathic Parkinson's disease are reported. Seventy six had nigral Lewy bodies, and in all of these Lewy bodies were also found in the cerebral cortex. In 24 cases without Lewy bodies, diagnoses included progressive supranuclear palsy, multiple system atrophy, Alzheimer's disease, Alzheimer-type pathology, and basal ganglia vascular disease. The retrospective application of recommended diagnostic criteria improved the diagnostic accuracy to 82%. These observations call into question current concepts of Parkinson's disease as a single distinct morbid entity.
This study investigates the hypothesis that, as a consequence of Parkinson's disease, disturbed caudate outflow will lead to deficits in cognitive functions dependent upon the integrity of the prefrontal cortex, the cortical focus of caudatofugal signals. Since Parkinson's disease also involves lesions in extrastriatal midbrain cells which reduce the intrinsic supply of dopamine to this cortical region, such functions are at double risk. Forty nondemented parkinsonian patients were drawn from a pool of 100 consecutive patients and matched with 40 normal control subjects according to age, education, IQ, and sex. All patients were quantitatively rated on neurological indices of disease. Neuropsychological assessment of the patient and normal groups included tests of general intelligence, psychomotor skills, memory, visuospatial and executive functions. No global cognitive decline was observed in the parkinsonian group. Moreover, memory and visuospatial abilities were generally intact. A small cluster of deficits emerged, interpreted as reflecting impairment in the ability to spontaneously generate efficient strategies when relying on self-directed task-specific planning. In addition, several tests thought to be sensitive to frontal lobe function distinguished patients with symptoms strongly lateralized to the right versus left side of the body. Deficits in strategic planning were later investigated in relation to severity of disease and to patient attributes including IQ and age, both of which were relevant to performance on specific tasks. Results were compared with previous investigations in parkinsonian patients and discussed from the perspective of both animal and human studies involving damage to the cerebral cortex and basal ganglia. As the prefrontal cortex is thought to play a crucial role in self-directed behavioural planning, the validity of an outflow model in predicting the consequences of caudate nucleus dysfunction was supported.
Parkinson's disease (PD) results primarily from the death of dopaminergic neurons in the substantia nigra. Current PD medications treat symptoms; none halt or retard dopaminergic neuron degeneration. The main obstacle to developing neuroprotective therapies is a limited understanding of the key molecular events that provoke neurodegeneration. The discovery of PD genes has led to the hypothesis that misfolding of proteins and dysfunction of the ubiquitin-proteasome pathway are pivotal to PD pathogenesis. Previously implicated culprits in PD neurodegeneration, mitochondrial dysfunction and oxidative stress, may also act in part by causing the accumulation of misfolded proteins, in addition to producing other deleterious events in dopaminergic neurons. Neurotoxin-based models (particularly MPTP) have been important in elucidating the molecular cascade of cell death in dopaminergic neurons. PD models based on the manipulation of PD genes should prove valuable in elucidating important aspects of the disease, such as selective vulnerability of substantia nigra dopaminergic neurons to the degenerative process.
Several tests from the CANTAB neuropsychological test battery previously shown to be sensitive to frontal lobe dysfunction were administered to a large group of normal volunteers (N = 341) ranging in age from 21 to 79 years. The main tests included a computerized form of the Tower of London test of planning, a self-ordered spatial working memory task, and a test of attentional set formation and shifting. A computerized form of the Corsi spatial span task was also given. Age-related graded declines in performance were seen, sometimes in a discontinuous manner, especially for the attentional set shifting task (at the extradimensional shift stage). Patterns of deficits reminiscent of frontal lobe or basal ganglia damage were observed in the oldest age group (74490.)
