A Pilot Trial of Dopamine Replacement for Dynamic Facial Expressions in Parkinson's Disease.

Background: Current conflict exists regarding the potential beneficial effects of dopamine medications on facial expressivity in Parkinson's disease. Via digital video analysis software, we previously found reduced facial movement (entropy) and slower time to reach peak entropy in individuals with Parkinson's disease compared to controls. Objectives: We aimed to determine whether levodopa medications improved parameters of dynamic facial expressions (amplitude, speed). Methods: A total of 34 individuals with idiopathic Parkinson's disease were videotaped making voluntary facial expressions (happy, fear, anger, disgust) when "on" and "off" levodopa. Participants were 52 to 80 years old, early to mid-stage disease, non-demented, and included more men (65%). Expressions were digitized and analyzed using software that extracted three variables: two indices of movement change (total entropy, percent entropy change) and time to reach peak expression. Results: Indices of facial movement (total entropy, peak entropy) and timing were significantly improved when patients were "on" vs "off" medication (all F's ≥ 3.00, P < 0.05). For total movement and time to reach peak entropy, levodopa-related improvements were emotion nonspecific. Levodopa-related improvement for peak entropy was driven primarily by happy expressions. There was no relationship between quantitative indices and clinical measures of mood (depression, anxiety) and motor disease severity. Conclusion: The effects of levodopa on Parkinson's disease voluntary facial movement and on timing were robust and consistent with those of levodopa on other intentional movements in Parkinson's disease. This improvement possibly occurred because of levodopa enhanced activation of face representation areas in fronto-cortical regions or because of less movement-based suppression.

Object-Location Memory Training in Older Adults Leads to Greater Deactivation of the Dorsal Default Mode Network.

Substantial evidence indicates that cognitive training can be efficacious for older adults, but findings regarding training-related brain plasticity have been mixed and vary depending on the imaging modality. Recent years have seen a growth in recognition of the importance of large-scale brain networks on cognition. In particular, task-induced deactivation within the default mode network (DMN) is thought to facilitate externally directed cognition, while aging-related decrements in this neural process are related to reduced cognitive performance. It is not yet clear whether task-induced deactivation within the DMN can be enhanced by cognitive training in the elderly. We previously reported durable cognitive improvements in a sample of healthy older adults (age range = 60-75) who completed 6 weeks of process-based object-location memory training (N = 36) compared to an active control training group (N = 31). The primary aim of the current study is to evaluate whether these cognitive gains are accompanied by training-related changes in task-related DMN deactivation. Given the evidence for heterogeneity of the DMN, we examine task-related activation/deactivation within two separate DMN branches, a ventral branch related to episodic memory and a dorsal branch more closely resembling the canonical DMN. Participants underwent functional magnetic resonance imaging (fMRI) while performing an untrained object-location memory task at four time points before, during, and after the training period. Task-induced (de)activation values were extracted for the ventral and dorsal DMN branches at each time point. Relative to visual fixation baseline: (i) the dorsal DMN was deactivated during the scanner task, while the ventral DMN was activated; (ii) the object-location memory training group exhibited an increase in dorsal DMN deactivation relative to the active control group over the course of training and follow-up; (iii) changes in dorsal DMN deactivation did not correlate with task improvement. These results indicate a training-related enhancement of task-induced deactivation of the dorsal DMN, although the specificity of this improvement to the cognitive task performed in the scanner is not clear.

Emotion modulation of the startle reflex in essential tremor: Blunted reactivity to unpleasant and pleasant pictures.

BACKGROUND: Essential tremor is a highly prevalent movement disorder characterized by kinetic tremor and mild cognitive-executive changes. These features are commonly attributed to abnormal cerebellar changes, resulting in disruption of cerebellar-thalamo-cortical networks. Less attention has been paid to alterations in basic emotion processing in essential tremor, despite known cerebellar-limbic interconnectivity. OBJECTIVES: In the current study, we tested the hypothesis that a psychophysiologic index of emotional reactivity, the emotion modulated startle reflex, would be muted in individuals with essential tremor relative to controls. METHODS: Participants included 19 essential tremor patients and 18 controls, who viewed standard sets of unpleasant, pleasant, and neutral pictures for six seconds each. During picture viewing, white noise bursts were binaurally presented to elicit startle eyeblinks measured over the orbicularis oculi. RESULTS: Consistent with past literature, controls' startle eyeblink responses were modulated according to picture valence (unpleasant > neutral > pleasant). In essential tremor participants, startle eyeblinks were not modulated by emotion. This modulation failure was not due to medication effects, nor was it due to abnormal appraisal of emotional picture content. CONCLUSIONS: Neuroanatomically, it remains unclear whether diminished startle modulation in essential tremor is secondary to aberrant cerebellar input to the amygdala, which is involved in priming the startle response in emotional contexts, or due to more direct disruption between the cerebellum and brainstem startle circuitry. If the former is correct, these findings may be the first to reveal dysregulation of emotional networks in essential tremor.

