Parkinson's disease-related network topographies characterized with resting state functional MRI.

Spatial covariance mapping can be used to identify and measure the activity of disease-related functional brain networks. While this approach has been widely used in the analysis of cerebral blood flow and metabolic PET scans, it is not clear whether it can be reliably applied to resting state functional MRI (rs-fMRI) data. In this study, we present a novel method based on independent component analysis (ICA) to characterize specific network topographies associated with Parkinson's disease (PD). Using rs-fMRI data from PD and healthy subjects, we used ICA with bootstrap resampling to identify a PD-related pattern that reliably discriminated the two groups. This topography, termed rs-MRI PD-related pattern (fPDRP), was similar to previously characterized disease-related patterns identified using metabolic PET imaging. Following pattern identification, we validated the fPDRP by computing its expression in rs-fMRI testing data on a prospective case basis. Indeed, significant increases in fPDRP expression were found in separate sets of PD and control subjects. In addition to providing a similar degree of group separation as PET, fPDRP values correlated with motor disability and declined toward normal with levodopa administration. Finally, we used this approach in conjunction with neuropsychological performance measures to identify a separate PD cognition-related pattern in the patients. This pattern, termed rs-fMRI PD cognition-related pattern (fPDCP), was topographically similar to its PET-derived counterpart. Subject scores for the fPDCP correlated with executive function in both training and testing data. These findings suggest that ICA can be used in conjunction with bootstrap resampling to identify and validate stable disease-related network topographies in rs-fMRI. Hum Brain Mapp 38:617-630, 2017. © 2016 Wiley Periodicals, Inc.

High-Intensity Exercise Acutely Increases Substantia Nigra and Prefrontal Brain Activity in Parkinson's Disease.

BACKGROUND Pathologic alterations in resting-state brain activity patterns exist among individuals with Parkinson's disease (PD). Since physical exercise alters resting-state brain activity in non-PD populations and improves PD symptoms, we assessed the acute effect of exercise on resting-state brain activity in exercise-trained individuals with PD. MATERIAL AND METHODS Resting-state functional magnetic resonance imaging (fMRI) was collected twice for 17 PD participants at the conclusion of an exercise intervention. The acute effect of exercise was examined for PD participants using the amplitude of low frequency fluctuation (ALFF) before and after a single bout of exercise. Correlations of clinical variables (i.e., PDQ-39 quality of life and MDS-UPDRS) with ALFF values were examined for the exercise-trained PD participants. RESULTS An effect of acute exercise was observed as an increased ALFF signal within the right ventromedial prefrontal cortex (PFC), left ventrolateral PFC, and bilaterally within the substantia nigra (SN). Quality of life was positively correlated with ALFF values within the vmPFC and vlPFC. CONCLUSIONS Given the role of the SN and PFC in motor and non-motor symptoms in PD, the acute increases in brain activity within these regions, if repeated frequently over time (i.e., exercise training), may serve as a potential mechanism underlying exercise-induced PD-specific clinical benefits.

Allocentric But Not Egocentric Pseudoneglect of Peripersonal Space.

BACKGROUND AND OBJECTIVE: Healthy adults often deviate leftward on line bisection tasks (allocentric pseudoneglect) but rightward on body part bisection tasks (egocentric pseudoneglect). People visually estimate distance in peripersonal space by comparing the distance to the length of a body part such as an arm's length (an egocentric reference) or using standard units of distance such as inches (an allocentric reference). Our objective was to learn whether people have pseudoneglect when estimating distances in peripersonal space using egocentric versus allocentric reference frames. METHODS: Twelve healthy participants standing either next to or 5 feet away from a wall were asked to move away from or toward the wall such that their shoulder would be what they judged to be an arm's length or a distance of 1, 2, or 3 feet from the wall. RESULTS: The participants estimated their arm's length more accurately than the standard units of distance (possibly related to learning and practice). Participants were more precise when estimating the length of their left than their right arm. When estimating standard units of distance, participants underestimated the distances on their left side more than on their right. CONCLUSIONS: Our results support the postulate that left pseudoneglect is an allocentric phenomenon related to a hemispheric asymmetry in computing allocentric distances. The participants underestimated 2 and 3 feet, but overestimated 1 foot. This dichotomy may relate to using focused versus distributed attention. The brain mechanisms leading to these asymmetries remain to be determined.

