- Saint Louis, Missouri, United States
Kevin J. Black
Washington University in St. Louis, Psychiatry, Faculty Member
- Psychiatry, Neuroscience, Pharmacology, Neuroimaging, Movement disorders, Neuropsychiatry, and 13 moreFMRI, Cerebral Blood Flow, Parkinson's Disease, Dopaminergic Neurotransmision, Drug development, Pharmacodynamics, Tourette Syndrome, Levodopa, Cognitive Science, Cognitive Neuroscience, Positron Emission Tomography, Baboons, and Dopamineedit
OBJECTIVE: We developed a novel method to map behavioral effects of deep brain stimulation (DBS) across a 3-dimensional brain region and to assign statistical significance after stringent type I error correction. This method was applied... more
OBJECTIVE:
We developed a novel method to map behavioral effects of deep brain stimulation (DBS) across a 3-dimensional brain region and to assign statistical significance after stringent type I error correction. This method was applied to behavioral changes in Parkinson disease (PD) induced by subthalamic nucleus (STN) DBS to determine whether these responses depended on anatomical location of DBS.
METHODS:
Fifty-one PD participants with STN DBS were evaluated off medication, with DBS off and during unilateral STN DBS with clinically optimized settings. Dependent variables included DBS-induced changes in Unified Parkinson Disease Rating Scale (UPDRS) subscores, kinematic measures of bradykinesia and rigidity, working memory, response inhibition, mood, anxiety, and akathisia. Weighted t tests at each voxel produced p images showing where DBS most significantly affected each dependent variable based on outcomes of participants with nearby DBS. Finally, a permutation test computed the probability that this p image indicated significantly different responses based on stimulation site.
RESULTS:
Most motor variables improved with DBS anywhere in the STN region, but several motor, cognitive, and affective responses significantly depended on precise location stimulated, with peak p values in superior STN/zona incerta (quantified bradykinesia), dorsal STN (mood, anxiety), and inferior STN/substantia nigra (UPDRS tremor, working memory).
INTERPRETATION:
Our method identified DBS-induced behavioral changes that depended significantly on DBS site. These results do not support complete functional segregation within STN, because movement improved with DBS throughout, and mood improved with dorsal STN DBS. Rather, findings support functional convergence of motor, cognitive, and limbic information in STN.
We developed a novel method to map behavioral effects of deep brain stimulation (DBS) across a 3-dimensional brain region and to assign statistical significance after stringent type I error correction. This method was applied to behavioral changes in Parkinson disease (PD) induced by subthalamic nucleus (STN) DBS to determine whether these responses depended on anatomical location of DBS.
METHODS:
Fifty-one PD participants with STN DBS were evaluated off medication, with DBS off and during unilateral STN DBS with clinically optimized settings. Dependent variables included DBS-induced changes in Unified Parkinson Disease Rating Scale (UPDRS) subscores, kinematic measures of bradykinesia and rigidity, working memory, response inhibition, mood, anxiety, and akathisia. Weighted t tests at each voxel produced p images showing where DBS most significantly affected each dependent variable based on outcomes of participants with nearby DBS. Finally, a permutation test computed the probability that this p image indicated significantly different responses based on stimulation site.
RESULTS:
Most motor variables improved with DBS anywhere in the STN region, but several motor, cognitive, and affective responses significantly depended on precise location stimulated, with peak p values in superior STN/zona incerta (quantified bradykinesia), dorsal STN (mood, anxiety), and inferior STN/substantia nigra (UPDRS tremor, working memory).
INTERPRETATION:
Our method identified DBS-induced behavioral changes that depended significantly on DBS site. These results do not support complete functional segregation within STN, because movement improved with DBS throughout, and mood improved with dorsal STN DBS. Rather, findings support functional convergence of motor, cognitive, and limbic information in STN.
