Quality of Life Changes Following the Onset of Cerebellar Ataxia: Symptoms and Concerns Self-reported by Ataxia Patients and Informants.

Semi-structured interviews of patient accounts and caregiver, or informant, perspectives are a beneficial resource for patients suffering from diseases with complex symptomatology, such as cerebellar ataxia. The aim of this study was to identify, quantify, and compare the ways in which cerebellar ataxia patients' and informants' quality of life had changed as a result of living with ataxia. Using a semi-structured interview, responses were collected from patients and informants regarding motor, cognitive, and psychosocial variables. Responses were also collected from patients and informants to open-ended questions that were subsequently categorized into 15 quality of life themes that best represented changes experienced by the patients and informants. Ataxia patients and informants agreed as to the severity of posture/gait, daily activities/fine motor tasks, speech/feeding/swallowing, and oculomotor/vision impairment. It was also demonstrated that severity ratings for specific motor-related functions strongly correlated with corresponding functions within the International Cooperative Ataxia Rating Scale (ICARS), and that this interview identified frequency associations between motor impairments and specific psychosocial difficulties, which could be useful for prognostic purposes. Overall, the information obtained from this study characterized the symptoms and challenges to ataxia patients and their caregivers, which could serve as a useful educational resource for those affected by ataxia, clinicians, and researchers.

The Cerebellum and Implicit Sequencing: Evidence from Cerebellar Ataxia.

The cerebellum recognizes sequences from prior experiences and uses this information to generate internal models that predict future outcomes in a feedforward manner [Front Hum Neurosci 8: 475, 2014; Cortex 47: 137-44, 2011; Cerebellum 7: 611-5, 2008; J Neurosci 26: 9107-16, 2006]. This process has been well documented in the motor domain, but the cerebellum's role in cognitive sequencing, within the context of implicit versus explicit processes, is not well characterized. In this study, we tested individuals with cerebellar ataxia and healthy controls to clarify the role of the cerebellum sequencing using variations on implicit versus explicit and motor versus cognitive demands across five experiments. Converging results across these studies suggest that cerebellar feedforward mechanisms may be necessary for sequencing in the implicit domain only. In the ataxia group, rhythmic tapping, rate of motor learning, and implicit sequence learning were impaired. However, for cognitive sequencing that could be accomplished using explicit strategies, the cerebellar group performed normally, as though they shifted to extra-cerebellar mechanisms to compensate. For example, when cognitive and motor functions relied on cerebellar function simultaneously, the ataxia group's motor function was unaffected, in contrast to that of controls whose motor performance declined as a function of cognitive load. These findings indicated that the cerebellum is not critical for all forms of sequencing per se. Instead, it plays a fundamental role for sequencing within the implicit domain, whether functions are motor or cognitive. Moreover, individuals with cerebellar ataxia are generally able to compensate for cognitive sequencing when explicit strategies are available in order to preserve resources for motor function.

Neuropsychiatric Symptoms as a Reliable Phenomenology of Cerebellar Ataxia.

While cerebellar ataxia (CA) is a neurodegenerative disease known for motor impairment, changes in mood have also been reported. A full account of neuropsychiatric symptomology in CA may guide improvements in treatment regimes, measure the presence and severity of sub-clinical neuropsychiatric disturbance symptomology in CA, and compare patient versus informant symptom recognition. Neuropsychiatric phenomena were gathered from CA patients with genetic and unknown etiologies and their informants (e.g., spouse or parent). Information was obtained from in-person interviews and the Center for Epidemiologic Studies Depression Scale. Responses were converted to the Neuropsychiatric Inventory-Questionnaire (NPI-Q) scores by consensus ratings. Patient NPI-Q scores were evaluated for symptom prevalence and severity relative to those obtained from healthy controls. Patient-informant NPI-Q score disagreements were evaluated. In this cohort, 95% of patients presented with at least one neuropsychiatric symptom and 51% of patients with three or more symptoms. The most common symptoms were anxiety, depression, nighttime behaviors (e.g., interrupted sleep), irritability, disinhibition, abnormal appetite, and agitation. The prevalence of these neuropsychiatric symptoms was uniform across patients with genetic versus unknown etiologies. Patient and informant symptom report disagreements reflected that patients noted sleep impairment and depression, while informants noted irritability and agitation. Neuropsychiatric disturbance is highly prevalent in patients with CA and contributes to the phenomenology of CA, regardless of etiology. Clinicians should monitor psychiatric health in their CA patients, considering that supplemental information from informants can help gauge the impact on family members and caregivers.