Hypometric allocentric and egocentric distance estimates in Parkinson disease.

OBJECTIVE AND BACKGROUND: Persons with Parkinson disease (PD) show hypometric movements and make hypometric estimates of imagined actions. These deficits may be related to misestimates of the length of body parts. Our objective was to learn whether patients with PD are impaired in their estimations of their arm's length and standard units of distance. METHODS: We tested 20 patients with PD, all on therapeutic doses of dopaminergic medications, and 13 healthy controls. In half of the trials, the participants stood so that either their right or left shoulder was adjacent to a wall; in the other half, their right or left shoulder was 5 feet from the wall. In the egocentric testing condition, they were asked to move their body toward or away from the wall to what they considered was an arm's length from the wall. In the allocentric testing condition, they were to move toward or away from the wall so that their proximal shoulder was a standard unit distance of 1, 2, or 3 feet from the wall. RESULTS: The patients with PD made much greater hypometric (too close to the wall) errors. Since at 5 feet from the wall they had to move farther to underestimate distances, their errors cannot be explained by hypometric movements. The results did not differ significantly by egocentric or allocentric estimation, side of shoulder proximity, or side of PD onset. CONCLUSIONS: Our findings support the idea that the egocentric and allocentric hypometria associated with PD is a perceptual rather than motor disorder.

The emerging postural instability phenotype in idiopathic Parkinson disease.

Identification of individuals at high risk for rapid progression of motor and cognitive signs in Parkinson disease (PD) is clinically significant. Postural instability and gait dysfunction (PIGD) are associated with greater motor and cognitive deterioration. We examined the relationship between baseline clinical factors and the development of postural instability using 5-year longitudinal de-novo idiopathic data (n = 301) from the Parkinson's Progressive Markers Initiative (PPMI). Logistic regression analysis revealed baseline features associated with future postural instability, and we designated this cohort the emerging postural instability (ePI) phenotype. We evaluated the resulting ePI phenotype rating scale validity in two held-out populations which showed a significantly higher risk of postural instability. Emerging PI phenotype was identified before onset of postural instability in 289 of 301 paired comparisons, with a median progression time of 972 days. Baseline cognitive performance was similar but declined more rapidly in ePI phenotype. We provide an ePI phenotype rating scale (ePIRS) for evaluation of individual risk at baseline for progression to postural instability.

Influence of left versus right hemibody onset Parkinson's disease on cardiovascular control.

Whereas the left hemisphere is involved in regulating the parasympathetic nervous system, the right hemisphere regulates the sympathetic. Given the asymmetrical onset of motor symptoms and neuropathology in PD, differences in cardiovascular functions might be expected between PD patients with left hemibody onset (LHO) versus right hemibody onset (RHO). A total of 66 PD patients served as participants, including 31 LHO patients and 35 RHO PD patients. All participants had their resting heart rate (HR) and blood pressure (BP) recorded. Although the LHO group had lower systolic BP, it had higher resting HR than did the RHO group. The reason for this dissociation is not known but might be related to asymmetrical vagus nerve control of the heart (SA node). Future researchers might want to use additional indices of cardiovascular functioning that are more precise measures of parasympathetic and sympathetic functioning, as well as learn the influence of dopaminergic medications.

Verbal and visuospatial memory in lateral onset Parkinson disease: time is of the essence.