IPT [N-(3-iodopropen-2-yl)-2-carbome-thoxy-3-(4-chlorophenyl) tropane] is a new cocain analogue which allows the presynaptic dopamine transporters to be imaged with single-photon emission tomography (SPET) as early as 1–2 h post injection. In the present study [123I]IPT SPET was performed in patients with Parkinson''s disease (PD) to analyse the relationship between specific dopamine tansporter binding and clinical features of the disease. Twenty-six PD patients (Hoehn and Yahr stages I-IV, age range 40–79 years) and eight age-matched controls were studied. SPET imaging was performed 90–120 min after injection of 160–185 MBq [123I]IPT using a triple-head camera. For semiquantitative evaluation of specific [123I]IPT binding, ratios between caudate, putamen and background regions were calculated. Specific [123I]IPT uptake was significantly reduced in PD patients compared to controls. Most patients showed a marked asymmetry with a more pronounced decrease in [123I]IPT binding on the side contralateral to the predominant clinical findings. The putamen was always more affected than the caudate. [123I]IPT binding was significantly correlated with disease duration (r=–0.7,Pr=–0.10,P=0.61). Specific [123I]IPT uptake in the caudate and putamen, and putamen to caudate ratios, decreased with increasing Hoehn and Yahr stage. Our findings indicate that [123I]IPT SPET may be a useful technique to estimate the extent of nigrostriatal degeneration in PD patients. Close relationships between striatal [123I]IPT binding and clinical features of the disease suggest that this method can be used to objectively follow the course and progression of PD. The reduced putamen to caudate ratios observed even in patients with mild, newly recognized symptoms indicate that particularly this parameter may help to establish the correct diagnosis in the early course of PD.
A standardized neuropsychological battery including measures of intellectual cognitive, memory, attention-concentration, language, abstraction and mental flexibility, and sensory and motor functions was administered to 21 hemiparkinsonian patients (14 with right side and 7 with left side symptoms) and 17 controls matched for age and education. Patients were impaired in all functions except sensory. For motor functions, impairment was ipsilateral to the side of symptoms. For cognitive functions, right side symptoms were associated with verbal deficits whereas left side symptoms were associated with spatial deficits. Thus, a pattern of neuropsychological deficits consistent with the lateralization of motor symptoms may appear in the early stages of the disease.
Several tests from the CANTAB neuropsychological test battery previously shown to be sensitive to frontal lobe dysfunction were administered to a large group of normal volunteers (N = 341) ranging in age from 21 to 79 years. The main tests included a computerized form of the Tower of London test of planning, a self-ordered spatial working memory task, and a test of attentional set formation and shifting. A computerized form of the Corsi spatial span task was also given. Age-related graded declines in performance were seen, sometimes in a discontinuous manner, especially for the attentional set shifting task (at the extradimensional shift stage). Patterns of deficits reminiscent of frontal lobe or basal ganglia damage were observed in the oldest age group (74-79). However, overall the data were only partially consistent with the hypothesis that frontal lobe functions are the most sensitive to effects of aging. Factor analyses showed that performance in the executive tests was not simply related to a measure of fluid intelligence, and their performance had a factor loading structure distinct from that for the CANTAB tests of visual memory and learning previously administered to the same sample. Finally, only limited support was found for the hypothesis that cognitive aging depends on slowed information processing.
• The University of Wisconsin Card-Sorting Test was used. The individual cards can be sorted on the basis either of the color, the number, or the form of the figures appearing on them. Color was arbitrarily selected as the initally "correct" sorting category. As each S sorted the cards he was told whether he was "right" or "wrong." As soon as S made a certain number of consecutive correct responses, E without explanation changed the "correct" basis of classification. Seven groups of about 20 Ss each were given 3, 4, 5, 6, 7, 8 and 10 reinforcing trials, respectively, before each shift. "Increasing the amount of reinforcement of original modes of response reduced the amount of perseveration of these responses when they suddenly became incorrect." Increased reinforcement also reduced the number of errors S made in reaching the new correct solution after deserting the old formerly correct one. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Recent research on Parkinson's disease (PD) suggests that executive functions are impaired but that visuospatial functions may be spared. This dissociation has been attributed to dysfunction in ascending dopaminergic pathways affecting the prefrontal cortex. We investigated these ideas in a sample of intellectually intact patients with idiopathic, optimally treated PD (N = 20) and in spouse controls (N = 15); the groups were divided into young (age < 60) and old subgroups, each comparable on education, vocabulary level, and Mini-Mental State scores. Six tasks were selected from a set of factor-referenced cognitive tests to measure three abilities: (1) ideational fluency (ability to generate ideas), (2) flexibility of use (ability to shift mental set), and (3) spatial orientation (ability to perceive spatial patterns). PD patients were impaired only on the ideational fluency factor (p = .01). An age-related deficit was seen on the spatial factor (p < .05) with a trend on the flexibility factor (.05 < p < .10). No interactions were significant. The findings suggest that when age and verbal intelligence are controlled, PD patients show no deficit on purely spatial tasks; in contrast, patients seem less able to generate ideas though capable of shifting from one idea to another.
