Two routes to value-based decisions in Parkinson's disease: differentiating incremental reinforcement learning from episodic memory.

Patients with Parkinson's disease are impaired at incremental reward-based learning. It is typically assumed that this impairment reflects a loss of striatal dopamine. However, many open questions remain about the nature of reward-based learning deficits in Parkinson's. Recent studies have found that a combination of different cognitive and computational strategies contribute even to simple reward-based learning tasks, suggesting a possible role for episodic memory. These findings raise critical questions about how incremental learning and episodic memory interact to support learning from past experience and what their relative contributions are to impaired decision-making in Parkinson's disease. Here we addressed these questions by asking patients with Parkinson's disease (n=26) both on and off their dopamine replacement medication and age- and education-matched healthy controls (n=26) to complete a task designed to isolate the contributions of incremental learning and episodic memory to reward-based learning and decision-making. We found that Parkinson's patients performed as well as healthy controls when using episodic memory, but were impaired at incremental reward-based learning. Dopamine replacement medication remediated this deficit while enhancing subsequent episodic memory for the value of motivationally relevant stimuli. These results demonstrate that Parkinson's patients are impaired at learning about reward from trial-and-error when episodic memory is properly controlled for, and that learning based on the value of single experiences remains intact in patients with Parkinson's disease.

Online cognitive testing in Parkinson's disease: advantages and challenges.

Parkinson's disease (PD) is primarily characterized by motor symptoms. Yet, many people with PD experience cognitive decline, which is often unnoticed by clinicians, although it may have a significant impact on quality of life. For over half a century, traditional in-person PD cognitive assessment lacked accessibility, scalability, and specificity due to its inherent limitations. In this review, we propose that novel methods of online cognitive assessment could potentially address these limitations. We first outline the challenges of traditional in-person cognitive testing in PD. We then summarize the existing literature on online cognitive testing in PD. Finally, we explore the advantages, but also the limitations, of three major processes involved in online PD cognitive testing: recruitment and sampling methods, measurement and participation, and disease monitoring and management. Taking the limitations into account, we aim to highlight the potential of online cognitive testing as a more accessible and efficient approach to cognitive testing in PD.

Corrigendum: Remote assessment of cognition in Parkinson's disease and cerebellar ataxia: the MoCA test in English and Hebrew.

[This corrects the article DOI: 10.3389/fnhum.2023.1325215.].

Advanced brain aging in Parkinson's disease with cognitive impairment.

Patients with Parkinson's disease and cognitive impairment (PD-CI) deteriorate faster than those without cognitive impairment (PD-NCI), suggesting an underlying difference in the neurodegeneration process. We aimed to verify brain age differences in PD-CI and PD-NCI and their clinical significance. A total of 94 participants (PD-CI, n = 27; PD-NCI, n = 34; controls, n = 33) were recruited. Predicted age difference (PAD) based on gray matter (GM) and white matter (WM) features were estimated to represent the degree of brain aging. Patients with PD-CI showed greater GM-PAD (7.08 ± 6.64 years) and WM-PAD (8.82 ± 7.69 years) than those with PD-NCI (GM: 1.97 ± 7.13, Padjusted = 0.011; WM: 4.87 ± 7.88, Padjusted = 0.049) and controls (GM: -0.58 ± 7.04, Padjusted = 0.004; WM: 0.88 ± 7.45, Padjusted = 0.002) after adjusting demographic factors. In patients with PD, GM-PAD was negatively correlated with MMSE (Padjusted = 0.011) and MoCA (Padjusted = 0.013) and positively correlated with UPDRS Part II (Padjusted = 0.036). WM-PAD was negatively correlated with logical memory of immediate and delayed recalls (Padjusted = 0.003 and Padjusted < 0.001). Also, altered brain regions in PD-CI were identified and significantly correlated with brain age measures, implicating the neuroanatomical underpinning of neurodegeneration in PD-CI. Moreover, the brain age metrics can improve the classification between PD-CI and PD-NCI. The findings suggest that patients with PD-CI had advanced brain aging that was associated with poor cognitive functions. The identified neuroimaging features and brain age measures can serve as potential biomarkers of PD-CI.

The Role of the Cerebellum in Learning to Predict Reward: Evidence from Cerebellar Ataxia.