OBJECTIVE: This investigation sought to study immediate and delayed verbal and visuospatial recall in Parkinson disease (PD) patients with left hemibody (LHO) and right hemibody (RHO) onset of motor symptoms and to examine the role of mental processing speed in recall of this information. BACKGROUND: Research is mixed regarding material specific memory impairments in LHO and RHO PD. However, earlier research has not used a factorial approach in investigating material specific memory in LHO and RHO PD. We hypothesized that LHO PD patients would exhibit an increase in performance following the delayed verbal free recall trial and either decline or stability in performance on the delayed visuospatial free recall trial. The opposite pattern was hypothesized for RHO PD patients. METHOD: The Hopkins Verbal Learning Test-revised (HVLT-R) and the Brief Visuospatial Memory Test-revised (BVMT-R) were administered to a sample of 28 LHO PD patients and 36 RHO PD patients. The Stroop Color-word Test was administered as a measure of mental processing speed. RESULTS: The results indicated that the RHO group experienced a significant decline in performance on verbal free recall from the immediate to the delayed trials and a significant improvement in performance from the immediate to the delayed visuospatial free recall trials. Additionally, a significant negative correlation was found between mental processing speed and changes in recall from the immediate to the delayed conditions for the RHO group. CONCLUSIONS: These results indicate that the RHO PD group experienced a significant decline in verbal free recall and a significant improvement in visuospatial free recall from the immediate to the delayed trials and that the LHO PD patients experienced no significant changes. Further, mental processing speed appears to influence the recall of information from the immediate to the delayed conditions.

Anxiety affects working memory only in left hemibody onset Parkinson disease patients.

OBJECTIVE: This investigation sought to examine the potential moderating influence of heightened anxiety on working memory in Parkinson disease (PD) patients. Further, we wanted to determine whether this moderating influence of anxiety differentially affects PD patients with left hemibody (LBH) versus right hemibody (RHB) onset of motor symptoms. BACKGROUND: Research has examined the neurocognitive effects of depression in PD. However, a paucity of research has examined the effects of heightened anxiety in PD. We predicted that LHB PD patients with heightened anxiety would perform worse on a measure of working memory than RHB PD patients. METHOD: A total of 59 PD patients completed the state-trait anxiety inventory and were also administered the digit span subtest of the Wechsler Memory Scale-III. RESULTS: The results supported the hypotheses, indicating that the LHB PD patients with heightened anxiety performed significantly worse than the RHB PD patients with heightened anxiety and the LHB PD patients with low anxiety. CONCLUSIONS: These findings suggest that left hemibody onset PD patients may experience more disability in their activities of daily living. Future research should explore whether differences also exist between PD patients with and without the diagnosed anxiety disorders.

Conceptual hypometria? An evaluation of conceptual mapping of space in Parkinson's disease.

When interacting with objects in their environment, patients with Parkinson's disease (PD) often make hypometric movements (e.g., micrographia). The purpose of this study was to learn if patients with PD, in the absence of overt actions or environmental stimuli, have egocentric (body-centered) conceptual (representational) hypometria. Actions can take place in either proximal or distal peri-personal space. Normally, the right hemisphere has a distal and the right a proximal attentional bias. We also want to learn if a patient with onset of disease in the right hemisphere would have a greater conceptual action hypometria than individuals with left hemispheric onset. Seventeen subjects with PD and 15 age-matched controls were given a questionnaire evaluating subjective perception of personal action space. The questionnaire asked individuals to rate, using a 0-5 scale, the distances between their body and hand when performing the various actions that take place in peri-personal space. When compared to control participants, participants with PD, and especially those with predominant left sided symptoms (right greater than left hemispheric dysfunction) had hypometric mental perceptions for actions that normally occur in far peri-personal space. Individuals with PD appear to demonstrate a conceptual hypometria, suggesting that there is a perturbation of their interactive representational maps and these maps appear to be more disordered by right than left hemisphere dysfunction. However, it is also possible that when making action distance computations, participants used covert actions and it was the hypometric covert actions that induced the computational hypometria.

Greater motor improvement in right hemibody Parkinson's patients after dopaminergic medications.

Due to motor and neuropathological asymmetries, Parkinson's disease (PD) patients with right hemibody onset (RHO) of symptoms may experience greater benefit from dopaminergic enhancing medications, relative to patients with left hemibody onset (LHO). We investigated this possibility by measuring UPDRS scores of 20 PD patients with LHO and 13 patients with RHO, both prior and subsequent to taking dopaminergic enhancing medications. Following treatment, the motor score from the UPDRS improved for both groups of patients. However, PD patients with RHO experienced greater improvement in motor functioning following administration of dopaminergic enhancing medications than those with LHO.

Micro- and Macrostructural White Matter Integrity in Never-Treated and Currently Unmedicated Patients With Schizophrenia and Effects of Short-Term Antipsychotic Treatment.

