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1.  Toward a universal treatment for cancer: cell inflation assisted chemotherapy 
Cancer Medicine  2013;2(4):421-426.
Cancers show considerable genetic and functional heterogeneity, preventing the development of a universal anticancer drug. Here, I argue that it is nevertheless possible to elaborate a therapeutic strategy that can be used in almost every cancer, exploiting the negative feedback effect of normal cells on the proliferation of their precursors. This method, termed cell inflation assisted chemotherapy, is aimed at blocking normal cell division prior to high-dose antimitotic chemotherapy. Evidence for a negative feedback effect on granulocyte production suggests that it is possible to prevent neutropenia by transfusion of autologous granulocytes. In a first step, this protocol will be devised to protect neutrophils and to prevent granulopenia in patients treated with intensive chemotherapy. In its simplest form, it will consist of a leukapheresis–storage–reinjection sequence just prior to drug administration. Then, if the proof of concept is established, a more systematic use of intensive cell cycle-specific chemotherapy, together with protection of other lineages through temporary mitotic blockade might be a treatment applicable for most cancers.
Negative feedback effect of normal cells on the proliferation of their precursors may be used to protect them from high-dose antimitotic chemotherapy, preventing myelosuppression. In its simplest form, cell inflation assisted chemotherapy will consist of a leukapheresis-storage-reinjection sequence just prior to drug administration.
PMCID: PMC3799276  PMID: 24156014
Cancer chemotherapy; granulocytes; myelosuppression; negative feedback
2.  Thalamic projection fiber integrity in de novo Parkinson’s disease 
Background and Purpose
Post-mortem studies of advanced Parkinson’s disease (PD) have revealed disease-related pathology in the thalamus with an apparent predilection for specific thalamic nuclei. In the present study, we used diffusion tensor imaging (DTI) to investigate in vivo the microstructural integrity of six thalamic regions in de novo PD patients relative to healthy controls.
Materials and Methods
Forty subjects (20 with early-stage, untreated PD and 20 age- and sex-matched controls) were studied with a high-resolution DTI protocol at 3 Tesla to investigate the integrity of thalamic nuclei projection fibers. Two blinded, independent raters drew regions of interest (ROIs) in the following six thalamic regions: anterior nucleus (AN), ventral anterior nucleus (VA), ventral lateral nucleus (VL), dorsomedial nucleus (DM), ventral posterior lateral nucleus (VPL)/ventral posterior medial nucleus (VPM), and pulvinar (PU). Fractional anisotropy (FA) values were then calculated from the projection fibers in each region.
FA values were reduced significantly in the fibers projecting from the AN, VA, and DM, but not the VPL/VPM and PU, in the PD group compared to the control group. In addition, there was a reduction in FA values that approached significance in the VL of PD patients. These findings were consistent across both raters.
The present study provides preliminary in vivo evidence of thalamic projection fiber degeneration in de novo PD and sheds light on the extent of disrupted thalamic circuitry as a result of the disease itself.
PMCID: PMC3669594  PMID: 22766668
Parkinson’s disease; thalamus; diffusion tensor imaging; tractography; fractional anisotropy; magnetic resonance imaging
3.  Force Control Deficits in Individuals with Parkinson’s Disease, Multiple Systems Atrophy, and Progressive Supranuclear Palsy 
PLoS ONE  2013;8(3):e58403.
This study examined grip force and cognition in Parkinson’s disease (PD), Parkinsonian variant of multiple system atrophy (MSAp), progressive supranuclear palsy (PSP), and healthy controls. PD is characterized by a slower rate of force increase and decrease and the production of abnormally large grip forces. Early-stage PD has difficulty with the rapid contraction and relaxation of hand muscles required for precision gripping. The first goal was to determine which features of grip force are abnormal in MSAp and PSP. The second goal was to determine whether a single variable or a combination of motor and cognitive measures would distinguish patient groups. Since PSP is more cognitively impaired relative to PD and MSAp, we expected that combining motor and cognitive measures would further distinguish PSP from PD and MSAp.
We studied 44 participants: 12 PD, 12 MSAp, 8 PSP, and 12 controls. Patients were diagnosed by a movement disorders neurologist and were tested off anti-Parkinsonian medication. Participants completed a visually guided grip force task wherein force pulses were produced for 2 s, followed by 1 s of rest. We also conducted four cognitive tests.