Individuals with Parkinson's disease were compared to normal control subjects on a series of widely used neuropsychological measures. The two groups were matched for gender, handedness, age, education, and occupation. The neuropsychological tests were chosen to measure two specific functions: (a) spatial orientation (i.e., measures of personal orientation, extrapersonal orientation, right/left orientation, and mental rotation), and (b) the ability to shift mental set (e.g., generating responses from alternating categories). The tests chosen to measure spatial orientation had no set-shifting component, and the tests chosen to measure set-shifting had no spatial orientation component. Multivariate statistical analyses revealed a significant difference between the subjects with Parkinson's disease and the control subjects on the measures of set-shifting ability. In contrast, no significant difference between the groups was observed on the measures of spatial orientation. These results are discussed in terms of the current speculation in the literature regarding the relationship between set-shifting deficits and a disruption of dopaminergic fibers to the prefrontal cortex in Parkinson's disease.
Few detailed clinico-pathological correlations of Parkinson's disease have been published. The pathological findings in 100 patients diagnosed prospectively by a group of consultant neurologists as having idiopathic Parkinson's disease are reported. Seventy six had nigral Lewy bodies, and in all of these Lewy bodies were also found in the cerebral cortex. In 24 cases without Lewy bodies, diagnoses included progressive supranuclear palsy, multiple system atrophy, Alzheimer's disease, Alzheimer-type pathology, and basal ganglia vascular disease. The retrospective application of recommended diagnostic criteria improved the diagnostic accuracy to 82%. These observations call into question current concepts of Parkinson's disease as a single distinct morbid entity.
Current knowledge of cognitive dysfunction in Parkinson's disease (PD) has largely been obtained from studies of chronically treated patients in whom effects of disease chronicity, treatment, depression and dementia are confounding factors. Studies of untreated patients have examined few cognitive domains and relationships between cognition, depression and motor disability have been incompletely explored. Accordingly, we studied 60 consecutive patients with newly diagnosed, untreated, idiopathic PD and 37 matched, healthy control subjects; no subject had clinical dementia or depression. All subjects received tests of specific processes of memory and cognition, including working memory, verbal and non-verbal short- and long-term memory, language, visuospatial capacity, set-formation and shifting and sequencing. Patients also received quantitative global clinical measures of severity of dementia, depression and motor disability. The PD group as a whole showed deficits in immediate recall of verbal material, language production and semantic fluency, set-formation, cognitive sequencing and working memory and visuomotor construction. However, this group was unimpaired in immediate memory span, long-term forgetting, naming, comprehension and visual perception. Language deficits and more severe frontal lobe impairments were confined to those PD patients scoring abnormally on a Mini Mental State examination. Motor disability correlated strongly with severity of depression but weakly with cognitive impairment. Cognitive sequencing, set-formation and set-shifting deficits tended to associate with depression, but otherwise there was no association between cognition and depression. The results indicate dissociation of cognition and motor control in early PD which suggests that cognitive dysfunction is largely independent of frontostriatal dopamine deficiency underlying motor disability. Some, but not all, of the frontal lobe deficits of chronic disease are detectable in early, untreated PD. The pathogenesis of the cognitive deficits shown here appears to involve extrastriatal dopamine systems or non-dopaminergic pathology. Longitudinal study is necessary to determine whether increasing disease duration exacerbates the early cognitive deficits and affects new cognitive domains, in addition to producing increasing motor disability.
A group of healthy control subjects and patients with Parkinson's disease were investigated using positron emission tomography and two tracers as indicators of different specific properties of the presynaptic dopaminergic system in caudate nucleus and putamen. The first tracer, 6-L-(18F)-fluorodopa, was used as an analog of levodopa to assess its regional brain uptake, conversion into, and retention as dopamine and further metabolites. The second tracer, (11C)-nomifensine was employed as an indicator of striatal monaminergic reuptake sites that are principally dopaminergic. We have used this tracer to assess dopaminergic nerve terminal density. In patients with Parkinson's disease, striatal uptake of both tracers was decreased, putamen being significantly more affected than caudate. Side-to-side differences of uptake in putamen, but not caudate, correlated with corresponding left-right differences of scored clinical motor performance. Both 6-L(18F)-fluorodopa and (11C)-nomifensine tracer uptake in putamen was decreased on average to 40% of normal values, suggesting that a substantial part of the cellular elements of the dopaminergic nigrostriatal system is still intact in living parkinsonian patients. This is in contrast to the generally extreme depletion of endogenous dopamine in the putamen of patients found at postmortem. Our results lend support to the search for drug treatments that protect against further nigrostriatal cell loss and that could be exhibited as soon as the disease manifests clinically. If successful, a sufficient striatal nerve terminal pool would remain so that the effectiveness of levodopa as a dopamine repletor could persist.