Stimulation region within the globus pallidus does not affect verbal fluency performance.

BACKGROUND: Subthalamic (STN) and globus pallidus (GP) deep brain stimulation (DBS) have been previously shown to be efficacious in the treatment of selected Parkinson patients with medication resistant motor fluctuations and/or tremor. Deep brain stimulation of the STN has been implicated with more cognitive and mood side effects as compared to GP DBS; however, more studies are needed to better understand possible target differences. Previously, Mikos et al. [1] reported worsening of verbal fluency depending on the stimulation location within the STN region. OBJECTIVE/HYPOTHESIS: The current study applied the methods used by Mikos et al. (2011) to a different sample of Parkinson patients who underwent GP DBS. Based on differences in the size and functional somatotopy between structures (GP 412 mm(3) vs. STN 167 mm(3)), we hypothesized that there would be a less robust relationship between volume of tissue activated, fluency performance, and stimulation contact within the GP compared to what was reported in the STN. METHODS: Patient-specific DBS models were created and the volume of tissue activated within the GP was calculated. These data were correlated with patients' verbal fluency performance at dorsal, optimal, and ventral stimulation contacts. RESULTS: In contrast to STN findings, there was no significant relationship between stimulation location and fluency performance in patients who received GP DBS. CONCLUSION(S): These results suggest that fluency may be less sensitive to stimulation location in the globus pallidus and thus there may be more flexibility in terms of DBS programming with GP DBS patients.

The APOE ε4 allele is associated with increased frontally mediated neurobehavioral symptoms in amnestic MCI.

The apolipoprotein E ε4 allele is a risk factor for late-onset Alzheimer disease (AD), and the frontal lobes may be among the regions that manifest effects of ε4 even early in the disease. We predicted that among patients with amnestic mild cognitive impairment (aMCI) and AD, ε4 would be associated with increased neurobehavioral symptoms when assessed using a measure sensitive to frontal lobe integrity. We obtained cognitive data and caregiver ratings on the Frontal Systems Behavior Scale (FrSBe) for aMCI patients (N=29 ε4 carriers; N=29 noncarriers) and AD patients (N=47 carriers; N=42 noncarriers). In both diagnostic groups, ε4 carriers had lower scores on tests of memory but did not differ on cognitive screening measures or tests of executive functioning. There were no differences in retrospective caregiver ratings of preillness status on the FrSBe by ε4 status in either diagnostic group. However, in the aMCI group, ε4 carriers had elevated current FrSBe Executive Dysfunction scores in comparison with noncarriers. In the AD group, there were no differences in current FrSBe scores by genotype group. Results indicate that ε4-related behavior change occurs in the aMCI stage but may not be apparent by the AD stage.

Factors related to extended hospital stays following deep brain stimulation for Parkinson's disease.

OBJECTIVE: Patients with Parkinson's disease (PD) are typically discharged from the hospital the day following deep brain stimulation (DBS) surgery; however, factors extending hospital stay are largely unknown. This study examined potential factors that might have corresponded to increased post-operative stays following unilateral DBS surgery. METHODS: A retrospective review was performed on 115 unilateral PD DBS patients. Age, gender, number of microelectrode passes, duration and severity of illness, and pre-operative neuropsychological scores were considered as possible contributors to length of stay. RESULTS: Most patients (79%) had a hospital stay of one day following surgery. The most frequent reasons for delayed discharge (>1 day) included mental status change (N = 6) and hemorrhage (N = 5). Those with delayed discharge had significantly lower pre-surgical cognitive screening scores (Mini-Mental State Evaluation; MMSE), higher pre-surgical "on" medication motor score, and more microelectrode passes than those with immediate discharge. In correlation analyses, increasing length of hospital stay was significantly associated with more microelectrode passes, higher pre-surgical "on" medication motor scores, and decreasing MMSE scores. When the significant variables from the preliminary analyses were entered into a Poisson regression model, a greater number of microelectrode passes as well as lower MMSE scores remained significant predictors of increased length of stay. CONCLUSIONS: The number of microelectrode passes utilized for DBS surgery as well as a patient's general cognitive status may be important factors related to extended hospital stay. UPDRS "on" medication motor score may also provide some predictive power for immediate post-operative morbidity in unilateral DBS patients.