Research Interests:
Adenosine A2a receptor antagonists reduce symptom severity in Parkinson disease (PD) and animal models. Rodent studies support the hypothesis that A2a antagonists produce this benefit by reducing the inhibitory output of the basal ganglia... more
Adenosine A2a receptor antagonists reduce symptom severity in Parkinson disease (PD) and animal models. Rodent studies support the hypothesis that A2a antagonists produce this benefit by reducing the inhibitory output of the basal ganglia indirect pathway. One way to test this hypothesis in humans is to quantify regional pharmacodynamic responses with cerebral blood flow (CBF) imaging. That approach has also been proposed as a tool to accelerate pharmaceutical dose finding, but has not yet been applied in humans to drugs in development. We successfully addressed both these aims with a perfusion magnetic resonance imaging (MRI) study of the novel adenosine A2a antagonist SYN115. During a randomized, double-blind, placebo-controlled, crossover study in 21 PD patients on levodopa but no agonists, we acquired pulsed arterial spin labeling MRI at the end of each treatment period. SYN115 produced a highly significant decrease in thalamic CBF, consistent with reduced pallidothalamic inhibition via the indirect pathway. Similar decreases occurred in cortical regions whose activity decreases with increased alertness and externally focused attention, consistent with decreased self-reported sleepiness on SYN115. Remarkably, we also derived quantitative pharmacodynamic parameters from the CBF responses to SYN115. These results suggested that the doses tested were on the low end of the effective dose range, consistent with clinical data reported separately. We conclude that (1) SYN115 enters the brain and exerts dose-dependent regional effects, (2) the most prominent of these effects is consistent with deactivation of the indirect pathway as predicted by preclinical studies; and (3) perfusion MRI can provide rapid, quantitative, clinically relevant dose-finding information for pharmaceutical development.
Research Interests:
Pharmacological challenge imaging has mapped, but rarely quantified, the sensitivity of a biological system to a given drug. We describe a novel method called rapid quantitative pharmacodynamic imaging. This method combines... more
Pharmacological challenge imaging has mapped, but rarely quantified, the sensitivity of a biological system to a given drug. We describe a novel method called rapid quantitative pharmacodynamic imaging. This method combines pharmacokinetic-pharmacodynamic modeling, repeated small doses of a challenge drug over a short time scale, and functional imaging to rapidly provide quantitative estimates of drug sensitivity including EC50 (the concentration of drug that produces half the maximum possible effect). We first test the method with simulated data, assuming a typical sigmoidal dose-response curve and assuming imperfect imaging that includes artifactual baseline signal drift and random error. With these few assumptions, rapid quantitative pharmacodynamic imaging reliably estimates EC50 from the simulated data, except when noise overwhelms the drug effect or when the effect occurs only at high doses. In preliminary fMRI studies of primate brain using a dopamine agonist, the observed noise level is modest compared with observed drug effects, and a quantitative EC50 can be obtained from some regional time-signal curves. Taken together, these results suggest that research and clinical applications for rapid quantitative pharmacodynamic imaging are realistic.
Research Interests:
BACKGROUND: Dopamine agonists and antagonists can reduce abnormal movements and vocalizations (tics) in Tourette syndrome (TS); however, dopamine-responsive abnormal function in specific brain regions has not been directly demonstrated in... more
BACKGROUND: Dopamine agonists and antagonists can reduce abnormal movements and vocalizations (tics) in Tourette syndrome (TS); however, dopamine-responsive abnormal function in specific brain regions has not been directly demonstrated in TS. We sought to identify dopamine-modulated brain regions that function abnormally in TS by combining functional magnetic resonance imaging (fMRI), a working memory (WM) task, and infusion of the dopamine prodrug levodopa (while blocking dopamine production outside the brain).METHODS: We obtained complete fMRI data in 8 neuroleptic-naive adults with a chronic tic disorder and in 10 well-matched tic-free control subjects.RESULTS: Different task-sensitive brain regions responded differently to the WM task depending on levodopa status and diagnostic group (analysis of variance [ANOVA], p <.001). Four regions showed interactions with diagnosis (ANOVA, p <.001). In TS subjects, the task induced excessive brain activity in parietal cortex, medial frontal gyrus, and thalamus. Levodopa normalized the excess activity. In left parietal cortex, the degree of normalization was greater in patients with higher levodopa plasma concentrations (n = 6; Spearman's r = -.84, p =.04) and a greater degree of diagnostic confidence of TS (r = -.71, p =.05).CONCLUSIONS: These results are consistent with a dopamine-influenced functional abnormality of brain response in TS and suggest testable hypotheses about the mechanism by which dopamine antagonists and agonists alleviate tics.