PD, MSAp, and PSP were slower at contracting and relaxing force and produced longer pulse durations compared to controls. PSP produced additional force pulses during the task and were more cognitively impaired relative to other groups. A receiver operator characteristic analysis revealed that the combination of number of pulses and Brief Test of Attention (BTA) discriminated PSP from PD, MSAp, and controls with a high degree of sensitivity and specificity.
Slowness in contracting and relaxing force represent general features of PD, MSAp, and PSP, whereas producing additional force pulses was specific to PSP. Combining motor and cognitive measures provides a robust method for characterizing behavioral features of PSP compared to MSAp and PD.
PMCID: PMC3594313  PMID: 23505500
4.  Combined measures of movement and force variability distinguish Parkinson’s disease from essential tremor 
To examine whether behavioral and electrophysiological measures of motor performance accurately differentiate Parkinson’s disease (PD) and essential tremor (ET).
Twenty-four patients (12 PD; 12 ET) performed isometric force, ballistic movements, and tremor tasks. Receiver operating characteristic (ROC) analyses were conducted on all dependent measures that were significantly different between the two patient groups.
Patients with PD were more impaired on measures of movement deceleration than ET. Patients with ET were more impaired on measures of force variability than PD. ROC analyses revealed that sensitivity and specificity were excellent when combining measures during the isometric force task (torque rise time and force variability; 92% sensitivity and 92% specificity; AUC = 0.97). When combining measures across the force and movement tasks, the ROC analysis revealed improved sensitivity and specificity (force variability and peak deceleration; 92% sensitivity and 100% specificity; AUC = 0.99).
Combining measures of force variability and movement deceleration accurately differentiate patients with PD from those with ET with high sensitivity and specificity.
If validated in a larger sample, these measures can serve as markers to confirm the diagnosis of PD or ET and thus, enhance decision making for appropriate treatments for patients with these respective diseases.
PMCID: PMC3183282  PMID: 21570904
Parkinson’s disease; Essential tremor; Variability; Bradykinesia; Biomarker
5.  Unbalanced replication as a major source of genetic instability in cancer cells 
The origin of genetic instability in tumors is a matter of debate: while the prevailing model postulates a mutator phenotype resulting from an alteration in a caretaker gene as a prerequisite for genetic alterations leading to tumor formation, there is evidence against this model in the majority of cancers. A model for chromosomal instability should take into account the role of oncogenes in directly stimulating DNA and cellular component replication, creating aberrant structures when overexpressed. I will distinguish here two distinct mechanisms for the genetic instability of tumors: primary and secondary. Primary genetic instability is dependent on the inactivation of genes involved in maintaining genetic stability (caretaker genes), whereas secondary genetic instability is dependent on genes involved in tumor progression, i.e. oncogenes and tumor suppressor genes of the gatekeeper type. Secondary genetic instability, the most frequent condition, can be explained by the fact that some of the genes involved in tumor progression control replication of cell structures from within, leading to replication unbalance.
PMCID: PMC3484411  PMID: 23119227
Genetic instability; tumorigenesis; oncogenes; tumor suppressor genes; DNA replication; cell replication; replication unbalance; chromosomal instability
6.  Spatiotemporal tuning of brain activity and force performance 
NeuroImage  2010;54(3):2226-2236.
The spatial and temporal features of visual stimuli are either processed independently or are conflated in specific cells of visual cortex. Although spatial and temporal features of visual stimuli influence motor performance, it remains unclear how spatiotemporal information is processed beyond visual cortex in brain regions that control movement. We used functional magnetic resonance imaging to examine how brain activity and force control are influenced by visual gain at a high visual feedback frequency of 6.4 Hz and a low visual feedback frequency of 0.4 Hz. At 6.4 Hz, increasing visual gain led to improved force performance and increased activity in classic areas of the visuomotor system – V5, IPL, SPL, PMv, SMA-proper, and M1. At 0.4 Hz, increasing gain also lead to improved force performance. In addition to activation in M1/PMd and IPL in the visuomotor system, increasing visual gain at 0.4 Hz also corresponded with activity in the striatal-frontal circuit including DLPFC, ACC, and widespread activity in putamen, caudate, and SMA-proper. This study demonstrates that the frequency of visual feedback drives where in the brain visual gain mediated reductions in force error are regulated.