Brainstem Pathologies Correlate With Depression and Psychosis in Parkinson's Disease.

BACKGROUND: The pathological hallmarks of Parkinson's disease include intraneuronal Lewy bodies, neuronal loss, and gliosis. We aim to correlate Parkinson's disease neuropsychiatric symptoms, (e.g., depression, psychosis, and anxiety) with the severity of neuropathology in the substantia nigra and locus coeruleus. METHODS: The brains of 175 participants with a primary pathologic diagnosis of Parkinson's disease were analyzed semi-quantitatively to ascertain the burden of neuronal loss and gliosis and Lewy body pathology within the locus coeruleus and substantia nigra. Participants' history of anxiety, depression, and psychosis were determined using a chart-extracted medical history or record of formal psychiatric evaluation. RESULTS: Of the sample, 56% (n = 98), 50% (n = 88), and 31.25% (n = 55) of subjects had a diagnosis of psychosis, depression, and anxiety, respectively. Psychosis (χ2 = 7.1, p = 0.008, df = 1) and depression (χ2 = 7.2, p = 0.007, df = 1) were associated with severe neuronal loss and gliosis in the substantia nigra but not in the locus coeruleus. No association was observed between anxiety and neuronal loss and gliosis in either region. No neuropsychiatric symptoms were associated with Lewy body score. After controlling for disease duration and dementia, psychosis (odds ratio [OR]: 3.1, 95% confidence interval [CI]: 1.5-6.4, χ2 = 9.4, p = 0.012, df = 1) and depression (OR: 2.6, 95% CI: 1.3-5.0, χ2 = 7.9, p = 0.005, df = 1) remained associated with severe neuronal loss and gliosis in the substantia nigra. CONCLUSION: These results suggest that psychosis and depression in Parkinson's disease are associated with the underlying neurodegenerative process and demonstrate that cell loss and gliosis may be a better marker of neuropsychiatric symptoms than Lewy body pathology.

Can patients with cerebellar disease switch learning mechanisms to reduce their adaptation deficits?

Systematic perturbations in motor adaptation tasks are primarily countered by learning from sensory-prediction errors, with secondary contributions from other learning processes. Despite the availability of these additional processes, particularly the use of explicit re-aiming to counteract observed target errors, patients with cerebellar degeneration are surprisingly unable to compensate for their sensory-prediction error deficits by spontaneously switching to another learning mechanism. We hypothesized that if the nature of the task was changed-by allowing vision of the hand, which eliminates sensory-prediction errors-patients could be induced to preferentially adopt aiming strategies to solve visuomotor rotations. To test this, we first developed a novel visuomotor rotation paradigm that provides participants with vision of their hand in addition to the cursor, effectively setting the sensory-prediction error signal to zero. We demonstrated in younger healthy control subjects that this promotes a switch to strategic re-aiming based on target errors. We then showed that with vision of the hand, patients with cerebellar degeneration could also switch to an aiming strategy in response to visuomotor rotations, performing similarly to age-matched participants (older controls). Moreover, patients could retrieve their learned aiming solution after vision of the hand was removed (although they could not improve beyond what they retrieved), and retain it for at least 1 year. Both patients and older controls, however, exhibited impaired overall adaptation performance compared to younger healthy controls (age 18-33 years), likely due to age-related reductions in spatial and working memory. Patients also failed to generalize, i.e. they were unable to adopt analogous aiming strategies in response to novel rotations. Hence, there appears to be an inescapable obligatory dependence on sensory-prediction error-based learning-even when this system is impaired in patients with cerebellar disease. The persistence of sensory-prediction error-based learning effectively suppresses a switch to target error-based learning, which perhaps explains the unexpectedly poor performance by patients with cerebellar degeneration in visuomotor adaptation tasks.