This study compares the performance of Parkinson's disease patients with age-matched controls on semantic and letter-initial verbal fluency tests. An analysis of variance revealed that Parkinsonian patients showed impaired word production. However when the covariates of age, present verbal ability (Mill Hill Synonyms) and severity of depression (Geriatric Depression Screening Scale) were included in an analysis of covariance, the significant effect of Parkinson's disease on verbal fluency disappeared. Instead, age and present verbal ability were revealed to be the significant sources of between subject variation in total verbal fluency performance; results indicated that increased age and lower present verbal ability resulted in poorer performance on the verbal fluency tests. Depression score was not a significant source of between subject variation. The results are discussed in relation to those recently reported by Gurd and Ward (1989).
Groups of patients with Parkinson's disease, either medicated, or unmedicated and early in the course, together with age- and IQ-matched control subjects were tested in two paradigms measuring different aspects of selective attention. The first set of tests compared visual discrimination learning following intra- and extra-dimensional shifts, using a "total change" design in which each shift was made in the presence of novel exemplars of the compound stimuli used as discriminanda. The second test consisted of a visual search task in which the number of alternatives was varied. The results of the first experiment showed a selective deficit in both groups of Parkinsonian subjects in their ability to perform an extra-dimensional shift. In the visual search task, the patients were less accurate, but responded with equivalent choice reaction times to those of controls. The results are discussed in terms of the nature of the attentional dysfunction that occurs in Parkinson's disease.
A pathological study of 21 patients with Parkinson's disease of asymmetrical onset revealed significant asymmetry of degeneration of the substantia nigra with greater neuronal loss contralateral to the initially affected body side. It has previously been suggested that decline in duration of effectiveness of levodopa doses in Parkinsonian patients with motor oscillations is caused by loss of nigro-striatal dopaminergic terminals with consequent reduction in striatal dopamine storage capacity. If this is true, duration of levodopa motor response should be shorter on the more severely affected body side in patients with asymmetrical disease, as loss of contralateral striatal dopamine storage capacity should be greater. Serial motor evaluations in 20 patients with asymmetrical Parkinson's disease failed to reveal any such asymmetry of duration of motor response to levodopa. It is suggested that striatal dopamine storage is not an important determinant of duration of clinical response to levodopa doses.
Information about the basal ganglia has accumulated at a prodigious pace over the past decade, necessitating major revisions in the authors' concepts of the structural and functional organization of these nuclei. Recent anatomical and physiological findings have further substantiated the concept of segregated basal ganglia-thalamocortical pathways, and reinforced the general principle that basal ganglia influences are transmitted only to restricted portions of the frontal lobe (even though the striatum receives projections from nearly the entire neocortex). Using the 'motor' circuit as a model, the authors have reexamined the available data on other portions of the basal ganglia-thalamocortical pathways and found that the evidence strongly suggests the existence of at least four additional circuits organized in parallel with the 'motor' circuit. In the discussion that follows, they review some of the anatomic and physiologic features of the 'motor circuit,' as well as the data that support the existence of the other proposed parallel circuits, which they have designated the 'oculomotor,' the 'dorsolateral prefrontal,' the 'lateral orbitofrontal,' and the 'anterior cingulate,' respectively. Each of these five basal ganglia-thalamocortical circuits appears to be centered upon a separate part of the frontal lobe. This list of basal ganglia-thalamocortical circuits is not intended to be exhaustive. In fact, if the conclusions suggested in this review are valid, future investigations might be expected to disclose not only further details (or the need for revisions) of these five circuits, but perhaps also the existence of additional parallel circuits whose identification is currently precluded by a paucity of data.