PMCID: PMC3008211  PMID: 20937396
basal ganglia; memory; prediction; visuomotor; fMRI
7.  Progressive Resistance Exercise and Parkinson's Disease: A Review of Potential Mechanisms 
Parkinson's Disease  2011;2012:124527.
This paper reviews the therapeutically beneficial effects of progressive resistance exercise (PRE) on Parkinson's disease (PD). First, this paper discusses the rationale for PRE in PD. Within the first section, the review discusses the central mechanisms that underlie bradykinesia and muscle weakness, highlights findings related to the central changes that accompany PRE in healthy individuals, and extends these findings to individuals with PD. It then illustrates the hypothesized positive effects of PRE on nigro-striatal-thalamo-cortical activation and connectivity. Second, it reviews recent findings of the use of PRE in individuals with PD. Finally, knowledge gaps of using PRE on individuals with PD are discussed along with suggestions for future research.
PMCID: PMC3236435  PMID: 22191068
8.  Blood Oxygenation Level Dependent Activation in Basal Ganglia Nuclei Relates to Specific Symptoms in De Novo Parkinson's Disease 
To aid the development of symptomatic and disease modifying therapies in Parkinson's disease (PD), there is a strong need to identify non-invasive measures of basal ganglia function that are sensitive to disease severity. This study examines the relation between blood oxygenation level dependent (BOLD) activation in every nucleus of the basal ganglia and symptom-specific disease severity in early stage, de novo PD. BOLD activation measured at 3 Tesla was compared between 20 early stage de novo PD patients and 20 controls during an established precision grip force task. In addition to the basal ganglia nuclei, activation in specific thalamic and cortical regions was examined. There were three novel findings. First, there were significant negative correlations between total motor Unified Parkinson's Disease Rating Scale (UPDRS) and BOLD activation in bilateral caudate, bilateral putamen, contralateral external segment of the globus pallidus, bilateral subthalamic nucleus, contralateral substantia nigra, and thalamus. Second, bradykinesia was the symptom that most consistently predicted BOLD activation in the basal ganglia and thalamus. Also, BOLD activation in the contralateral internal globus pallidus was related to tremor. Third, the reduced cortical activity in primary motor cortex and supplementary motor area in de novo PD did not relate to motor symptoms. These findings demonstrate that BOLD activity in nuclei of the basal ganglia relates most consistently to bradykinesia. The findings demonstrate that functional magnetic resonance imaging has strong potential to serve as a non-invasive marker for the state of basal ganglia function in de novo PD.
PMCID: PMC2952037  PMID: 20725915
fMRI; Parkinson's disease; Basal Ganglia; BOLD; disease severity
9.  Maintaining Force Control Despite Changes in Emotional Context Engages Dorsomedial Prefrontal and Premotor Cortex 
Cerebral Cortex (New York, NY)  2011;22(3):616-627.
Viewing emotional as compared with neutral images results in an increase in force production. An emotion-driven increase in force production has been associated with increased brain activity in ventrolateral prefrontal cortex and primary motor cortex (M1). In many instances, however, force production must be held constant despite changes in emotional state and the neural circuits underlying this form of control are not well understood. To address this issue, we designed a task in which subjects viewed pleasant, unpleasant, and neutral images during a force production task. We measured brain activity using functional magnetic resonance imaging and examined functional connectivity between emotion and motor circuits. Despite similar force performance across conditions, increased brain activity was evidenced in dorsomedial prefrontal cortex (dmPFC) and left ventral premotor cortex (PMv) when force was produced during emotional as compared with neutral conditions. Connectivity analyses extended these findings by demonstrating a task-dependent functional circuit between dmPFC and ventral and dorsal portions of premotor cortex. Our findings show that when force production has to be consistent despite changes in emotional context, a functional circuit between dmPFC and PMv and dorsal premotor cortex is engaged.
PMCID: PMC3278319  PMID: 21677029
10.  Predicting Grip Force Amplitude Involves Circuits in the Anterior Basal Ganglia 
NeuroImage  2009;49(4):3230.