Research Interests:
Dopamine can induce fascinating, complex human behavioral states, including disinhibition, euphoria, or elaborate stereotypies, whereas dopamine deficiency can cause anxiety or sadness. Limited data suggest that these phenomena may... more
Dopamine can induce fascinating, complex human behavioral states, including disinhibition, euphoria, or elaborate stereotypies, whereas dopamine deficiency can cause anxiety or sadness. Limited data suggest that these phenomena may involve dysfunction of orbital frontal cortex, cingulate cortex, or ventral striatum. The dopamine D3 receptor (D3R) has an anatomic distribution that suggests it could mediate these effects, but almost no data directly demonstrate the regional functional effects of D3R activation. We used quantitative positron emission tomography (PET), [15O]water, and the D3-preferring dopamine agonist pramipexole to identify D3-mediated regional cerebral blood flow (rCBF) responses in living primates. We studied seven normal baboons ventilated with 70% nitrous oxide, and analyzed results voxelwise in a common atlas space. At clinically relevant doses, pramipexole produced statistically robust decreases in rCBF in bilateral orbitofrontal cortex, thalamus, operculum, posterior and anterior (subgenual) cingulate cortex, and insula (in decreasing order of significance). Cortical areas related to movement were relatively unaffected, and rCBF did not change in cerebellum or visual cortex. The dose-response curve and duration of pramipexole's effects suggest that these rCBF responses indicate functional effects of a D3-preferring agonist. A D2-preferring agonist studied under the same conditions produced a quantitatively different pattern of responses. We conclude that a dopamine D3 receptor agonist preferentially affects brain activity in prefrontal and limbic cortex, and speculate that dopamine's effects on these regions via D3Rs may mediate some of the known psychiatric complications of dopamine deficiency or excess.
Coregistration of functional brain images across many subjects offers several experimental advantages and is widely used for studies in humans. Voxel-based coregistration methods require a high-quality 3-D template image, preferably one... more
Coregistration of functional brain images across many subjects offers several experimental advantages and is widely used for studies in humans. Voxel-based coregistration methods require a high-quality 3-D template image, preferably one that corresponds to a published atlas. Template images are available for human, but we could not find an appropriate template for neuroimaging studies in baboon. Here we describe the formation of a T1-weighted structural MR template image and a PET blood flow template, derived from 9 and 7 baboons, respectively. Custom software aligns individual MR images to the MRI template; human supervision is needed only to initially estimate any gross rotational misalignment. In these aligned individual images, internal subcortical fiducial points correspond closely to a photomicrographic baboon atlas with an average error of 1.53 mm. Cortical test points showed a mean error of 1.99 mm compared to the mean location for each point. Alignment of individual PET blood flow images directly to the PET template was compared to a two-step alignment process via each subject's MR image. The two transformations were identical within 0.41 mm, 0.54 degrees, and 1.0% (translation, rotation, and linear stretch; mean). These quantities provide a check on the validity of the alignment software as well as of the template images. The baboon structural MR and blood flow PET templates are available on the Internet (purl.org/net/kbmd/b2k) and can be used as targets for any image registration software.Copyright 2001 Academic Press.