Recent findings in animals have challenged the traditional view of the cerebellum solely as the site of motor control, suggesting that the cerebellum may also be important for learning to predict reward from trial-and-error feedback. Yet, evidence for the role of the cerebellum in reward learning in humans is lacking. Moreover, open questions remain about which specific aspects of reward learning the cerebellum may contribute to. Here we address this gap through an investigation of multiple forms of reward learning in individuals with cerebellum dysfunction, represented by cerebellar ataxia cases. Nineteen participants with cerebellar ataxia and 57 age- and sex-matched healthy controls completed two separate tasks that required learning about reward contingencies from trial-and-error. To probe the selectivity of reward learning processes, the tasks differed in their underlying structure: while one task measured incremental reward learning ability alone, the other allowed participants to use an alternative learning strategy based on episodic memory alongside incremental reward learning. We found that individuals with cerebellar ataxia were profoundly impaired at reward learning from trial-and-error feedback on both tasks, but retained the ability to learn to predict reward based on episodic memory. These findings provide evidence from humans for a specific and necessary role for the cerebellum in incremental learning of reward associations based on reinforcement. More broadly, the findings suggest that alongside its role in motor learning, the cerebellum likely operates in concert with the basal ganglia to support reinforcement learning from reward.

Remote assessment of cognition in Parkinson's disease and Cerebellar Ataxia: the MoCA test in English and Hebrew.

There is a critical need for accessible neuropsychological testing for basic research and translational studies worldwide. Traditional in-person neuropsychological studies are inherently difficult to conduct because testing requires the recruitment and participation of individuals with neurological conditions. Consequently, studies are often based on small sample sizes, are highly time-consuming, and lack diversity. To address these challenges, in the last decade, the utilization of remote testing platforms has demonstrated promising results regarding the feasibility and efficiency of collecting patient data online. Herein, we tested the validity and generalizability of remote administration of the Montreal Cognitive Assessment (MoCA) test. We administered the MoCA to English and Hebrew speakers from three different populations: Parkinson's disease, Cerebellar Ataxia, and healthy controls via video conferencing. First, we found that the online MoCA scores do not differ from traditional in-person studies, demonstrating convergent validity. Second, the MoCA scores of both our online patient groups were lower than controls, demonstrating construct validity. Third, we did not find differences between the two language versions of the remote MoCA, supporting its generalizability to different languages and the efficiency of collecting binational data (USA and Israel). Given these results, future studies can utilize the remote MoCA, and potentially other remote neuropsychological tests to collect data more efficiently across multiple different patient populations, language versions, and nations.

Neuroimaging approaches to cognition in Parkinson's disease.

While direct visualization of Lewy body accumulation within the brain is not yet possible in living Parkinson's disease patients, brain imaging studies offer insights into how the buildup of Lewy body pathology impacts different regions of the brain. Unlike biological biomarkers and purely behavioral research, these brain imaging studies therefore offer a unique opportunity to relate brain localization to cognitive function and dysfunction in living patients. Magnetic resonance imaging studies can reveal physical changes in brain structure as they relate to different cognitive domains and task specific impairments. Functional imaging studies use a combination of task and resting state magnetic resonance imaging, as well as positron emission tomography and single photon emission computed tomography, and can be used to determine changes in blood flow, neuronal activation and neurochemical changes in the brain associated with PD cognition and cognitive impairments. Other unique advantages to brain imaging studies are the ability to monitor changes in brain structure and function longitudinally as patients progress and the ability to study changes in brain function when patients are exposed to different pharmacological manipulations. This is particularly true when assessing the effects of dopaminergic replacement therapy on cognitive function in Parkinson's disease patients. Together, this chapter will describe imaging studies that have helped identify structural and functional brain changes associated with cognition, cognitive impairment, and dementia in Parkinson's disease.

Recent advances in using diffusion tensor imaging to study white matter alterations in Parkinson's disease: A mini review.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disease with cardinal motor symptoms. In addition to motor symptoms, PD is a heterogeneous disease accompanied by many non-motor symptoms that dominate the clinical manifestations in different stages or subtypes of PD, such as cognitive impairments. The heterogeneity of PD suggests widespread brain structural changes, and axonal involvement appears to be critical to the pathophysiology of PD. As α-synuclein pathology has been suggested to cause axonal changes followed by neuronal degeneration, diffusion tensor imaging (DTI) as an in vivo imaging technique emerges to characterize early detectable white matter changes due to PD. Here, we reviewed the past 5-year literature to show how DTI has helped identify axonal abnormalities at different PD stages or in different PD subtypes and atypical parkinsonism. We also showed the recent clinical utilities of DTI tractography in interventional treatments such as deep brain stimulation (DBS). Mounting evidence supported by multisite DTI data suggests that DTI along with the advanced analytic methods, can delineate dynamic pathophysiological processes from the early to late PD stages and differentiate distinct structural networks affected in PD and other parkinsonism syndromes. It indicates that DTI, along with recent advanced analytic methods, can assist future interventional studies in optimizing treatments for PD patients with different clinical conditions and risk profiles.