The ability to grip objects allows us to perform many activities of daily living such as eating and drinking. Lesions to and disorders of the basal ganglia can cause deficits in grip force control. Although the prediction of grip force amplitude is an important component of performing a grip force task, the extant literature suggests that this process may not include the basal ganglia. This study used functional magnetic resonance imaging (fMRI) to explore the functional brain mechanisms underlying the prediction of grip force amplitude. The mean force and duration of force did not vary across prediction levels. As anticipated, the reaction time decreased with the level of grip force predictions. In confirmation of previous studies, the parieto-frontal and cerebellar circuits increased their fMRI signal as grip force predictability increased. In addition, the novel finding was that anterior nuclei in the basal ganglia such as caudate and anterior putamen also had an fMRI signal that increased with the level of grip force prediction. In contrast, the fMRI signal in posterior nuclei of the basal ganglia did not change with the level of prediction. These findings provide new evidence indicating that anterior basal ganglia nuclei are involved in the predictive scaling of precision grip force control. Further, the results provide additional support for the planning and parameterization model of the basal ganglia by demonstrating than specific anterior nuclei of the basal ganglia are involved in planning grip force.
PMCID: PMC2818558  PMID: 19944767
11.  Cortical and Subcortical Mechanisms for Precisely Controlled Force Generation and Force Relaxation 
Cerebral Cortex (New York, NY)  2009;19(11):2640-2650.
Gripping objects during everyday manual tasks requires the coordination of muscle contractions and muscle relaxations. The vast majority of studies have focused on muscle contractions. Although previous work has examined the motor cortex during muscle relaxation, the role of brain areas beyond motor cortex remains to be elucidated. The present study used functional magnetic resonance imaging to directly compare slow and precisely controlled force generation and force relaxation in humans. Contralateral primary motor cortex and bilateral caudate nucleus had greater activity during force generation compared with force relaxation. Conversely, right dorsolateral prefrontal cortex (DLPFC) had greater activity while relaxing force compared with generating force. Also, anterior cingulate cortex had greater deactivation while relaxing force compared with generating force. These findings were further strengthened by the fact that force output parameters such as the amplitude, rate, duration, variability, and error did not affect the brain imaging findings. These results demonstrate that the neural mechanisms underlying slow and precisely controlled force relaxation differ across prefrontal–striatal and motor cortical–striatal circuits. Moreover, this study demonstrates that the DLPFC is not only involved in slow and precisely controlled force generation, but has greater involvement in regulating slow and precisely controlled muscle relaxation.
PMCID: PMC2758679  PMID: 19254959
basal ganglia; force; motor cortex; prefrontal cortex; relaxation
12.  Basal Ganglia Mechanisms Underlying Precision Grip Force Control 
The classic grasping network has been well studied but thus far the focus has been on cortical regions in the control of grasping. Sub-cortically, specific nuclei of the basal ganglia have been shown to be important in different aspects of precision grip force control but these findings have not been well integrated. In this review we outline the evidence to support the hypothesis that key basal ganglia nuclei are involved in parameterizing specific properties of precision grip force. We review literature from different areas of human and animal work that converges to build a case for basal ganglia involvement in the control of precision gripping. Following on from literature showing anatomical connectivity between the basal ganglia nuclei and key nodes in the cortical grasping network, we suggest a conceptual framework for how the basal ganglia could function within the grasping network, particularly as it relates to the control of precision grip force.
PMCID: PMC2684813  PMID: 19428499
grasping; network; gripping; sub-cortical; imaging
13.  Variability of EMG patterns: a potential neurophysiological marker of Parkinson’s disease? 
This study evaluated whether changes in the electromygraphic (EMG) pattern during rapid point-to-point movements in individuals diagnosed with PD can: 1) distinguish PD subjects from healthy subjects and 2) determine if differences in the EMG pattern reflect disease severity in PD.
Three groups of 10 PD subjects and 10 age/sex matched healthy subjects performed rapid 72° point-to-point elbow flexion movements. PD subjects were divided, a priori, into three groups based upon off medication motor UPDRS score.