Research Interests:
Neuroimaging studies are increasingly performed in macaque species, including the pig-tailed macaque (Macaca nemestrina). At times experimental questions can be answered by analysis of functional images in individual subjects and... more
Neuroimaging studies are increasingly performed in macaque species, including the pig-tailed macaque (Macaca nemestrina). At times experimental questions can be answered by analysis of functional images in individual subjects and reference to a structural image in that subject. However, coregistration of functional brain images across many subjects offers the experimental advantage of enabling voxel-based analysis over multiple subjects and is therefore widely used in human studies. Voxel-based coregistration methods require a high-quality 3D template image. We created such templates, derived from T1-weighted MRI and blood-flow PET images from 12 nemestrina monkeys. We designed the macaque templates to be maximally compatible with the baboon template images described in a companion paper, to facilitate cross-species comparison of functional imaging data. Here we present data showing the reliability and validity of automatic image registration to the template. Alignment of selected internal fiducial points was accurate to within 1.9 mm overall (mean) even across species. The template images, along with copies aligned to the UCLA nemestrina brain atlas, are available on the Internet (purl.org/net/kbmd/n2k) and can be used as targets with any image registration software.Copyright 2001 Academic Press.
Research Interests: Research Methodology, Neuroimaging, Magnetic Resonance Imaging, MRI, Positron Emission Tomography, and 17 moreImage Registration, Brain Mapping, Software, Papio, Brain, Baboons, PET imaging, Female, Animals, Functional Imaging, Neuroimage, Male, Three Dimensional Imaging, Validity and Reliability, Single Photon Emission Computed Tomography, Blood Flow, and Mr Imaging
Changes in the function of dopamine D1-influenced neuronal pathways may be important to the pathophysiology of several human diseases. We recently developed methods for averaging functional imaging data across nonhuman primate subjects;... more
Changes in the function of dopamine D1-influenced neuronal pathways may be important to the pathophysiology of several human diseases. We recently developed methods for averaging functional imaging data across nonhuman primate subjects; in this study, we apply this method for the first time to map brain responses to experimental dopamine agonists in vivo. Here we report the use of positron emission tomography (PET) in seven normal baboons to measure the regional cerebral blood flow (rCBF) responses produced by an acute dose of the dopamine D1 full agonist SKF82958. The most significant rCBF increases were in bilateral temporal lobe, including amygdala and superior temporal sulcus (6–17%, P < 0.001). Blood flow decreased in thalamus, pallidum, and pons (4–7%, P = 0.001). Furthermore the rCBF responses were dose-dependent and had a half-life of ∼30 min, similar to that reported for the drug's antiparkinsonian effects. Absolute whole-brain blood flow did not change, suggesting that these local changes in rCBF reflect neuronal rather than direct vascular effects of the agonist. The prominent temporal lobe response to a D1 agonist supports and extends our recent observations that levodopa produces prominent amygdala activation both in humans and in other primates. We speculate that levodopa may exert its known effects on mood in humans through increased amygdala activity, mediated in part by D1 receptors.
Research Interests:
Research Interests:
Tic disorders are childhood onset neuropsychiatric disorders characterized by motor and/or vocal tics. Research has demonstrated that children with chronic tics (including Tourette syndrome and Chronic Tic Disorder: TS/CTD) can suppress... more
Tic disorders are childhood onset neuropsychiatric disorders characterized by motor and/or vocal tics. Research has demonstrated that children with chronic tics (including Tourette syndrome and Chronic Tic Disorder: TS/CTD) can suppress tics, particularly when an immediate, contingent reward is given for successful tic suppression. As a diagnosis of TS/CTD requires tics to be present for at least one year, children in these tic suppression studies had been living with tics for quite some time. Thus, it is unclear whether the ability to inhibit tics is learned over time or present at tic onset. Resolving that issue would inform theories of how tics develop and how behavior therapy for tics works. We investigated tic suppression in school-age children as close to the time of tic onset as possible, and no later than six months after onset. Children were asked to suppress their tics both in the presence and absence of a contingent reward. Results demonstrated that these children, like children with TS/CTD, have some capacity to suppress tics, and that immediate reward enhances that capacity. These findings demonstrate that the modulating effect of reward on inhibitory control of tics is present within months of tic onset, before tics have become chronic.