Clinical Efficacy and Dosing of Vibrotactile Coordinated Reset Stimulation in Motor and Non-motor Symptoms of Parkinson's Disease: A Study Protocol.

Enhanced neuronal synchronization of the subthalamic nucleus (STN) is commonly found in PD patients and corresponds to decreased motor ability. Coordinated reset (CR) was developed to decouple synchronized states causing long lasting desynchronization of neural networks. Vibrotactile CR stimulation (vCR) was developed as non-invasive therapeutic that delivers gentle vibrations to the fingertips. A previous study has shown that vCR can desynchronize abnormal brain rhythms within the sensorimotor cortex of PD patients, corresponding to sustained motor relief after 3 months of daily treatment. To further develop vCR, we created a protocol that has two phases. Study 1, a double blinded randomized sham-controlled study, is designed to address motor and non-motor symptoms, sensorimotor integration, and potential calibration methods. Study 2 examines dosing effects of vCR using a remote study design. In Study 1, we will perform a 7-month double-blind sham-controlled study including 30 PD patients randomly placed into an active vCR or inactive (sham) vCR condition. Patients will receive stimulation for 4 h a day in 2-h blocks for 6 months followed by a 1-month pause in stimulation to assess long lasting effects. Our primary outcome measure is the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III off medication after 6 months of treatment. Secondary measures include a freezing of gait (FOG) questionnaire, objective motor evaluations, sensorimotor electroencephalography (EEG) results, a vibratory temporal discrimination task (VTDT), non-motor symptom evaluations/tests such as sleep, smell, speech, quality of life measurements and Levodopa Equivalent Daily Dose (LEDD). Patients will be evaluated at baseline, 3, 6, and 7 months. In the second, unblinded study phase (Study 2), all patients will be given the option to receive active vCR stimulation at a reduced dose for an additional 6 months remotely. The remote MDS-UPDRS part III off medication will be our primary outcome measure. Secondary measures include sleep, quality of life, objective motor evaluations, FOG and LEDD. Patients will be evaluated in the same time periods as the first study. Results from this study will provide clinical efficacy of vCR and help validate our investigational vibrotactile device for the purpose of obtaining FDA clearance. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT04877015.

Emotional and Utilitarian Appraisals of Moral Dilemmas Are Encoded in Separate Areas and Integrated in Ventromedial Prefrontal Cortex.

Moral judgment often requires making difficult tradeoffs (e.g., is it appropriate to torture to save the lives of innocents at risk?). Previous research suggests that both emotional appraisals and more deliberative utilitarian appraisals influence such judgments and that these appraisals often conflict. However, it is unclear how these different types of appraisals are represented in the brain, or how they are integrated into an overall moral judgment. We addressed these questions using an fMRI paradigm in which human subjects provide separate emotional and utilitarian appraisals for different potential actions, and then make difficult moral judgments constructed from combinations of these actions. We found that anterior cingulate, insula, and superior temporal gyrus correlated with emotional appraisals, whereas temporoparietal junction and dorsomedial prefrontal cortex correlated with utilitarian appraisals. Overall moral value judgments were represented in an anterior portion of the ventromedial prefrontal cortex. Critically, the pattern of responses and functional interactions between these three sets of regions are consistent with a model in which emotional and utilitarian appraisals are computed independently and in parallel, and passed to the ventromedial prefrontal cortex where they are integrated into an overall moral value judgment. Significance statement: Popular accounts of moral judgment often describe it as a battle for control between two systems, one intuitive and emotional, the other rational and utilitarian, engaged in winner-take-all inhibitory competition. Using a novel fMRI paradigm, we identified distinct neural signatures of emotional and utilitarian appraisals and used them to test different models of how they compete for the control of moral behavior. Importantly, we find little support for competitive inhibition accounts. Instead, moral judgments resembled the architecture of simple economic choices: distinct regions represented emotional and utilitarian appraisals independently and passed this information to the ventromedial prefrontal cortex for integration into an overall moral value signal.