Measures related to the EMG pattern distinguished all PD subjects and 9 out of 10 healthy subjects, resulting in 100% sensitivity. Further, significant correlations were shown between EMG measures and the motor UPDRS score. After 30 months, the one healthy subject whose EMG pattern was abnormal was reexamined. The EMG measures remained abnormal and the motor UPDRS score went from 0 to 10. Parkinson’s disease was diagnosed.
Measures related to the variability of the EMG pattern during rapid point-to-point movements provide neurophysiological measures that objectively distinguish PD subjects from healthy subjects. These measures also correlate with disease severity.
EMG measures may provide a non-invasive measure that is sensitive and specific for identifying individuals with PD.
PMCID: PMC2679966  PMID: 19084473
Isotonic movements; Parkinson’s disease; electromyographic (EMG) activity; disease severity; disease progression
14.  Changes in the Relationship Between Movement Velocity and Movement Distance in Primary Focal Hand Dystonia 
Journal of motor behavior  2008;40(4):301-313.
The authors examined the relationship between movement velocity and distance and the associated muscle activation patterns in 18 individuals with focal hand dystonia (FHD) compared with a control group of 18 individuals with no known neuromuscular condition. Participants performed targeted voluntary wrist and elbow flexion movements as fast as possible across 5 movement distances. Individuals with FHD were slower than controls across all distances, and this difference was accentuated for longer movements. Muscle activation patterns were triphasic in the majority of individuals with FHD, and muscle activation scaled with distance in a similar manner to controls. Cocontraction did not explain movement slowing in individuals with dystonia, but there was a trend toward underactivation of the 1st agonist burst in the dystonic group. The authors concluded that slowness is a consistent feature of voluntary movement in FHD and is present even in the absence of dystonic posturing. Underactivation of the 1st agonist burst appears to be the most likely reason to explain slowing.
PMCID: PMC2657478  PMID: 18628107
agonist; cocontraction; focal hand dystonia
15.  Role of Individual Basal Ganglia Nuclei in Force Amplitude Generation 
Journal of neurophysiology  2007;98(2):821-834.
The basal ganglia-thalamo-cortical loop is an important neural circuit that regulates motor control. A key parameter that the nervous system regulates is the level of force to exert against an object during tasks such as grasping. Previous studies indicate that the basal ganglia do not exhibit increased activity with increasing amplitude of force, although these conclusions are based mainly on the putamen. The present study used functional magnetic resonance imaging to investigate which regions in the basal ganglia, thalamus, and motor cortex display increased activity when producing pinch-grip contractions of increasing force amplitude. We found that the internal portion of the globus pallidus (GPi) and subthalamic nucleus (STN) had a positive increase in percent signal change with increasing force, whereas the external portion of the globus pallidus, anterior putamen, posterior putamen, and caudate did not. In the thalamus we found that the ventral thalamic regions increase in percent signal change and activation volume with increasing force amplitude. The contralateral and ipsilateral primary motor/somatosensory (M1/S1) cortices had a positive increase in percent signal change and activation volume with increasing force amplitude, and the contralateral M1/S1 had a greater increase in percent signal change and activation volume than the ipsilateral side. We also found that deactivation did not change across force in the motor cortex and basal ganglia, but that the ipsilateral M1/S1 had greater deactivation than the contralateral M1/S1. Our findings provide direct evidence that GPi and STN regulate the amplitude of force output. These findings emphasize the heterogeneous role of individual nuclei of the basal ganglia in regulating specific parameters of motor output.
PMCID: PMC2367092  PMID: 17567775
16.  Role of the Basal Ganglia and Frontal Cortex in Selecting and Producing Internally Guided Force Pulses 
NeuroImage  2007;36(3):793-803.
The basal ganglia comprise a crucial circuit involved in force production and force selection, but the specific role of each nucleus to the production of force pulses and the selection of pulses of different force amplitudes remains unknown. We conducted an fMRI study in which participants produced force using a precision grip while a) holding a steady-state force, b) performing a series of force pulses with similar amplitude, and c) selecting force pulses of different amplitude. Region of interest analyses were conducted in the basal ganglia and frontal cortex to compare percent signal change during force pulse versus steady-state force production, and compare force amplitude selection to force production when selection of force amplitude was not present. There were three novel findings in the basal ganglia. First, the caudate nucleus increased activation during the selection of different force amplitudes when compared to producing a series of similar force pulses. Second, GPi, STN, and posterior putamen increased activation during the production of similar force amplitudes when compared to holding a steady-state force, and maintained similar activation during the production of different force amplitudes in which force selection was required. Third, GPe and anterior putamen had increased activation during the production of similar force pulses and further increased activation during the selection of different force pulses. These findings suggest that anterior basal ganglia nuclei are involved in selecting the amplitude of force contractions and posterior basal ganglia nuclei regulate basic aspects of dynamic force pulse production.