Visuospatial Organization and Recall in Cerebellar Ataxia.

Poor visuospatial skills can disrupt activities of daily living. The cerebellum has been implicated in visuospatial processing, and patients with cerebellar injury often exhibit poor visuospatial skills, as measured by impaired memory for the figure within the Rey-Osterrieth complex figure task (ROCF). Visuospatial skills are an inherent aspect of the ROCF; however, figure organization (i.e., the order in which the figure is reconstructed by the participant) can influence recall ability. The objective of this study was to examine and compare visuospatial and organization skills in people with cerebellar ataxia. We administered the ROCF to patients diagnosed with cerebellar ataxia and healthy controls. The cerebellar ataxia group included patients that carried a diagnosis of spinocerebellar ataxia (any subtype), autosomal dominant cerebellar ataxia, or cerebellar ataxia with unknown etiology. Primary outcome measures were organization and recall performance on the ROCF, with supplemental information derived from cognitive tests of visuospatial perception, working memory, processing speed, and motor function. Cerebellar ataxia patients revealed impaired figure organization relative to that of controls. Figure copy was impaired in the patients, but their subsequent recall performance was normal, suggesting compensation from initial organization and copying strategies. In controls, figure organization predicted recall performance, but this relationship was not observed in the patients. Instead, processing speed predicted patients' recall accuracy. Supplemental tasks indicated that visual perception was intact in the cerebellar ataxia group and that performance deficits were more closely tied to organization strategies than with visuospatial skills.

Domain-specific cognitive impairment in non-demented Parkinson's disease psychosis.

INTRODUCTION: In Parkinson's disease (PD), psychosis is associated with cognitive impairment that may be more profound in particular cognitive domains. Our goal was to determine whether psychosis in non-demented PD participants is associated with domain-specific cognitive impairment on the Mini-Mental State Exam (MMSE). METHODS: The Morris K. Udall Parkinson's Disease Research Center of Excellence Longitudinal Study at Johns Hopkins is a prospective study that was initiated in 1998. Clinical assessments are conducted at two-year intervals at the Johns Hopkins Hospital. We analyzed data from 137 enrolled participants with idiopathic PD. Psychosis diagnoses were established by psychiatrist interview per DSM-IV criteria. An incident dementia diagnosis resulted in exclusion from analysis for that evaluation and any future evaluations in that participant. We used logistic regression with generalized estimated equations (GEE) to model the time-varying relationship between MMSE subscale scores and psychosis, adjusting for potential confounding variables identified through univariable analysis. RESULTS: Thirty-one unique psychosis cases were recorded among non-demented participants. Fifty total evaluations with psychosis present were analyzed. In multivariable regressions, psychosis was associated with lower scores on the orientation (relative odds ratio, rOR: 0.73; 95% CI: 0.58-0.93; p = 0.011), language (rOR: 0.64; 95% CI: 0.48-0.86; p = 0.003), and intersecting pentagon (rOR: 0.43; 95% CI: 0.20-0.92 p = 0.030) subscales of the MMSE. CONCLUSIONS: In PD, executive dysfunction, disorientation, and impaired language comprehension may be associated with psychosis. Our findings suggest that the corresponding MMSE subscales may be useful in identifying participants with a higher likelihood of developing psychosis. Copyright © 2017 John Wiley & Sons, Ltd.

Reward, attention, and HIV-related risk in HIV+ individuals.