In recent years, several attempts have been made to characterize the nature of the cognitive deficits shown by patients with Parkinson's disease. It has been suggested variously that they have difficulty in switching cognitive set, in performing effortful (or controlled) as opposed to automatic tasks, or that their impairment is found in tasks which maximize the amount of 'self-directed task specific planning'. It is proposed that this latter distinction may be reformulated in terms of the degree of internal versus external attentional control which is required by the task. An experiment is described which attempted to manipulate this parameter. A version of the Stroop colour-word test was used, in which the words 'red' and 'green' were presented in the complementary coloured 'ink'. Subjects responded either to the colour of the ink in which the word was written or the colour named by the word. The relevant attribute changed at intervals during the course of the experiment. In one condition, the relevant stimulus attribute was cued before each trial. In another condition, subjects had to remember which attribute was currently relevant. Results revealed that patients with Parkinson's disease were impaired mainly on the second version of the task which required internal attentional control. The results are discussed in relation to the models of Working Memory (Baddeley, 1986), and attentional control (Norman and Shallice, 1980). Exploration of these models leads to the formulation of a theory in which the crucial determinant of cognitive impairment in Parkinson's disease is reduced resources in the Supervisory Attentional System. Provided the demands of the task are within the patient's available attentional resources the patient may not show any deficit. If, however, the attentional demands exceed available resources, as in tasks which depend upon internal cues, then deficits will be observed.
A wide range of cognitive impairments can be observed in patients with Parkinson's disease. A close parallel exists between these deficits and those found following damage to prefrontal cortex. Anatomical evidence is reviewed which reveals a complex pattern of neuronal circuits connecting the frontal cortex and basal ganglia. All these circuits are in some way dependent upon dopamine, suggesting that changes in the levels of dopamine stimulation may alter performance on 'frontal' tests. To test this hypothesis, a group of patients with Parkinson's disease were assessed both on and off levodopa treatment, on a range of tests selected from the human and animal experimental literature as being sensitive to disruption of prefrontal cortex. A variable pattern of results was obtained. On one test, a measure of verbal fluency, patients were impaired, compared with normal controls, only when off levodopa. On two measures, associative conditional learning and subject-ordered pointing, patients were impaired only when on levodopa, while on the final measures, the Wisconsin Card Sorting Test, patients were impaired both on and off levodopa. Two mechanisms are discussed to explain these results, one based on the effects of dopamine depletion, and the other based on the adverse effects of dopamine overstimulation. The results suggest that different areas of prefrontal cortex are involved in the tasks employed, and that functional levels of dopamine in separate areas of cortex and caudate may differ crucially in Parkinson's disease.
This study investigates the hypothesis that, as a consequence of Parkinson's disease, disturbed caudate outflow will lead to deficits in cognitive functions dependent upon the integrity of the prefrontal cortex, the cortical focus of caudatofugal signals. Since Parkinson's disease also involves lesions in extra-striatal midbrain cells which reduce the extrinsic supply of dopamine to this cortical region, such functions are at double risk. Forty nondemented parkinsonian patients were drawn from a pool of 100 consecutive patients and matched with 40 normal control subjects according to age, education, IQ, and sex. All patients were quantitatively rated on neurological indices of disease. Neuropsychological assessment of the patient and normal groups included tests of general intelligence, psychomotor skills, memory, visuospatial and executive functions. No global cognitive decline was observed in the parkinsonian group. Moreover, memory and visuospatial abilities were generally intact. A small cluster of deficits emerged, interpreted as reflecting impairment in the ability to spontaneously generate efficient strategies when relying on self-directed task-specific planning. In addition, several tests thought to be sensitive to frontal lobe function distinguished patients with symptoms strongly lateralized to the right versus left side of the body. Deficits in strategic planning were later investigated in relation to severity of disease and to patient attributes including IQ and age, both of which were relevant to performance on specific tasks. Results were compared with previous investigations in parkinsonian patients and discussed from the perspective of both animal and human studies involving damage to the cerebral cortex and basal ganglia. As the prefrontal cortex is thought to play a crucial role in self-directed behavioural planning, the validity of an outflow model in predicting the consequences of caudate nucleus dysfunction was supported.
Neuropsychological tests known to reveal abnormalities in patients with frontal lobe damage were used to explore cognitive function in 30 mildly disabled, right-handed patients with idiopathic Parkinson's disease. None of the patients had received treatment and all had normal CT brain scans. Patients with depression or high ischaemia scores were excluded from the study and similar selection criteria were used for the age-matched controls. No impairment of general intellectual function was found in the patients using the WAIS and New Adult Reading IQ tests and no abnormalities were apparent on cognitive estimates and two-choice Recognition Memory Tests. Patients with Parkinson's disease, however, had significantly greater difficulty in shifting conceptual sets and produced more perseverative errors on both the modified Wisconsin Card Sorting Test and Benton's Word Fluency Test. These subtle cognitive difficulties might underlie the mental inflexibility and rigidity of Parkinson's disease and could be attributed to destruction of the ascending dopaminergic mesocorticolimbic pathway.