Research Interests:
Tics are repeated, usually suppressible movements or vocalizations. They are the defining features of tic disorders including Tourette syndrome, but many people have them for shorter durations at some point in childhood. This editorial... more
Tics are repeated, usually suppressible movements or vocalizations. They are the defining features of tic disorders including Tourette syndrome, but many people have them for shorter durations at some point in childhood. This editorial marks the beginning of the F1000Research: Tics specialty section, an effort to provide a single portal to modern research on tics and tic disorders. Publications in F1000Research: Tics benefit from F1000Research’s novel approach to publishing, in which articles can be published within days of submission. Peer review happens after publication and is fully open. When the submitted article or a revision is approved, it is promptly submitted to repositories including NIH’s PubMed Central. In addition to research articles and reviews, F1000Research: Tics will publish study protocols, clinical practice articles, case reports, and data notes. The home page will also provide links to expert recommendations of articles that have appeared elsewhere, and to relevant posters from scientific meetings (http://f1000.com/posters/). F1000Research’s approach is enabled by the capabilities of internet publication, including space to publish the full results of a study rather than just a few graphs selected from the data. Publishing methodologically sound studies without requiring subjective editorial judgments of novelty or broad appeal brings numerous advantages, including minimizing publication bias and shining the light of openness on peer review. To celebrate the launch of the Tics section, F1000Research is offering discounted article processing charges for manuscripts submitted by March 1st 2015. I have had good experiences publishing in F1000Research, and look forward to seeing a wide range of tic-related manuscripts submitted.
Research Interests:
The basal ganglia (BG) comprise a set of subcortical nuclei with sensorimotor, cognitive, and limbic subdivisions, indicative of functional organization. BG dysfunction in several developmental disorders suggests the importance of the... more
The basal ganglia (BG) comprise a set of subcortical nuclei with sensorimotor, cognitive, and limbic subdivisions, indicative of functional organization. BG dysfunction in several developmental disorders suggests the importance of the healthy maturation of these structures. However, few studies have investigated the development of BG functional organization. Using resting-state functional connectivity MRI (rs-fcMRI), we compared human child and adult functional connectivity of the BG with rs-fcMRI-defined cortical systems. Because children move more than adults, customized preprocessing, including volume censoring, was used to minimize motion-induced rs-fcMRI artifact. Our results demonstrated functional organization in the adult BG consistent with subdivisions previously identified in anatomical tracing studies. Group comparisons revealed a developmental shift in bilateral posterior putamen/pallidum clusters from preferential connectivity with the somatomotor "face" system in childhood to preferential connectivity with control/attention systems (frontoparietal, ventral attention) in adulthood. This shift was due to a decline in the functional connectivity of these clusters with the somatomotor face system over development, and no change with control/attention systems. Applying multivariate pattern analysis, we were able to reliably classify individuals as children or adults based on BG-cortical system functional connectivity. Interrogation of the features driving this classification revealed, in addition to the somatomotor face system, contributions by the orbitofrontal, auditory, and somatomotor hand systems. These results demonstrate that BG-cortical functional connectivity evolves over development, and may lend insight into developmental disorders that involve BG dysfunction, particularly those involving motor systems (e.g., Tourette syndrome).
Research Interests:
Tourette syndrome (TS) is a heritable neuropsychiatric disorder commonly complicated by obsessions and compulsions, but defined by frequent unwanted movements (motor tics) and vocalizations (phonic tics) that develop in childhood or... more
Tourette syndrome (TS) is a heritable neuropsychiatric disorder commonly complicated by obsessions and compulsions, but defined by frequent unwanted movements (motor tics) and vocalizations (phonic tics) that develop in childhood or adolescence. In recent years, research on TS has progressed rapidly on several fronts. Inspired by the Fifth International Scientific Symposium on Tourette Syndrome, the articles in this special issue review advances in the phenomenology, epidemiology, genetics, pathophysiology, and treatment of TS.
Research Interests:
To determine how different methods of normalizing for global cerebral blood flow (gCBF) affect image quality and sensitivity to cortical activation, pulsed arterial spin labeling (pASL) scans obtained during a visual task were normalized... more
To determine how different methods of normalizing for global cerebral blood flow (gCBF) affect image quality and sensitivity to cortical activation, pulsed arterial spin labeling (pASL) scans obtained during a visual task were normalized by either additive or multiplicative normalization of modal gCBF. Normalization by either method increased the statistical significance of cortical activation by a visual stimulus. However, image quality was superior with additive normalization, whether judged by intensity histograms or by reduced variability within gray and white matter.