BACKGROUND: Schizophrenia is associated with progressive white matter changes, but it is unclear whether antipsychotic medications contribute to these. Our objective was to characterize effects of short-term treatment with risperidone on white matter diffusion indices. METHODS: We recruited 42 patients with schizophrenia (30 never treated and 12 currently untreated) and 42 matched healthy control subjects in this prospective case-control neuroimaging study. Patients received a 6-week trial of risperidone. Using diffusion tensor imaging, we assessed microstructural (fractional anisotropy, mean diffusivity, and radial diffusivity) and macrostructural (radial fiber trophy) white matter integrity deficits in unmedicated patients compared with control subjects and change in white matter integrity in patients before and after antipsychotic treatment (mean risperidone dose at end point was 3.73 ± 1.72 mg). RESULTS: At baseline, fractional anisotropy was decreased in the left medial temporal white matter (cluster extent: 123 voxels; Montreal Neurological Institute peak coordinates: x = -51, y = -44, z = -7; α < .05), and mean diffusivity was increased in the fusiform/lingual gyrus white matter extending to the hippocampal part of the cingulum (cluster extent: 185 voxels; peak coordinates: x = -27, y = -49, z = 2; α < .04) in patients compared with control subjects. Radial diffusivity and macrostructure were not abnormal. None of the diffusion indices showed a significant change after 6 weeks of treatment with both voxelwise and whole-brain white matter analyses. CONCLUSIONS: We demonstrate microstructural white matter integrity abnormalities in the absence of macrostructural impairment in unmedicated patients with primarily early-stage schizophrenia. In our data, we found no significant white matter changes after short-term treatment with risperidone.

A longitudinal neurite and free water imaging study in patients with a schizophrenia spectrum disorder.

Diffusion tensor imaging (DTI) studies show widespread white matter abnormalities in schizophrenia, but it is difficult to directly relate these parameters to biological processes. Neurite orientation dispersion and density imaging (NODDI) is geared toward biophysical characterization of white matter microstructure, but only few studies have leveraged this technique to study white matter alterations. We recruited 42 schizophrenia patients (30 antipsychotic-naïve and 12 currently untreated) and 42 matched controls in this prospective study. We assessed the orientation dispersion index (ODI) and extracellular free water (FW) using single-shell DTI data before and after a 6-week trial of risperidone. Longitudinal data were available for 27 patients. Voxelwise analyses showed significantly increased ODI in the posterior limb of the internal capsule in unmedicated patients (242 voxels; x = -24; y = 6; z = 6; p < 0.01; α < 0.04), but no alterations in FW. Whole brain measures did not reveal alterations in ODI but a 6.3% trend-level increase in FW in unmedicated SZ (t = -1.873; p = 0.07). Baseline ODI was negatively correlated with subsequent response to antipsychotic treatment (r = -0.38; p = 0.049). Here, we demonstrated altered fiber complexity in medication-naïve and unmedicated patients with a schizophrenia spectrum illness. Lesser whole brain fiber uniformity was predictive of poor response to treatment, suggesting this measure may be a clinically relevant biomarker. Interestingly, we found no significant changes in NODDI indices after short-term treatment with risperidone. Our data show that biophysical diffusion models have promise for the in vivo evaluation of brain microstructure in this devastating neuropsychiatric syndrome.

Spatial emotional akinesia in Parkinson disease.