Human immunodeficiency virus (HIV) is often contracted through engaging in risky reward-motivated behaviors such as needle sharing and unprotected sex. Understanding the factors that make an individual more vulnerable to succumbing to the temptation to engage in these risky behaviors is important to limiting the spread of HIV. One potential source of this vulnerability concerns the degree to which an individual is able to resist paying attention to irrelevant reward information. In the present study, we examine this possible link by characterizing individual differences in value-based attentional bias in a sample of HIV+ individuals with varying histories of risk-taking behavior. Participants learned associations between experimental stimuli and monetary reward outcome. The degree of attentional bias for these reward-associated stimuli, reflected in their ability to capture attention when presented as task-irrelevant distractors, was then assessed both immediately and six months following reward learning. Value-driven attentional capture was related to substance abuse history and non-planning impulsiveness during the time leading up to contraction of HIV as measured via self-report. These findings suggest a link between the ability to ignore reward-associated information and prior HIV-related risk-taking behavior. Additionally, particular aspects of HIV-associated neurocognitive disorders were related to attentional bias, including motor deficits commonly associated with HIV-induced damage to the basal ganglia.

Consensus paper: the cerebellum's role in movement and cognition.

While the cerebellum's role in motor function is well recognized, the nature of its concurrent role in cognitive function remains considerably less clear. The current consensus paper gathers diverse views on a variety of important roles played by the cerebellum across a range of cognitive and emotional functions. This paper considers the cerebellum in relation to neurocognitive development, language function, working memory, executive function, and the development of cerebellar internal control models and reflects upon some of the ways in which better understanding the cerebellum's status as a "supervised learning machine" can enrich our ability to understand human function and adaptation. As all contributors agree that the cerebellum plays a role in cognition, there is also an agreement that this conclusion remains highly inferential. Many conclusions about the role of the cerebellum in cognition originate from applying known information about cerebellar contributions to the coordination and quality of movement. These inferences are based on the uniformity of the cerebellum's compositional infrastructure and its apparent modular organization. There is considerable support for this view, based upon observations of patients with pathology within the cerebellum.

Consensus paper: Language and the cerebellum: an ongoing enigma.

In less than three decades, the concept "cerebellar neurocognition" has evolved from a mere afterthought to an entirely new and multifaceted area of neuroscientific research. A close interplay between three main strands of contemporary neuroscience induced a substantial modification of the traditional view of the cerebellum as a mere coordinator of autonomic and somatic motor functions. Indeed, the wealth of current evidence derived from detailed neuroanatomical investigations, functional neuroimaging studies with healthy subjects and patients and in-depth neuropsychological assessment of patients with cerebellar disorders shows that the cerebellum has a cardinal role to play in affective regulation, cognitive processing, and linguistic function. Although considerable progress has been made in models of cerebellar function, controversy remains regarding the exact role of the "linguistic cerebellum" in a broad variety of nonmotor language processes. This consensus paper brings together a range of different viewpoints and opinions regarding the contribution of the cerebellum to language function. Recent developments and insights in the nonmotor modulatory role of the cerebellum in language and some related disorders will be discussed. The role of the cerebellum in speech and language perception, in motor speech planning including apraxia of speech, in verbal working memory, in phonological and semantic verbal fluency, in syntax processing, in the dynamics of language production, in reading and in writing will be addressed. In addition, the functional topography of the linguistic cerebellum and the contribution of the deep nuclei to linguistic function will be briefly discussed. As such, a framework for debate and discussion will be offered in this consensus paper.

An fMRI analysis of verbal and non-verbal working memory in people with a past history of opioid dependence.

Introduction: Working memory describes the ability to maintain and manipulate information held in mind, and it is a fundamental aspect of executive function. Within drug addiction, impairments of executive control over behavior are thought to lead to poor decision making and risky behaviors. Previous research has demonstrated working memory (WM) and executive function difficulties in opioid-dependent individuals, but the neural underpinnings of such impairments in this population are not well understood. Methods: This study used functional magnetic resonance imaging to examine the neural mechanisms involved in WM in 13 opioid-dependent, methadone-maintained participants (OP) and 13 matched, healthy controls (HC). A Sternberg item-recognition task was administered with three conditions: (1) a "verbal" condition in which participants determined whether any six visually presented target letters matched a probe item that was presented 4-6 s later, (2) a "non-verbal" condition in which participants were presented with a Chinese character and, following a 4-6 s delay, determined whether the character matched the probe item, and (3) a "control" condition in which participants were presented with three horizontal lines and following the same delay, determined whether the lines matched a probe item (always the same three lines). Functional magnetic resonance imaging (fMRI) contrasts focused on the delay (or "maintenance") phase for verbal and non-verbal conditions relative to the control condition. Results: Accuracy on the WM task did not differ between groups, but the OP group was significantly slower to respond. The fMRI imaging results indicated differences in brain activity between the OP and HC groups. fMRI-guided regions of interest correlated with age of first alcohol and THC use, suggesting that early substance use, in addition to years of opioid-abuse, may have played a role in the OP group's WM performance. Discussion: A deeper understanding of these neural differences between opioid-dependent individuals and their healthy control counterparts helps shed light on fundamental ways in which substance use impacts the brain and cognition, potentially opening up novel avenues for therapeutic targets to treat substance use disorder.