PMCID: PMC1950146  PMID: 17451971
17.  Heavy chain–only antibodies are spontaneously produced in light chain–deficient mice 
The Journal of Experimental Medicine  2007;204(13):3271-3283.
In healthy mammals, maturation of B cells expressing heavy (H) chain immunoglobulin (Ig) without light (L) chain is prevented by chaperone association of the H chain in the endoplasmic reticulum. Camelids are an exception, expressing homodimeric IgGs, an antibody type that to date has not been found in mice or humans. In camelids, immunization with viral epitopes generates high affinity H chain–only antibodies, which, because of their smaller size, recognize clefts and protrusions not readily distinguished by typical antibodies. Developmental processes leading to H chain antibody expression are unknown. We show that L−/− (κ−/−λ−/−-deficient) mice, in which conventional B cell development is blocked at the immature B cell stage, produce diverse H chain–only antibodies in serum. The generation of H chain–only IgG is caused by the loss of constant (C) γ exon 1, which is accomplished by genomic alterations in CH1-circumventing chaperone association. These mutations can be attributed to errors in class switch recombination, which facilitate the generation of H chain–only Ig-secreting plasma cells. Surprisingly, transcripts with a similar deletion can be found in normal mice. Thus, naturally occurring H chain transcripts without CH1 (VHDJH-hinge-CH2-CH3) are selected for and lead to the formation of fully functional and diverse H chain–only antibodies in L−/− animals.
PMCID: PMC2150980  PMID: 18086860
18.  Effects of Deep Brain Stimulation and Medication on Strength, Bradykinesia, and Electromyographic Patterns of the Ankle Joint in Parkinson’s Disease 
We investigated the control of movement in 12 patients with Parkinson’s disease (PD) after they received surgically implanted high-frequency stimulating electrodes in the subthalamic nucleus (STN). The experiment studied ankle strength, movement velocity, and the associated electromyographic patterns in PD patients, six of whom had tremor at the ankle. The patients were studied off treatment, ON STN deep brain stimulation (DBS), on medication, and on medication plus STN DBS. Twelve matched control subjects were also examined. Medication alone and STN DBS alone increased patients’ ankle strength, ankle velocity, agonist muscle burst amplitude, and agonist burst duration, while reducing the number of agonist bursts during movement. These findings were similar for PD patients with and without tremor. The combination of medication plus STN DBS normalized maximal strength at the ankle joint, but ankle movement velocity and electromyographic patterns were not normalized. The findings are the first to demonstrate that STN DBS and medication increase strength and movement velocity at the ankle joint.
PMCID: PMC2373255  PMID: 16124011
deep brain stimulation; subthalamic nucleus; bradykinesia; electromyography; Parkinson’s disease; tremor
19.  Deep Brain Stimulation and Medication for Parkinsonian Tremor During Secondary Tasks 
This study examined the efficacy of subthalamic nucleus (STN), deep brain stimulation (DBS), and medication for resting tremor during performance of secondary tasks. Hand tremor was recorded using accelerometry and electromyography (EMG) from 10 patients with Parkinson’s disease (PD) and ten matched control subjects. The PD subjects were examined off treatment, on STN DBS, on medication, and on STN DBS plus medication. In the first experiment, tremor was recorded in a quiet condition and during a cognitive task designed to enhance tremor. In the second experiment, tremor was recorded in a quiet condition and during isometric finger flexion (motor task) with the contralateral limb at 5% of the maximal voluntary contraction (MVC) that was designed to suppress tremor. Results showed that: (1) STN DBS and medication reduced tremor during a cognitive task that exacerbated tremor, (2) STN DBS normalized tremor frequency in both the quiet and cognitive task conditions, whereas tremor amplitude was only normalized in the quiet condition, (3) a secondary motor task reduced tremor in a similar manner to STN DBS. These findings demonstrate that STN DBS still suppresses tremor in the presence of a cognitive task. Furthermore, a secondary motor task of the opposite limb suppresses tremor to levels comparable to STN DBS.