Post-mortem neurochemical studies in Parkinson's disease (PD) have shown that, in addition to the typical nigro-striatal dopamine denervation, there exists a concomitant neocortical monoamine fibre deafferentation (of variable severity) whose role in motor, and especially in associated cognitive and affective impairment, remains elusive. We have extensively examined whether PET imaging with11C-S-Nomifensine (11C-NMF), a radioligand of the dopamine and norepinephrine presynaptic reuptake sites which has been used so far to investigate the striatum, could provide a method for assessing in vivo the neocortical monoamine terminal loss in PD; previously, this has been a little addressed and controversial issue. To this end, we prospectively selected a highly homogeneous sample of nine non-demented, non-depressed idiopathic PD patients with mild to marked side-to-side asymmetry in motor impairment. In addition to recovering the previously-reported correlations withputaminal
11C-NMF specific uptake asymmetries, the clinical motor asymmetries also significantly correlated in the clinically expected direction toneocortical (especially frontal)11C-NMF asymmetries, suggesting the monoamine neocortical denervation might play a direct role in motor impairment in PD. These results demonstrate that it is possible to assess in vivo the neocortical monoamine terminal loss, and to elucidate its potential role in the complex cognitive and affective impairment, in both PD and atypical degenerative parkinsonism.
Parkinson's disease (PD) is associated with specific cognitive deficits in the absence of dementia, including the inability to suppress previously learned responses in a changed context. Our goal was to determine whether this set-shifting deficit is sufficient to account for impaired performance on a problem-solving task, or, instead, whether it is necessary to postulate deficits in one or more other cognitive capacities, such as logical deduction. Deductive reasoning and other conceptual abilities were assessed in 15 nondemented subjects with PD who had never been medicated, 15 nondemented subjects with PD who were currently receiving medication, and 15 healthy elderly control subjects. On a deductive reasoning task, Poisoned Food Problems, the PD groups made more errors than the control group. The PD groups' error pattern was characterized by intrusions of information from previous problems. By contrast, the PD groups made appropriate assessments of redundant and irrelevant information that appeared in these problems, and performed normally on other tests of concept formation and problem solving that did not require set shifting, indicating that the capacities for logical deduction and concept formation were intact. The set-shifting deficit, conceptualized as a difficulty in suppressing a prepotent response, appears to be a primary cognitive impairment in PD and presumably arises from dysfunction of the nigrostriatal-dorsolateral prefrontal cortex complex loop.
Studies attempting to relate cognitive impairment to asymmetry of motor symptoms in Parkinson's disease (PD) have found contradictory results. We examined 88 patients with unilateral onset of idiopathic PD who underwent a comprehensive neuropsychological assessment, including language, visuospatial abilities, abstraction and reasoning, attention and mental tracking, set shifting, and memory. Patients whose motor signs began on the left side of the body consistently performed more poorly on the battery of cognitive measures than did patients with right-side onset. Significant differences were found on immediate and delayed verbal recall, word retrieval, semantic verbal fluency, visuospatial analysis, abstract reasoning, attention span, and mental tracking. These differences could not be attributed to differences in the overall severity of motor symptoms at the time of cognitive assessment, or the current pattern of motor asymmetry. This finding suggests that damage to right-hemisphere dopamine systems plays a disproportionately greater role in PD-related cognitive decline than a presumably comparable left-hemisphere dopamine depletion.
Frontal lobe and basal ganglia lesions have been associated with similar cognitive impairments, although their specialized roles in behavior are likely to be different. We examined whether these structures mediate distinctive or overlapping aspects of a complex behavioral process that has been associated with both neural sites, i.e. cognitive flexibility. Patients with focal ischemic lesions to the frontal lobe and basal ganglia were compared on two forms of cognitive flexibility: (1) shifting response set (i.e. reactive flexibility), and (2) producing a diversity of ideas (i.e. spontaneous flexibility). Results indicated that frontal lobe and basal ganglia damage each caused a similar degree of impairment in reactive flexibility, both groups performing at a significantly lower level than posterior cortical lesion and normal comparison groups. However, frontal lobe damage markedly disturbed spontaneous flexibility, while performance after basal ganglia lesion was significantly higher and comparable to posterior cortical lesions. Findings suggest that the frontal lobe and basal ganglia participate differently in the neural substrate of cognitive flexibility. The frontal lobe appears to mediate spontaneous flexibility. The production of diverse ideas may require direct cortical-cortical interactions by the frontal lobe in order to access knowledge systems with novel strategies that transcend the most common semantic linkages. In contrast the corticostriate system appears to mediate reactive flexibility, as the frontal lobe, basal ganglia and their interconnections are required for its operation.