BACKGROUND/OBJECTIVES: Patients with Parkinson disease (PD) exhibit motor and frontal-executive dysfunction and often seem to be emotionally apathetic. We investigated whether PD patients have alterations in their emotional reactivity and how this might impact their proximal (avoidance) versus distal (approach) allocation of attention-intention. METHODS: Nine participants with PD and 9 normal controls were asked to judge the valence (pleasant-positive vs. unpleasant-negative) and arousal of 30 pictures from the International Affective Picture System. Participants were instructed to rate the pictures by marking 14-cm radial lines placed in front of them. On those lines where the subjects were going to rate emotional valence, the lines had a happy face at 1 end and a sad face at the other and when rating the arousal, they were presented with lines that had an "excited" and a "calm" face at opposite ends. For the emotional ratings, the dependent measures were the distances from the end of the line that had the "calm" or "sad" face to the participants' mark. For the approach-avoidance analysis, the dependent measure was the distance from the bottom of the line, regardless of the position of faces. RESULTS: The PD patients did not differ from controls when judging valence, but their judgments of arousal was lower than that of the controls. In addition, in contrast to the controls when judging neutral pictures and arousal, the PD patients, independent of the proximal or distal position of the sad/happy faces or excited/calm faces, demonstrated an overall proximal bias. When presented with emotional versus neutral stimuli, the control group reduced their extrapersonal spatial bias, whereas the subjects with PD did not change their spatial bias. CONCLUSIONS: The judgments of valence made by the subjects with PD were the same as that of the controls. These judgments might be based on cognitive decisions and as our PD subjects were not demented they could accurately determine valence. In contrast, judgments of arousal were reduced in the PD participants, and this result might reflect these patients impaired arousal-activation systems. Although emotional, versus neutral stimuli, induced a proximal deviation in the responses of the control subjects, the subjects with PD did not change their spatial bias. This Parkinsonian "emotional akinesia" might be related to either a reduced capacity to experience emotions or to an inability of emotional experiences to influence intentional and attentional systems.

Attentional grasp in Parkinson disease.

BACKGROUND: Patients with Parkinson disease (PD) have deficits in the neurotransmitter systems important for the normal allocation of attention. We sought to examine how the presence of PD influences the spatial allocation of reactive (bottom-up) and volitional (top-down) attention. METHODS: To assess the spatial allocation of attention, we used the line bisection task. When assessing "bottom-up" attention, lateral blinking lights were or were not present during the time the PD and normal subjects were attempting to perform line bisections. In the top-down condition, these subjects were asked to name the color of the laterally presented light before bisecting lines. RESULTS: In the bottom-up condition, when compared with control subjects, the participants with PD were not abnormally distracted, but in the top-down condition, imperative stimuli on the right side of the line seemed to influence the PD subjects' allocation of attention. CONCLUSIONS: The results suggest that when voluntarily allocating attention rightward, PD patients have difficulty disengaging and/or reallocating their attention. This disengagement deficit might be related to the frontal-executive dysfunction associated with PD.

Induction of tyrosine hydroxylase expression by the transcription factor Pitx3.

Transcription factors are fate determining regulatory factors in dopaminergic neuronal development and differentiation. Among them, Nurr1 is the most extensively studied, but the importance of Pitx3 has recently been appreciated. Over-expression of both factors has been utilized to enhance the dopaminergic differentiation of stem cells for transplantation into models of Parkinson's disease. Previous studies however have seen conflicting results regarding the induction of tyrosine hydroxylase expression and dopaminergic differentiation induced by over-expression of Pitx3. Here we show that over-expression of Pitx3 and Nurr1 induced endogenous tyrosine hydroxylase expression as well as a tyrosine hydroxylase promoter-reporter construct in a human non-neuronal and mouse embryonic stem cell lines. Combined simultaneous expression of Nurr1 and Pitx3 however did not lead to enhancement of tyrosine hydroxylase expression over that of either factor alone in either of the cell lines or with either method. These results suggest that other regulatory elements may also be involved in regulation of tyrosine hydroxylase expression. There was also a lack of a correlation between the expression levels of tyrosine hydroxylase with that of the transcription factor constructs. To yield a robust dopaminergic differentiation a combinatorial or successive treatment with different transcription factors may be more effective.

Lessons learned in deep brain stimulation for movement and neuropsychiatric disorders.

The introduction of deep brain stimulation (DBS) as a treatment for medication-refractory essential tremor in the late 1980s revealed, for the first time, that "chronically" implanted brain hardware had the potential to modulate neurologic function with surprisingly low morbidity. Over time, the therapeutic promise of DBS has become evident in Parkinson's disease and dystonia. In some experienced centers, complex tremor disorders, such as posttraumatic Holmes tremor and the tremor of multiple sclerosis, are being increasingly targeted. More recently, other indications, including obsessive-compulsive disorder, Tourette's syndrome, major depression, and chronic pain, have been proposed. As the field has expanded, our knowledge about potential cognitive side effects of DBS has also expanded. This article reviews the current knowledge regarding the impact of stimulation of the subthalamic nucleus, globus pallidus internus, and ventralis intermedius nucleus of the thalamus on symptoms in essential tremor, Parkinson's disease, and dystonia. Also discussed are the emerging targets, what is known about the cognitive sequelae of DBS, and what has been learned about the complications and therapeutic failures.