Research Interests:
Rationale: Synaptic dopamine (DA) release induced by amphetamine or other experimental manipulations can displace [11C]raclopride (RAC*) from dopamine D2-like receptors. We hypothesized that exogenous levodopa might increase dopamine... more
Rationale: Synaptic dopamine (DA) release induced by amphetamine or other experimental manipulations can displace [11C]raclopride (RAC*) from dopamine D2-like receptors. We hypothesized that exogenous levodopa might increase dopamine release at striatal synapses under some conditions but not others, allowing a more naturalistic assessment of presynaptic dopaminergic function. Presynaptic dopaminergic abnormalities have been reported in Tourette syndrome (TS).
Objective: Test whether levodopa induces measurable synaptic DA release in healthy people at rest, and gather pilot data in TS.
Methods: This double-blind crossover study used RAC* and positron emission tomography (PET) to measure synaptic dopamine release 4 times in each of 10 carbidopa-pretreated, neuroleptic-naïve adults: before and during an infusion of
levodopa on one day and placebo on another (in random order). Five subjects had TS and 5 were matched controls. RAC* binding potential (BPnd) was quantified in predefined anatomical volumes of interest (VOIs). A separate analysis compared BPnd voxel by voxel over the entire brain.
Results: A release declined between the first and second scan of each day (p=0.012), including on the placebo day. Levodopa did not significantly reduce striatal RAC* binding and striatal binding did not differ significantly between TS and control groups. However, levodopa’s effect on DA release differed significantly in a right midbrain region (p=0.002, corrected), where levodopa displaced RAC* by 59% in control subjects but _increased_ BPnd by 74% in TS subjects.
Discussion: Decreased DA release on the second scan of the day is consistent with the few previous studies with a similar design, and may indicate habituation to study procedures. We hypothesize that mesostriatal DA neurons fire relatively little while subjects rest, possibly explaining the non-significant effect of levodopa on striatal RAC* binding. The modest sample size argues for caution in interpreting the group difference in midbrain DA release with levodopa.
Objective: Test whether levodopa induces measurable synaptic DA release in healthy people at rest, and gather pilot data in TS.
Methods: This double-blind crossover study used RAC* and positron emission tomography (PET) to measure synaptic dopamine release 4 times in each of 10 carbidopa-pretreated, neuroleptic-naïve adults: before and during an infusion of
levodopa on one day and placebo on another (in random order). Five subjects had TS and 5 were matched controls. RAC* binding potential (BPnd) was quantified in predefined anatomical volumes of interest (VOIs). A separate analysis compared BPnd voxel by voxel over the entire brain.
Results: A release declined between the first and second scan of each day (p=0.012), including on the placebo day. Levodopa did not significantly reduce striatal RAC* binding and striatal binding did not differ significantly between TS and control groups. However, levodopa’s effect on DA release differed significantly in a right midbrain region (p=0.002, corrected), where levodopa displaced RAC* by 59% in control subjects but _increased_ BPnd by 74% in TS subjects.
Discussion: Decreased DA release on the second scan of the day is consistent with the few previous studies with a similar design, and may indicate habituation to study procedures. We hypothesize that mesostriatal DA neurons fire relatively little while subjects rest, possibly explaining the non-significant effect of levodopa on striatal RAC* binding. The modest sample size argues for caution in interpreting the group difference in midbrain DA release with levodopa.