Cognitive declines after unilateral deep brain stimulation surgery in Parkinson's disease: a controlled study using Reliable Change, part II.

Deep brain stimulation (DBS) surgery, an effective treatment for medication-refractory Parkinson's disease (PD), may also lead to selective cognitive declines. In this continuation of a report by Zahodne et al. (2009), we compare cognitive performance of 24 PD patients who underwent unilateral implantation of the globus pallidus internal segment (GPi) or subthalamic nucleus (STN) to that of 19 PD controls. We used group statistical comparisons as well as Reliable Change Indexes (RCIs) to examine performance on measures of memory, processing speed, executive function, and visuospatial perception at baseline and 16 months after surgery. Significant between-group differences were noted on a psychomotor processing speed task. However, a significantly higher proportion of DBS patients than controls demonstrated reliable individual decline on a word list recall task (HVLT-R) and on several processing speed tests. Reliable improvements were noted on tests of visuospatial functioning. There was variability in individual outcome on executive functioning tests, with a small proportion of DBS patients demonstrating reliable decline and some demonstrating reliable improvement. Use of Reliable Change highlights the occurrence of individual variability, revealing declines and improvements in a small proportion of unilateral DBS patients that were not evident upon group comparison. These findings must be interpreted in light of group-level differences between the PD control and DBS patients on demographic and disease-related factors.

How cautious should we be when assessing apathy with the Unified Parkinson's Disease Rating Scale?

Current practice often assesses apathy with a single item from the Unified Parkinson's Disease Rating Scale (UPDRS, item 4). Yet, the relationship between the UPDRS item 4 and the validated Apathy Scale (AS) is unknown. The purpose of this study was to evaluate the operating characteristics of UPDRS item 4 in relation to the AS. Three hundred and one patients with PD were administered the AS and the UPDRS. We compared the UPDRS item 4 to the standard AS classification of > or =14 as apathetic. A receiver operating characteristics (ROC) curve was obtained, and sensitivity, specificity, positive, and negative predictive power were calculated. The ROC curve showed area under the curve as 0.75. A cut-off of 1 had good sensitivity (81%) but poor specificity (53%; high false positive rate). A cut-off point of 2 had acceptable specificity (87%) but poor sensitivity (52%, high false negative rate). Continuing to increasing the cut-off point (e.g., 3, 4) continues to increase specificity at the expense of dramatically reducing sensitivity. These findings suggest the use of caution when screening for apathy with item 4 due to its poor sensitivity in relation to the AS.

Awareness of expressivity deficits in non-demented Parkinson disease.

A masked facial expression, one of the hallmark features of Parkinson disease (PD), can form the basis for misattributions by others about a patient's mood or interest levels. Reports of preserved intensity of internal emotional experience in PD participants raise the question of whether patients are aware of their outward expressivity levels. The aim of the present study was to determine whether PD participants exhibit deficits in overall emotional expressivity, and if so, whether they are aware of these deficits. We evaluated 37 non-demented PD participants and 21 comparison participants using the Berkeley Expressivity Questionnaire (BEQ). To examine awareness of emotional expressivity, we compared participant self-ratings of their own expressivity to ratings made by family members or close friends. Participants also completed questionnaires regarding depression and apathy and underwent motor examination and cognitive screening. PD participants' self-ratings of emotional expressivity were significantly lower than comparison participants' self-ratings. Even so, the PD participants viewed themselves as experiencing equivalent levels of emotional intensity to comparison participants, based on analysis of the BEQ subscales. Informant and PD participant self-ratings did not differ, indicating that PD participants accurately appraise the extent of their reduced expressivity. These findings suggest that anosognosia for emotional expressivity is not a prominent feature of nondemented Parkinson disease. Importantly, PD participants are aware of their reduced expressivity and report experiencing emotions as intensely as comparison participants. These findings highlight the view that diminished emotional expressivity in PD should not be mistaken for decreased subjective emotional experience.

Does deep brain stimulation induce apathy in Parkinson's disease?

Chronic deep brain stimulation (DBS) is an important therapeutic advancement for the treatment of motor symptoms in Parkinson's disease (PD). However, its effects on non-motor symptoms are not well understood. Several studies have reported motivational disturbances and apathy after DBS surgery. Recent studies are beginning to more carefully examine the relationship between DBS and apathy. This review summarizes and evaluates the current state of the literature on apathy after DBS surgery, discusses methodological limitations in the literature, and makes suggestions for future research.

Stability of neuropsychological performance in anorexia nervosa.