An fMRI investigation of cerebellar function during verbal working memory in methadone maintenance patients.

Working memory is impaired in opioid-dependent individuals, yet the neural underpinnings of working memory in this population are largely unknown. Previous studies in healthy adults have demonstrated that working memory is supported by a network of brain regions that includes a cerebro-cerebellar circuit. The cerebellum, in particular, may be important for inner speech mechanisms that assist verbal working memory. This study used functional magnetic resonance imaging to examine brain activity associated with working memory in five opioid-dependent, methadone-maintained patients and five matched, healthy controls. An item recognition task was administered in two conditions: (1) a low working memory load "match" condition in which participants determined whether target letters presented at the beginning of the trial matched a probe item, and (2) a high working memory load "manipulation" condition in which participants counted two alphabetical letters forward of each of the targets and determined whether either of these new items matched a probe item. Response times and accuracy scores were not significantly different between the groups. FMRI analyses indicated that, in association with higher working memory load ("manipulation" condition), the patient group exhibited hyperactivity in the superior and inferior cerebellum and amygdala relative to that of controls. At a more liberal statistical threshold, patients exhibited hypoactivity in the left prefrontal and medial frontal/pre-SMA regions. These results indicate that verbal working memory in opioid-dependent individuals involves a disrupted cerebro-cerebellar circuit and shed light on the neuroanatomical basis of working memory impairments in this population.

Characterization of basal ganglia volume changes in the context of HIV and polysubstance use.

HIV and psychoactive substances can impact the integrity of the basal ganglia (BG), a neural substrate of cognition, motor control, and reward-seeking behaviors. This study assessed BG gray matter (GM) volume as a function of polysubstance (stimulant and opioid) use and HIV status. We hypothesized that comorbid polysubstance use and HIV seropositivity would alter BG GM volume differently than would polysubstance use or HIV status alone. We collected structural MRI scans, substance use history, and HIV diagnoses. Participants who had HIV (HIV +), a history of polysubstance dependence (POLY +), both, or neither completed assessments for cognition, motor function, and risk-taking behaviors (N = 93). All three clinical groups showed a left-lateralized pattern of GM reduction in the BG relative to controls. However, in the HIV + /POLY + group, stimulant use was associated with increased GM volume within the globus pallidus and putamen. This surpassed the effects from opioid use, as indicated by decreased GM volume throughout the BG in the HIV-/POLY + group. Motor learning was impaired in all three clinical groups, and in the HIV + /POLY + group, motor learning was associated with increased caudate and putamen GM volume. We also observed associations between BG GM volume and risk-taking behaviors in the HIV + /POLY- and HIV-/POLY + groups. The effects of substance use on the BG differed as a function of substance type used, HIV seropositivity, and BG subregion. Although BG volume decreased in association with HIV and opioid use, stimulants can, inversely, lead to BG volume increases within the context of HIV.

Quantitative susceptibility mapping of basal ganglia iron is associated with cognitive and motor functions that distinguish spinocerebellar ataxia type 6 and type 3.