Effects of face feature and contour crowding in facial expression adaptation.

Prolonged exposure to a visual stimulus, such as a happy face, biases the perception of subsequently presented neutral face toward sad perception, the known face adaptation. Face adaptation is affected by visibility or awareness of the adapting face. However, whether it is affected by discriminability of the adapting face is largely unknown. In the current study, we used crowding to manipulate discriminability of the adapting face and test its effect on face adaptation. Instead of presenting flanking faces near the target face, we shortened the distance between facial features (internal feature crowding), and reduced the size of face contour (external contour crowding), to introduce crowding. We are interested in whether internal feature crowding or external contour crowding is more effective in inducing crowding effect in our first experiment. We found that combining internal feature and external contour crowding, but not either of them alone, induced significant crowding effect. In Experiment 2, we went on further to investigate its effect on adaptation. We found that both internal feature crowding and external contour crowding reduced its facial expression aftereffect (FEA) significantly. However, we did not find a significant correlation between discriminability of the adapting face and its FEA. Interestingly, we found a significant correlation between discriminabilities of the adapting and test faces. Experiment 3 found that the reduced adaptation aftereffect in combined crowding by the external face contour and the internal facial features cannot be decomposed into the effects from the face contour and facial features linearly. It thus suggested a nonlinear integration between facial features and face contour in face adaptation.

When size matters: attention affects performance by contrast or response gain.

Covert attention, the selective processing of visual information in the absence of eye movements, improves behavioral performance. We found that attention, both exogenous (involuntary) and endogenous (voluntary), can affect performance by contrast or response gain changes, depending on the stimulus size and the relative size of the attention field. These two variables were manipulated in a cueing task while stimulus contrast was varied. We observed a change in behavioral performance consonant with a change in contrast gain for small stimuli paired with spatial uncertainty and a change in response gain for large stimuli presented at one location (no uncertainty) and surrounded by irrelevant flanking distracters. A complementary neuroimaging experiment revealed that observers' attention fields were wider with than without spatial uncertainty. Our results support important predictions of the normalization model of attention and reconcile previous, seemingly contradictory findings on the effects of visual attention.

Perceptual asymmetries are preserved in short-term memory tasks.

Visual performance is heterogeneous at isoeccentric locations; it is better on the horizontal than on the vertical meridian and worse at the upper than at the lower region of the vertical meridian (Carrasco, Talgar, & Cameron, 2001; Talgar & Carrasco, 2002). It is unknown whether these performance inhomogeneities are also present in spatial frequency tasks and whether asymmetries present during encoding of visual information also emerge in visual short-term memory (VSTM) tasks. Here, we investigated the similarity of the perceptual and VSTM tasks in spatial frequency discrimination (Experiments 1 and 2) and perceived spatial frequency (Experiments 3 and 4). We found that (1) performance in both simultaneous (perceptual) and delayed (VSTM) spatial frequency discrimination tasks varies as a function of location; it is better along the horizontal than along the vertical meridian; and (2) perceived spatial frequency in both tasks is higher along the horizontal than along the vertical meridian. These results suggest that perceived spatial frequency may mediate performance differences in VSTM tasks across the visual field, implying that the quality with which we encode information affects VSTM.

Orientation-selective adaptation to illusory contours in human visual cortex.

Humans can perceive illusory or subjective contours in the absence of any real physical boundaries. We used an adaptation protocol to look for orientation-selective neural responses to illusory contours defined by phase-shifted abutting line gratings in the human visual cortex. We measured functional magnetic resonance imaging (fMRI) responses to illusory-contour test stimuli after adapting to an illusory-contour adapter stimulus that was oriented parallel or orthogonal to the test stimulus. We found orientation-selective adaptation to illusory contours in early (V1 and V2) and higher-tier visual areas (V3, hV4, VO1, V3A/B, V7, LO1, and LO2). That is, fMRI responses were smaller for test stimuli parallel to the adapter than for test stimuli orthogonal to the adapter. In two control experiments using spatially jittered and phase-randomized stimuli, we demonstrated that this adaptation was not just in response to differences in the distribution of spectral power in the stimuli. Orientation-selective adaptation to illusory contours increased from early to higher-tier visual areas. Thus, both early and higher-tier visual areas contain neurons selective for the orientation of this type of illusory contour.