INTRODUCTION: We investigated the stability of neuropsychological performance and eating disorder (EDO) symptoms before, immediately after, and 2 years after inpatient treatment. We also examined relationships between neuropsychological and EDO measures. METHODS: Sixteen women who were admitted for inpatient treatment of anorexia nervosa participated in three evaluations: (1) at admission to the hospital, (2) at discharge, and (3) at a follow-up exam approximately two years after discharge. RESULTS: Body mass index increased significantly from each testing session to the next. Endorsement of eating disorder symptoms was significantly decreased at discharge and at follow-up compared to admission. In terms of cognitive performance, total scores on a brief neuropsychological battery (RBANS) were significantly greater at follow-up than at admission. We found no relationships between EDO symptoms and cognitive function at any of the three sessions. CONCLUSIONS: The current findings suggest that EDO symptoms and cognitive performance in anorexia nervosa patients can show improvement as long as two years after hospitalization, but there is no evidence that EDO symptoms are related to neuropsychological performance.

Tardive parkinsonism in a bipolar patient: post-mortem examination supports a physiological rather than pathological dysfunction.

We describe a case of tardive parkinsonism in the setting of bipolar syndrome, and we offer pathological confirmation that idiopathic Parkinson disease was not the underlying etiology. A 74-year-old Hispanic woman with a history of bipolar disease was noted to have oro-buccal-lingual chorea and parkinsonian symptoms such as resting tremor, rigidity, bradykinesia, and gait disorder persisting several months after neuroleptic discontinuation. She had minor improvement in ambulation with levodopa treatment, and she significantly improved in ambulation only during her manic states. Examination of the subject's post-mortem brain revealed no explicit evidence of degeneration in substantia nigra or other brainstem centers, and no nigral or cortical Lewy bodies were present. Glial cytoplasmic inclusions (characteristic of multiple systems atrophy) and globose neurofibrillary tangles (seen in progressive supranuclear palsy) were not seen either. This patient's presentation was most consistent with neuroleptic-induced parkinsonism and tardive dyskinesia; the etiology was likely related to previous neuroleptic exposure.

Morphology of the cerebral cortex in preclinical Huntington's disease.

OBJECTIVE: Cortical morphology was evaluated in subjects with known gene expansion for Huntington's disease and no manifest disease. METHOD: Magnetic resonance imaging scans were obtained for 24 subjects with preclinical Huntington's disease and were compared to those for 24 matched healthy subjects by means of novel imaging methods to quantify aspects of cortical structure. RESULTS: In relation to the comparison subjects, those with preclinical Huntington's disease showed altered cortex morphology with enlargement of gyral crowns and abnormally thin sulci. These changes were manifested in global alterations of gyral and sulcal shape. CONCLUSION: These findings lend support to the notion that, in addition to the degenerative process, abnormal neural development may also be an important process in the pathoetiology of Huntington's disease.

fMRI detection of early neural dysfunction in preclinical Huntington's disease.

Neuropsychological and neuroimaging changes have been observed in individuals with the Huntington's disease (HD) gene expansion prior to the onset of manifest HD. This cross-sectional fMRI study of preclinical HD (pre-HD) individuals was conducted to determine if functional brain changes precede deficits in behavioral performance and striatal atrophy. Twenty-six pre-HD and 13 demographically matched healthy participants performed a time reproduction task while undergoing fMRI scanning. Pre-HD participants were divided into two groups (n=13 each): FAR (>12 years to estimated onset [YEO] of manifest HD) and CLOSE (<12 YEO). The CLOSE group demonstrated behavioral deficits, striatal atrophy, and reduced neural activation in the left putamen, SMA, left anterior insula and right inferior frontal gyrus. The FAR group showed reduced neural activation in the right anterior cingulate and right anterior insula. The FAR group also demonstrated increased neural activation in the left sensorimotor, left medial frontal gyrus, left precentral gyrus, bilateral superior temporal gyri and right cerebellum. The fMRI changes in the FAR group occurred in the relative absence of striatal atrophy and behavioral performance deficits. These results suggest that fMRI is sensitive to neural dysfunction occurring more than 12 years prior to the estimated onset of manifest HD.

Deep brain stimulation and the role of the neuropsychologist.

Deep brain stimulation (DBS) now plays an important role in the treatment of Parkinson's disease, tremor, and dystonia. DBS may also have a role in the treatment of other disorders such as obsessive-compulsive disorder, Tourette's syndrome, and depression. The neuropsychologist plays a crucial role in patient selection, follow-up, and management of intra-operative and post-operative effects (Pillon, 2002; Saint-Cyr & Trepanier, 2000). There is now emerging evidence that DBS can induce mood, cognitive, and behavioral changes. These changes can have dramatic effects on patient outcome. There have been methodological problems with many of the studies of DBS on mood, cognition, and behavior. The neuropsychologist needs to be aware of these issues when following up patients, and constructing future studies. Additionally, this article will review all aspects of the DBS procedure that can result in mood, cognitive, and behavioral effects and what role(s) the neuropsychologist should play in screening and follow-up.