Background: In spinocerebellar ataxia type 3 (SCA3), volume loss has been reported in the basal ganglia, an iron-rich brain region, but iron content has not been examined. Recent studies have reported that patients with SCA6 have markedly decreased iron content in the cerebellar dentate, coupled with severe volume loss. Changing brain iron levels can disrupt cognitive and motor functions, yet this has not been examined in the SCAs, a disease in which iron-rich regions are affected. Methods: In the present study, we used quantitative susceptibility mapping (QSM) to measure tissue magnetic susceptibility (indicating iron concentration), structural volume, and normalized susceptibility mass (indicating iron content) in the cerebellar dentate and basal ganglia in people with SCA3 (n = 10) and SCA6 (n = 6) and healthy controls (n = 9). Data were acquired using a 7T Philips MRI scanner. Supplemental measures assessed motor, cognitive, and mood domains. Results: Putamen volume was lower in both SCA groups relative to controls, replicating prior findings. Dentate susceptibility mass and volume in SCA6 was lower than in SCA3 or controls, also replicating prior findings. The novel finding was that higher basal ganglia susceptibility mass in SCA6 correlated with lower cognitive performance and greater motor impairment, an association that was not observed in SCA3. Cerebellar dentate susceptibility mass, however, had the opposite relationship with cognition and motor function in SCA6, suggesting that, as dentate iron is depleted, it relocated to the basal ganglia, which contributed to cognitive and motor decline. By contrast, basal ganglia volume loss, rather than iron content, appeared to drive changes in motor function in SCA3. Conclusion: The associations of higher basal ganglia iron with lower motor and cognitive function in SCA6 but not in SCA3 suggest the potential for using brain iron deposition profiles beyond the cerebellar dentate to assess disease states within the cerebellar ataxias. Moreover, the role of the basal ganglia deserves greater attention as a contributor to pathologic and phenotypic changes associated with SCA.

A multimodal neuroimaging study of brain abnormalities and clinical correlates in post treatment Lyme disease.

Lyme disease is the most common vector-borne infectious disease in the United States. Post-treatment Lyme disease (PTLD) is a condition affecting 10-20% of patients in which symptoms persist despite antibiotic treatment. Cognitive complaints are common among those with PTLD, suggesting that brain changes are associated with the course of the illness. However, there has been a paucity of evidence to explain the cognitive difficulties expressed by patients with PTLD. This study administered a working memory task to a carefully screened group of 12 patients with well-characterized PTLD and 18 healthy controls while undergoing functional MRI (fMRI). A subset of 12 controls and all 12 PTLD participants also received diffusion tensor imaging (DTI) to measure white matter integrity. Clinical variables were also assessed and correlated with these multimodal MRI findings. On the working memory task, the patients with PTLD responded more slowly, but no less accurately, than did controls. FMRI activations were observed in expected regions by the controls, and to a lesser extent, by the PTLD participants. The PTLD group also hypoactivated several regions relevant to the task. Conversely, novel regions were activated by the PTLD group that were not observed in controls, suggesting a compensatory mechanism. Notably, three activations were located in white matter of the frontal lobe. DTI measures applied to these three regions of interest revealed that higher axial diffusivity correlated with fewer cognitive and neurological symptoms. Whole-brain DTI analyses revealed several frontal lobe regions in which higher axial diffusivity in the patients with PTLD correlated with longer duration of illness. Together, these results show that the brain is altered by PTLD, involving changes to white matter within the frontal lobe. Higher axial diffusivity may reflect white matter repair and healing over time, rather than pathology, and cognition appears to be dynamically affected throughout this repair process.

The association between educational attainment and SCA 3 age of onset and disease course.

BACKGROUND: The number of trinucleotide CAG repeats is inversely correlated with the age at onset (AAO) of motor symptoms in individuals with Spinocerebellar Ataxia type 3 (SCA 3) and may be responsible for 50%-60% of the variability in AAO. Drawing from a social determinants of health model, we sought to determine if educational attainment further contributes to the AAO and motor symptom progression of SCA 3. METHODS: We performed a retrospective chart review in which twenty individuals met criteria for inclusion and had been seen by an ataxia specialist at our hospital between January 2005 and July 2019. AAO of motor symptoms and Scale for Assessment and Rating of Ataxia (SARA) scores were used as primary outcome measures. RESULTS: Using a linear regression, we found that having greater CAG repeat length and greater than 16 years of education results in an earlier AAO. The importance of the CAG repeat length on AAO, however, is greater amongst individuals with lower education. Using a linear mixed model evaluating SARA score over time with AAO, we found that less than 16 years of education is associated with faster progression of the disease. CONCLUSION: In our group of SCA 3 patients, level of education correlated with both the AAO and SARA scores. Though our findings need to be confirmed with a larger cohort, our study suggests that level of education can have a strong influence on health outcomes in SCA 3 and possibly other groups of patients with ataxia.