Research Interests:
Intravenous levodopa has been used in a multitude of research studies due to its more predictable pharmacokinetics compared to the oral form, which is used frequently as a treatment for Parkinson's disease (PD). Levodopa is the precursor... more
Intravenous levodopa has been used in a multitude of research studies due to its more predictable pharmacokinetics compared to the oral form, which is used frequently as a treatment for Parkinson's disease (PD). Levodopa is the precursor for dopamine, and intravenous dopamine would strongly affect vascular tone, but peripheral decarboxylase inhibitors are intended to block such effects. Pulse and blood pressure, with orthostatic changes, were recorded before and after intravenous levodopa or placebo-after oral carbidopa-in 13 adults with a chronic tic disorder and 16 tic-free adult control subjects. Levodopa caused no statistically or clinically significant changes in blood pressure or pulse. These data add to previous data that support the safety of i.v. levodopa when given with adequate peripheral inhibition of DOPA decarboxylase.
Research Interests:
About 200 journal articles reported research on Tourette syndrome and other tic disorders in 2014. Here we briefly summarize a few of the reports that seemed most important or interesting, ranging from animal models to human studies.... more
About 200 journal articles reported research on Tourette syndrome and other tic disorders in 2014. Here we briefly summarize a few of the reports that seemed most important or interesting, ranging from animal models to human studies. Readers can comment on our choices or provide their own favorites using the tools on the online article.
Research Interests: Genetics, Deep Brain Stimulation, Metacognition, MRI, Functional MRI, and 21 moreLongitudinal Research, Literature Review, Histamine, Behavior Therapy, Inheritance, Animal Models in Psychiatry, Biofeedback, Exercise, Follow-up studies, Dopamine Receptors, Etiology, Negative Reinforcement, Behavioral Animal Models, Remission, Longitudinal Studies, Animal models, Habit Reversal Therapy, Dopamine D1-like Receptors, Premonitory urge, Comprehensive Behavioral Intervention for Tics (CBIT), and Ecopipam
PET studies have provided mixed evidence regarding central D2/D3 dopamine receptor binding and its relationship with obesity as measured by body mass index (BMI). Other aspects of obesity may be more tightly coupled to the dopaminergic... more
PET studies have provided mixed evidence regarding central D2/D3 dopamine receptor binding and its relationship with obesity as measured by body mass index (BMI). Other aspects of obesity may be more tightly coupled to the dopaminergic system. We characterized obesity-associated behaviors and determined if these related to central D2 receptor (D2R) specific binding independent of BMI. Twenty-two obese and 17 normal-weight participants completed eating- and reward-related questionnaires and underwent PET scans using the D2R-selective and nondisplaceable radioligand (N-[11C]methyl)benperidol. Questionnaires were grouped by domain (eating related to emotion, eating related to reward, non-eating behavior motivated by reward or sensitivity to punishment). Normalized, summed scores for each domain were compared between obese and normal-weight groups and correlated with striatal and midbrain D2R binding. Compared to normal-weight individuals, the obese group self-reported higher rates of eating related to both emotion and reward (p < 0.001), greater sensitivity to punishment (p = 0.06), and lower non-food reward behavior (p < 0.01). Across normal-weight and obese participants, self-reported emotional eating and non-food reward behavior positively correlated with striatal (p < 0.05) and midbrain (p < 0.05) D2R binding, respectively. In conclusion, an emotional eating phenotype may reflect altered central D2R function better than other commonly used obesity-related measures such as BMI.