Subliminal attentional modulation in crowding condition.

In the crowding phenomenon, recognition of a visual target is impaired by other similar visual stimuli (distracters) presented near the target. This effect may be due largely to insufficient resolution of spatial attention. We showed that attention could subliminally enhance orientation selective adaptation to illusory lines in the crowding condition where target-distractor separation is beyond the limit of spatial resolution of attention. Despite the traditionally held close link between attention and awareness, here we provided evidence for subliminal attentional modulation for orientation stimuli that could not have been consciously perceived.

Attentional modulation of adaptation to illusory lines.

Selective visual attention modulates neuronal activation in various cortical areas. This type of neuronal modulation could happen even in the early stages of visual processing where specific attributes of visual stimuli are processed. It has been shown that different forms of visual aftereffects, such as tilt aftereffect, motion aftereffect, and figural aftereffect, are modulated by attention. In this study, we investigated the effect of visual attention on adaptation to illusory lines. In the first experiment, orientation selective adaptation to a peripheral illusory line was measured in three conditions: (1) poor attention condition in which subjects performed a dual task (even-odd judgment) at the fixation point during the adaptation period, (2) partial attention condition in which subjects only observed successively presented digits at the fixation point and did not perform the task during the adaptation period, and (3) full attention condition in which no visual stimuli were presented at the fixation point. Results showed that the magnitude of adaptation systematically decreased as the attentional load at the fixation point increased. In the second experiment, two transparent illusory contours were presented during the adaptation period, and tilt aftereffects to attended and non-attended illusory lines were compared. The magnitude of tilt aftereffect to the attended illusory line was significantly greater than that to the non-attended illusory line even when non-attended illusory contour was more visually salient. Because visual areas V2 and V1 are the first stage in the processing of illusory contours, we could conclude that visual attention has modulatory effects on the activation of neurons in these areas.

Orientation-selective adaptation during motion-induced blindness.

When a global moving pattern is superimposed on high-contrast stationary or slowly moving stimuli, the latter occasionally disappear for periods of several seconds (motion-induced blindness, MIB). Here, an adaptation paradigm was used to determine if orientation-selective adaptation still occurs for the stimulus that is no longer visible. Two slowly drifting high-contrast Gabor patches were presented to observers. As soon as both patches disappeared, one was eliminated from the screen. After 2 s, two low-contrast Gabor patches were presented as tests at the same locations and observers were asked to report their orientations. The observers' performance was significantly higher when the orientation of the low-contrast test patch was orthogonal to the orientation of the high-contrast adapting patch (p < 0.0001) for the location where the patch was present during MIB, even though it was perceptually invisible. The observers' performance was not significantly different at the adjacent control location where the stimulus was absent during the MIB. Although no stimulus was visible at either location, orientation-selective adaptation was preserved only for the location at which the patch remained present. Since orientation information is processed in low-level visual areas such as the primary visual cortex (V1), we conclude that MIB originates in an area higher than V1.

Orientation-selective adaptation to crowded illusory lines.

Visual adaptation has been successfully used as a psychophysical tool for studying the functional organisation of visual awareness. It has been shown that orientation-selective adaptation to a grating pattern occurs in crowded conditions. In such conditions, simultaneous presentation of flanking distractors pushes the target stimulus out of conscious perception and severely impairs orientation discrimination in the periphery of the visual field. In the present study, orientation-selective adaptation to illusory lines induced by two line gratings abutting each other with a phase shift was examined in crowded and non-crowded conditions. To rule out the effects of lower level adaptations we used an animation paradigm in which the orientations of the two line gratings were altered repeatedly during adaptation phase without any change in the orientation of the resulting illusory line. Although performance of subjects in reporting the orientation of crowded illusory lines was at chance level, orientation-selective adaptation was preserved for crowded as well as non-crowded adapting targets. Two control experiments demonstrated that adaptation to endpoints of real lines at the location of abutting grating lines had minimal effect on the adaptation to illusory lines; and changes in the configuration of endpoints could not be responsible for better performance when adapting and test stimuli were different. We conclude that a crowding effect occurs after illusory lines have been processed in the visual stream. Since illusory lines seem to be represented at relatively early stages of visual processing (e.g. area V2), adaptation to crowded illusory stimuli suggests that neuronal activation in those early stages is not necessarily correlated with conscious perception.