Functional topography of the cerebellum in verbal working memory.

Speech-both overt and covert-facilitates working memory by creating and refreshing motor memory traces, allowing new information to be received and processed. Neuroimaging studies suggest a functional topography within the sub-regions of the cerebellum that subserve verbal working memory. Medial regions of the anterior cerebellum support overt speech, consistent with other forms of motor execution such as finger tapping, whereas lateral portions of the superior cerebellum support speech planning and preparation (e.g., covert speech). The inferior cerebellum is active when information is maintained across a delay, but activation appears to be independent of speech, lateralized by modality of stimulus presentation, and possibly related to phonological storage processes. Motor (dorsal) and cognitive (ventral) channels of cerebellar output nuclei can be distinguished in working memory. Clinical investigations suggest that hyper-activity of cerebellum and disrupted control of inner speech may contribute to certain psychiatric symptoms.

How the motor system integrates with working memory.

Working memory is vital for basic functions in everyday life. During working memory, one holds a finite amount of information in mind until it is no longer required or when resources to maintain this information are depleted. Convergence of neuroimaging data indicates that working memory is supported by the motor system, and in particular, by regions that are involved in motor planning and preparation, in the absence of overt movement. These "secondary motor" regions are physically located between primary motor and non-motor regions, within the frontal lobe, cerebellum, and basal ganglia, creating a functionally organized gradient. The contribution of secondary motor regions to working memory may be to generate internal motor traces that reinforce the representation of information held in mind. The primary aim of this review is to elucidate motor-cognitive interactions through the lens of working memory using the Sternberg paradigm as a model and to suggest origins of the motor-cognitive interface. In addition, we discuss the implications of the motor-cognitive relationship for clinical groups with motor network deficits.

Onset and Remission of Psychosis in Parkinson's Disease: Pharmacologic and Motoric Markers.

BACKGROUND: Psychosis is among the most disabling complications of Parkinson's disease (PD). The chronicity of PD psychosis remains understudied and the relative importance of dopaminergic therapy versus the disease process itself in engendering psychosis remains unclear. OBJECTIVES: To examine pharmacologic and motoric correlates of PD psychosis onset and remission in a longitudinally monitored PD cohort. METHODS: We analyzed data from 165 participants enrolled in a longitudinal PD study through the Morris K. Udall Parkinson's Disease Research Center of Excellence at Johns Hopkins University. Evaluations included formal psychiatric assessment and were conducted at two-year intervals. Regression with generalized estimated equations (GEE) was used to produce unadjusted and adjusted estimates for time-varying longitudinal associations between psychosis and putative risk factors. RESULTS: Sixty-two participants (37.6%) were diagnosed with psychosis during at least one evaluation. Of forty-nine participants with psychosis followed over multiple evaluations, 13 (26.5%) demonstrated remission despite significant Hoehn & Yahr stage increase (p=0.009); two of these cases later relapsed. Multivariable regression with GEE identified dementia diagnosis, akinesia-rigidity, anticholinergic usage, and levodopa-carbidopa dose to be significantly associated with psychosis, while disease duration was not. A sub-analysis of 30 incident psychosis cases suggested that dopamine agonist dose was lowered after psychosis onset with a compensatory increase in levodopa-carbidopa dosage. CONCLUSIONS: Our findings suggest that in the context of standard therapy, PD-related psychotic disorder can remit at a frequency of approximately 27%. Additionally, akinetic-rigid motor impairment was more strongly associated with psychosis than disease duration, independent of cognitive impairment and medications.