Using a primate analogue of the Wisconsin Card Sort Test, this study demonstrated, for the first time, that lesions of the prefrontal cortex in monkeys produce a qualitatively similar impairment in attentional set-shifting to that seen following prefrontal cortical damage in humans. Although damage to the prefrontal cortex did not disrupt the ability of marmosets, a New World monkey, to maintain an attentional set, it did disrupt their ability to shift an attentional set. It also impaired their performance on discrimination reversal, object retrieval, and spatial delayed response, consistent with the effects of prefrontal damage in Old World monkeys. Comparison of the cognitive processes underlying discrimination reversal, object retrieval, and attentional set-shifting reveals the various types of inhibitory control provided by the prefrontal cortex.
IPT [N-(3-iodopropen-2-yl)- 2beta-carbomethoxy-3beta-(4-chlorophenyl) tropane] is a new cocaine analogue which allows the presynaptic dopamine transporters to be imaged with single-photon emission tomography (SPET) as early as 1-2 h post injection. In the present study [123I]IPT SPET was performed in patients with Parkinson's disease (PD) to analyse the relationship between specific dopamine tansporter binding and clinical features of the disease. Twenty-six PD patients (Hoehn and Yahr stages I-IV, age range 40-79 years) and eight age-matched controls were studied. SPET imaging was performed 90-120 min after injection of 160-185 MBq [123I]IPT using a triple-head camera. For semiquantitative evaluation of specific [123I]IPT binding, ratios between caudate, putamen and background regions were calculated. Specific [123I]IPT uptake was significantly reduced in PD patients compared to controls. Most patients showed a marked asymmetry with a more pronounced decrease in [123I]IPT binding on the side contralateral to the predominant clinical findings. The putamen was always more affected than the caudate. [123I]IPT binding was significantly correlated with disease duration (r=-0.7, P<0.0001) but not with the age of PD patients (r=-0.10, P=0. 61). Specific [123I]IPT uptake in the caudate and putamen, and putamen to caudate ratios, decreased with increasing Hoehn and Yahr stage. Our findings indicate that [123I]IPT SPET may be a useful technique to estimate the extent of nigrostriatal degeneration in PD patients. Close relationships between striatal [123I]IPT binding and clinical features of the disease suggest that this method can be used to objectively follow the course and progression of PD. The reduced putamen to caudate ratios observed even in patients with mild, newly recognized symptoms indicate that particularly this parameter may help to establish the correct diagnosis in the early course of PD.
Two new tasks designed to individualize and assess aspects of cognitive flexibility and complex integration were administered to patients with schizophrenia (n = 16), Parkinson's disease (PD; n = 25) and Huntington's disease (HD; n = 12). Findings indicated impaired performance in the schizophrenic and HD groups on components of solution fluency, reactive flexibility and integration. The PD group demonstrated normal performance on all but the solution fluency and reaction time measures. These findings corroborate previous studies suggesting that executive and problem solving disturbances feature in schizophrenia and HD and that these functions may not be as severely affected in medicated PD. Slowed reaction time by both dementia groups is explained with reference to the concept of bradyphrenia.
Twelve patients with focal damage of the frontal cortex and 12 patients with mild, medicated, early stage Parkinson's disease switched between letter- and digit=naming tasks on every second trial of a task-switching paradigm. Compared with age- and IQ-matched control performance, patients with left-sided, but not right-sided, frontal damage exhibited markedly increased time costs associated with these predictable switches only when there was a general incidence of interference or 'crosstalk' between the tasks, and particularly so when the available task cues were relatively weak and arbitrary. The same patients also showed evidence of an increased sensitivity to the facilitatory and inhibitory effects of previous processing, when required to switch between tasks. Both groups of patients (with left- or right-sided frontal damage) exhibited slow, disorganized performance early in practice. In contrast to these frontal effects, the Parkinson's disease patients showed little indication of larger time costs of task switches but they did show progressive increases in the error costs, while age- and IQ-matched control subjects showed reductions. We propose that while both left and right frontal cortical areas are involved in the organization of cognitive and motor processes in situations involving novel task demands, only the left frontal cortex is involved in the dynamic reconfiguring between already-established task-sets, and specifically, that it is the site of an executive mechanism responsible for the modulation of exogenous task-set activity. Finally, dopaminergic transmission, along the nigrostriatal pathway, may be implicated in sustaining various cognitive and motor processes over prolonged periods, including the operation of those executive control mechanisms that accomplish reconfiguring between task-sets.