PMCID: PMC2366974  PMID: 17469210
tremor; Parkinson’s disease; deep brain stimulation; subthalamic nucleus; secondary task
20.  Intermittent Visuomotor Processing in the Human Cerebellum, Parietal Cortex, and Premotor Cortex 
Journal of neurophysiology  2005;95(2):922-931.
The cerebellum, parietal cortex, and premotor cortex are integral to visuomotor processing. The parameters of visual information that modulate their role in visuomotor control are less clear. From motor psychophysics, the relation between the frequency of visual feedback and force variability has been identified as nonlinear. Thus we hypothesized that visual feedback frequency will differentially modulate the neural activation in the cerebellum, parietal cortex, and premotor cortex related to visuomotor processing. We used functional magnetic resonance imaging at 3 Tesla to examine visually guided grip force control under frequent and infrequent visual feedback conditions. Control conditions with intermittent visual feedback alone and a control force condition without visual feedback were examined. As expected, force variability was reduced in the frequent compared with the infrequent condition. Three novel findings were identified. First, infrequent (0.4 Hz) visual feedback did not result in visuomotor activation in lateral cerebellum (lobule VI/Crus I), whereas frequent (25 Hz) intermittent visual feedback did. This is in contrast to the anterior intermediate cerebellum (lobule V/VI), which was consistently active across all force conditions compared with rest. Second, confirming previous observations, the parietal and premotor cortices were active during grip force with frequent visual feedback. The novel finding was that the parietal and premotor cortex were also active during grip force with infrequent visual feedback. Third, right inferior parietal lobule, dorsal premotor cortex, and ventral premotor cortex had greater activation in the frequent compared with the infrequent grip force condition. These findings demonstrate that the frequency of visual information reduces motor error and differentially modulates the neural activation related to visuomotor processing in the cerebellum, parietal cortex, and premotor cortex.
PMCID: PMC2366036  PMID: 16267114
21.  Effects of STN DBS on Rigidity in Parkinson’s Disease 
We quantified the effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and medication on Parkinsonian rigidity using an objective measure of work about the elbow joint during a complete cycle of imposed 1-Hz sinusoidal oscillations. Resting and activated rigidity were analyzed in four experimental conditions: 1) off treatment; 2) on DBS; 3) on medication; and 4) on DBS plus medication. Rigidity at the elbow joint was also assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS). We tested ten patients who received STN DBS and ten age-matched neurologically healthy control subjects. The activated rigidity condition increased work in both Parkinson’s disease (PD) patients and control subjects. In PD patients, STN DBS reduced both resting and activated rigidity as indicated by work and the UPDRS rigidity score. This is the first demonstration that STN stimulation reduces rigidity using an objective measure such as work. In contrast, the presurgery dose of antiparkinsonian medication did not significantly improve the UPDRS rigidity score and reduced work only in the activated rigidity condition. Our results suggest that STN DBS may be more effective in alleviating rigidity in the upper limb of PD patients than medications administered at presurgery dosage level.
PMCID: PMC2365513  PMID: 17601186
Arm; human; movement disorders; rigidity
22.  Effects of STN DBS on Memory Guided Force Control in Parkinson’s Disease (June 2007) 
This study examined the control of elbow force in nine patients with Parkinson’s disease when visual feedback was available and when visual feedback was removed to determine how medication (Meds) and unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) affect memory guided force control. Patients were examined in each of four treatment conditions: 1) off treatment; 2) Meds; 3) STN DBS; and 4) Meds plus STN DBS. With visual feedback available, there was no difference in force output across treatment conditions. When visual feedback was removed force output drifted under the target in both the off-treatment and the Meds conditions. However, when on STN DBS or Meds plus STN DBS force output drifted above the target. As such, only STN DBS had a significant effect on force output in the vision removed condition. Increased force output when on STN DBS may have occurred due to disruptions in the basal ganglia-thalamo-cortical circuitry. We suggest that modulation of output of the internal segment of the globus pallidus by STN DBS may drive the effect of STN DBS on memory guided force control.