Treatment of acute intracranial vertebrobasilar dissection with angioplasty and stent placement: report of two cases.

Acute vertebrobasilar dissection may cause subarachnoid hemorrhage by rupturing through the adventia or cerebral infarct by progressive occlusion of the true lumen. Recent reports on the endovascular management of this condition have focused on treatment of pseudoaneurysms. We report two cases where angioplasty or stent placement was successfully used to improve compromised blood flow secondary to vertebrobasilar dissection.

Ventral tegmental area/midbrain functional connectivity and response to antipsychotic medication in schizophrenia.

Medication management in schizophrenia is a lengthy process, as the lack of clinical response can only be confirmed after at least 4 weeks of antipsychotic treatment at a therapeutic dose. Thus, there is a clear need for the discovery of biomarkers that have the potential to accelerate the management of treatment. Using resting-state functional MRI, we examined the functional connectivity of the ventral tegmental area (VTA), the origin of the mesocorticolimbic dopamine projections, in 21 healthy controls and 21 unmedicated patients with schizophrenia at baseline (pre-treatment) and after 1 week of treatment with the antipsychotic drug risperidone (1-week post-treatment). Group-level functional connectivity maps were obtained and group differences in connectivity were assessed on the groups' participant-level functional connectivity maps. We also examined the relationship between pre-treatment/1-week post-treatment functional connectivity and treatment response. Compared with controls, patients exhibited significantly reduced pre-treatment VTA/midbrain connectivity to multiple cortical and subcortical regions, including the dorsal anterior cingulate cortex (dACC) and thalamus. After 1 week of treatment, VTA/midbrain connectivity to bilateral regions of the thalamus was re-established. Pre-treatment VTA/midbrain connectivity strength to dACC was positively correlated with good response to a 6-week course of risperidone, whereas pre-treatment VTA/midbrain connectivity strength to the default mode network was negatively correlated. Our findings suggest that VTA/midbrain resting-state connectivity may be a useful biomarker for the prediction of treatment response.

Anxiety and depression severity are related to right but not left onset Parkinson's disease duration.

Depression and anxiety have both been associated with relative left frontal hypoactivation and the motor symptoms of Parkinson's disease typically begin in a lateral or asymmetrical fashion. Hence, PD patients with right hemibody onset may experience heightened depression and anxiety. However, research is mixed regarding whether right or left hemibody onset PD is associated with elevated levels of depression and anxiety. This literature, though, has not considered the potential moderating variable of disease duration. We hypothesized that disease duration would be positively correlated with measures of depression and anxiety in right but not left hemibody onset PD patients. The results indicated that scores on the Geriatric Depression Scale, Beck Depression Inventory-II, and the State Trait Anxiety Scale - State correlated positively with disease duration, but only in the right hemibody onset group of PD patients. Thus, right hemibody onset PD is associated with more severe depressive and anxiety symptoms, but only when disease duration is considered.

Pilot safety and feasibility study of treadmill aerobic exercise in Parkinson disease with gait impairment.

This pilot study evaluated the safety and feasibility of a 3-month progressive treadmill aerobic exercise (TM-AEX) program for persons with Parkinson disease with gait impairment. Eight subjects underwent a treadmill stress test to determine eligibility. Of these subjects, three were referred for further cardiac evaluation and five were enrolled. In 136 TM-AEX sessions, 11 falls or near falls and 9 episodes (8 asymptomatic) of systolic blood pressure drops >20 mmHg occurred. Harness supports prevented injury from falls. TM-AEX significantly improved the subjects' total Unified Parkinson's Disease Rating Scale scores and peak ambulatory workload capacities. This study suggests that an aerobic exercise program is feasible for persons who have Parkinson disease with gait impairment; however, precautions must be taken to prevent falls. Systolic blood pressure instability during exercise points to the need for autonomic dysfunction monitoring. Our data indicate that TM-AEX may reduce symptom severity and improve fitness. Further studies are needed for a better understanding of the risks and benefits of TM-AEX in this population.