Impairments on lexical and semantic fluency tasks occur in both cortical and subcortical dementia. Recent reports that the average size of phonemic and semantic clusters is reduced in Alzheimer's disease (AD), but not in Parkinson's disease (PD) could support the hypothesis that in AD verbal fluency deficits arise from degraded memory storage while in PD the same impairments result from defective retrieval. In the present study, patients with AD, PD with dementia, or Huntington's disease produced fewer words, fewer switching responses and smaller semantic cluster sizes. Patients with multiple sclerosis, regardless of whether or not they were demented, produced fewer words and switching responses, but normal size clusters, and patients with PD without dementia performed normally on all fluency measures. These results indicate that reductions in cluster size on verbal fluency tests are best interpreted as changes in the efficiency of access to lexical and semantic memory stores. The findings are also consistent with the idea that patterns of cognitive impairment may differ among diseases that result in subcortical dementia.
Indirect evidence from human and monkey investigations supports the idea that impaired frontal tasks in Parkinson's disease (PD) may result from striato-frontal disruption caused by dopamine (DA) denervation of the caudate nucleus. To directly investigate this hypothesis, we used PET with 11C-S-Nomifensine (11C-S-NMF), a sensitive marker of striatal DA denervation, in 10 non-demented PD patients in whom two frontal executive tests, the object alternation (OA) and the conditional associative learning (CAL) tasks, thought to reflect mainly set-shifting/inhibition and planning, respectively, were given. In addition, the central executive function of verbal working memory was assessed with the Brown Peterson paradigm (BPP). We found a highly significant correlation between right caudate 11C-S-NMF specific binding and OA performance, less significant and reverse-direction correlations between CAL performance and putamen 11C-S-NMF binding, and no significant correlation with BPP performance. Thus, caudate DA denervation may subtend poor set-shifting/inhibition process in PD. Our results also point to distinct and complex relationships between striatal DA and specific frontal tasks.
In contrast to early failures, recent functional brain imaging studies have shown that medial temporal lobe (MTL) structures are active during performance of a variety of tasks. These studies have revealed three properties of the MTL that are consistent with its critical role in establishing new declarative memories. First, the MTL is automatically engaged whenever an event is experienced, with the side of activation (left, right) dependent on the nature of the material presented (verbal, nonverbal). Second, the strength or amount of activity depends on how well the material is encoded. Deep encoding will produce more MTL activity than shallow encoding. Depth of encoding-related increases in activity are more commonly seen on the left, because deep encoding is nearly always synonymous with encoding for meaning, and, therefore, depends on left-lateralized language mechanisms. Third, the amount of MTL activity depends on novelty. Unfamiliar events and contexts will produce more MTL activity than familiar events and contexts. Novelty-related increases are more commonly seen on the right, perhaps reflecting the greater role of the right hemisphere in maintaining tonic attention and arousal. These findings suggest a hemispheric division of labor involving encoding for meaning (left) and novelty detection (right), both of which lead to better remembering.
Patients with Parkinson's disease (PD) show impairments on tasks that require them to switch attention between two perceptual dimensions (extradimensional (ED) shifting). It has been suggested that ED shifting deficits can be caused by two separate mechanisms, 'learned irrelevance' and 'perseveration'. This study set out to test the hypothesis that enhanced learned irrelevance is present in medicated patients with PD. An enhancement of learned irrelevance in PD patients should result in increased errors on a 'deficit' shift relative to controls and decreased errors on an 'improvement' shift. A similar pair of deficit and improvement shifts were used to detect possible enhanced perseveration in patients. Instead of showing the predicted patterns of deficit and improvement, patients displayed a consistent deficit on those shifts that required that they switch their attention to a different dimension (ED shifts). In contrast, patients were not impaired on shifts that required no such shift of attention (intradimensional shifts). Although there was an increase in errors at the learned irrelevance deficit shift, a similar increase at the learned irrelevance improvement shift shows that enhanced learned irrelevance is not responsible for either of these results. Patients were no more distractible than controls, but displayed increased 'loss of set' as measured by errors generated after a rule was learned. These results point to the existence of exaggerated, rigid selective attention in patients with PD rather than a breakdown in the ability to selectively attend. There was no evidence for the existence of enhanced learned irrelevance in the patients.