Startling facts about emotion in Parkinson's disease: blunted reactivity to aversive stimuli.

The amygdala is closely linked to basal ganglia circuitry and plays a key role in danger detection and fear-potentiated startle. Based on recent findings of amygdalar abnormalities in Parkinson's disease, we hypothesized that non-demented patients with this illness would show blunted reactivity during aversive/unpleasant events, as indexed by diminished emotional modulation of the startle eyeblink response. To test this hypothesis, 23 idiopathic patients with Parkinson's disease and 17 controls viewed standardized sets of aversive, pleasant and neutral pictures for 6 s each. During this time, white noise bursts (50 ms, 95 db) were binaurally presented to elicit startle eyeblink responses, measured from electrodes over the orbicularis oculi. After viewing each picture, subjects provided ratings of valence and arousal. The Parkinson's disease patients were in the early to middle stages of their disease, not demented or depressed, and were tested 'on' dopaminergic medication. The two groups were similar in age, education, gender and cognitive screening status. The control group had larger startle responses when viewing negative, aversive pictures than neutral or pleasant pictures. As predicted, startle enhancement during aversive pictures was significantly muted in the Parkinson's disease patients. This blunting was not due to abnormalities in the mechanics of the startle eyeblink per se. Nor was it related to depression symptoms, medications (psychotropics), or failure to perceive/appreciate the negative meaning of aversive pictures (i.e. normal valence ratings). Reduced startle reactivity in the disease group was related to disease severity (Hoehn-Yahr) and occurred in the context of reduced arousal ratings of aversive pictures. These findings of blunted startle reactivity add to the literature on emotional changes associated with Parkinson's disease. The basis for this muted reactivity is unknown but may involve an amygdala-based translational defect whereby the results of cognitive appraisal are not appropriately transcoded into somato-motor-arousal responses normally associated with an aversive motivational state. This may arise from faulty dopaminergic gating of the amygdala, resulting in 'inhibition' of the amygdala in the manner described by Marowsky et al. (Marowsky A, Yanagawa Y, Obata K, Vogt E. Neuron 2005; 48: 1025-37). More broadly, the findings of muted reactivity to aversive stimuli may reflect a 'bradylimbic' affective disturbance in patients with Parkinson's disease. Future studies are needed to address whether the physiologic blunting observed here might be a useful correlate of apathy.

Brain structure in preclinical Huntington's disease.

BACKGROUND: Huntington's disease (HD) is traditionally conceptualized as a degenerative disease of the striatum. Recent scientific advances, however, have suggested neurodevelopmental contributions and extrastriatal brain abnormalities. This study was designed to assess the morphology of the brain in participants who had previously undergone elective DNA analyses for the HD mutation who did not currently have a clinical diagnosis of HD (preclinical HD subjects). METHODS: Twenty-four preclinical participants with the gene expansion for HD underwent brain magnetic resonance imaging and were compared with a group of 24 healthy control subjects, matched by gender and age. RESULTS: Huntington's disease preclinical participants had substantial morphologic differences from controls throughout the cerebrum. Volume of the cerebral cortex was significantly increased in preclinical HD, whereas the basal ganglia and cerebral white matter volume were substantially decreased. CONCLUSIONS: In individuals with the HD gene mutation who are considered healthy (preclinical for manifest disease), the morphology of the brain is substantially altered compared with matched control subjects. Although decreased volumes of the striatum and cerebral white matter could represent early degenerative changes, the novel finding of enlarged cortex suggests that developmental pathology occurs in HD.

White matter volume and cognitive dysfunction in early Huntington's disease.

BACKGROUND: Structural abnormalities of the striatum and cognitive impairments have consistently been shown in patients with Huntington's disease (HD). Fewer studies have examined other cerebral structures in early HD and potential associations with cognition. METHOD: Ten patients with early HD and 10 matched control subjects underwent magnetic resonance imaging to provide quantitative measures (volumes) of cortical gray and white matter and the caudate, putamen, and thalamus. Patients completed the Unified Huntington's Disease Rating Scale, including three cognitive tasks. RESULTS: Although striatal volumes were clearly reduced, white matter was also morphologically abnormal. Cortical gray matter volume was not significantly correlated with cognitive performance. However, the cognitive tasks were most highly correlated with cerebral white matter and, to a lesser degree, striatal volume. CONCLUSIONS: Cerebral white matter volume may be an important variable to examine in future studies of HD.