PMCID: PMC2361426  PMID: 17601184
Deep brain stimulation (DBS); force; globus pallidus; motor memory; vision
23.  Role of Hyperactive Cerebellum and Motor Cortex in Parkinson’s Disease 
NeuroImage  2007;35(1):222-233.
Previous neuroimaging studies have found hyperactivation in the cerebellum and motor cortex and hypoactivation in the basal ganglia in patients with Parkinson’s disease (PD) but the relationship between the two has not been established. This study examined whether cerebellar and motor cortex hyperactivation is a compensatory mechanism for hypoactivation in the basal ganglia or is a pathophysiological response that is related to the signs of the disease. Using a BOLD contrast fMRI paradigm PD patients and healthy controls performed automatic and cognitively controlled thumb pressing movements. Regions of interest analysis quantified the BOLD activation in motor areas, and correlations between the hyperactive and hypoactive regions were performed, along with correlations between the severity of upper limb rigidity and BOLD activation. There were three main findings. First, the putamen, supplementary motor area (SMA) and pre-SMA were hypoactive in PD patients. The left and right cerebellum and the contralateral motor cortex were hyperactive in PD patients. Second, PD patients had a significant negative correlation between the BOLD activation in the ipsilateral cerebellum and the contralateral putamen. The correlation between the putamen and motor cortex was not significant. Third, the BOLD activation in the motor cortex was positively correlated with the severity of upper limb rigidity, but the BOLD activation in the cerebellum was not correlated with rigidity. Further, the activation in the motor cortex was not correlated with upper extremity bradykinesia. These findings provide new evidence supporting the hypothesis that hyperactivation in the ipsilateral cerebellum is a compensatory mechanism for the defective basal ganglia. Our findings also provide the first evidence from neuroimaging that hyperactivation in the contralateral primary motor cortex is not a compensatory response but is directly related to upper limb rigidity.
PMCID: PMC1853309  PMID: 17223579
24.  Hemisphere-Specific Effects of Subthalamic Nucleus Deep Brain Stimulation on Speaking Rate and Articulatory Accuracy of Syllable Repetitions in Parkinson’s Disease 
This study tested the hypothesis that left versus right deep brain stimulation (DBS) of the subthalamic nucleus (STN) would have differential effects on speech. Twenty right-handed individuals with advanced Parkinson’s disease (PD) underwent unilateral STN DBS. Ten were operated on the right and 10 on the left hemisphere as indicated by severity of nonspeech motor function. Speech was evaluated before surgery and 3 to 6 months after surgery with stimulator-off and with stimulator-on, with all participants off anti-parkinsonian medication for 12 hours before evaluation. Evaluators and patient speakers were blinded to the stimulator status at the postsurgery evaluations. Motor performance was assessed with UPDRS-III. Each participant produced three samples of diadochokinetic syllables. Syllable rate, syllable and vowel duration, VOT, and F0 were obtained. The diadochokinetic syllables were rated for articulatory accuracy and speaking rate. Twenty graduate clinicians served as judges. The samples were randomly presented via headphones. A mixed ANOVA with repeated measures was used to assess the significance of the changes in UPRS-III scores and speech measures. The results indicated that unilateral STN DBS produced improvement in nonspeech motor function regardless of the side of stimulation. In contrast, the changes in articulatory accuracy and syllable rate associated with the STN DBS were hemisphere specific.
PMCID: PMC2239259  PMID: 18270553
25.  Rate of force production and relaxation is impaired in patients with focal hand dystonia 
Parkinsonism & related disorders  2006;12(6):363-371.
One factor, which may contribute to slowed movement in dystonia, is impairment in controlling the voluntary rate of motor output. This study examined the ability of patients with focal hand dystonia to rapidly turn force on and off at the wrist and elbow joints. Dystonic patients were slower than controls in rapidly turning on force from rest at both joints, passively relaxing force and rapidly reversing force output from a steady-state flexion contraction. Adding a preload did not improve the ability of dystonic subjects to rapidly turn on force. These results support the idea that dystonia is a disorder of impaired motor cortical activation, possibly due to basal ganglia dysfunction.
PMCID: PMC2094389  PMID: 16731028
Writer’s cramp; Isometric; Motor control; Basal ganglia

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