Research Interests: Personality Psychology, Personality, Obesity, Eating Disorders, Persistence, and 24 morePositron Emission Tomography, Binge-eating Disorders, Reward, Striatum, Behavioral Inhibition, Punishment, Temperament, Bis/bas, Body Mass Index, Emotional Eating, Craving, NMB, Binge Eating Disorder, Oral Glucose Tolerance Test, Binge eating, Harm Avoidance, Dopamine D2-like Receptors, Midbrain, BIS/BAS, personality, Midbrain Dopamine Neurons, Novelty Seeking, Behavioral Inhibition System, N-methyl-benperidol, and Temperament and Character Inventory (TCI)
Tic disorders are childhood onset neuropsychiatric disorders characterized by motor and/or vocal tics. Research has demonstrated that children with chronic tics (including Tourette syndrome and Chronic Tic Disorder: TS/CTD) can suppress... more
Tic disorders are childhood onset neuropsychiatric disorders characterized by motor and/or vocal tics. Research has demonstrated that children with chronic tics (including Tourette syndrome and Chronic Tic Disorder: TS/CTD) can suppress tics, particularly when an immediate, contingent reward is given for successful tic suppression. As a diagnosis of TS/CTD requires tics to be present for at least one year, children in these tic suppression studies had been living with tics for quite some time. Thus, it is unclear whether the ability to inhibit tics is learned over time or present at tic onset. Resolving that issue would inform theories of how tics develop and how behavior therapy for tics works. We investigated tic suppression in school-age children as close to the time of tic onset as possible, and no later than six months after onset. Children were asked to suppress their tics both in the presence and absence of a contingent reward. Results demonstrated that these children, like children with TS/CTD, have some capacity to suppress tics, and that immediate reward enhances that capacity. These findings demonstrate that the modulating effect of reward on inhibitory control of tics is present within months of tic onset, before tics have become chronic.
Research Interests:
Introduction: The National Board of Medical Examiners (NBME) subject examinations are used as a standardized metric for performance in required clerkships for third-year medical students. While several medical schools have implemented a... more
Introduction:
The National Board of Medical Examiners (NBME) subject examinations are used as a standardized metric for performance in required clerkships for third-year medical students. While several medical schools have implemented a review session to help consolidate knowledge acquired during the clerkship, the effects of such an intervention are not yet well-established. An improvement in NBME psychiatry examination scores has previously been reported with a single end-of-clerkship review session, but this was limited by a small sample size and the fact that attendance at the review session was optional, leading to likely selection bias.
Methods:
A 1.5-hour structured review session was conducted for medical students in the last week of each 4-week psychiatry clerkship between September 2014 and July 2015. Students were required to attend unless excused due to scheduling conflicts. Scores on the NBME psychiatry subject exam were compared with those of students taking the examination in the corresponding time period in each of the previous two academic years.
Results:
83 students took the exam during the experimental period, while 176 took the exam during the control period. Statistically significant improvements were found in mean score (p=0.03), mean for the two lowest scores in each group (p<0.0007), and percentage of students scoring 70 or less (p=0.03). Percentage of students achieving the maximum possible score (99) was higher in the experimental group, but did not reach significance (p=0.06).
Conclusions:
An end-of-clerkship review session led to increased mean scores on the NBME psychiatry subject examination, particularly for students at the lower end of the score range. Future research should investigate the impact of such an intervention in other specialties and other institutions.
The National Board of Medical Examiners (NBME) subject examinations are used as a standardized metric for performance in required clerkships for third-year medical students. While several medical schools have implemented a review session to help consolidate knowledge acquired during the clerkship, the effects of such an intervention are not yet well-established. An improvement in NBME psychiatry examination scores has previously been reported with a single end-of-clerkship review session, but this was limited by a small sample size and the fact that attendance at the review session was optional, leading to likely selection bias.
Methods:
A 1.5-hour structured review session was conducted for medical students in the last week of each 4-week psychiatry clerkship between September 2014 and July 2015. Students were required to attend unless excused due to scheduling conflicts. Scores on the NBME psychiatry subject exam were compared with those of students taking the examination in the corresponding time period in each of the previous two academic years.
Results:
83 students took the exam during the experimental period, while 176 took the exam during the control period. Statistically significant improvements were found in mean score (p=0.03), mean for the two lowest scores in each group (p<0.0007), and percentage of students scoring 70 or less (p=0.03). Percentage of students achieving the maximum possible score (99) was higher in the experimental group, but did not reach significance (p=0.06).
Conclusions:
An end-of-clerkship review session led to increased mean scores on the NBME psychiatry subject examination, particularly for students at the lower end of the score range. Future research should investigate the impact of such an intervention in other specialties and other institutions.
Research Interests:
Introduction: The National Board of Medical Examiners (NBME) subject examinations are used as a standardized metric for performance in required clerkships for third-year medical students. While several medical schools have implemented a... more
Introduction:
The National Board of Medical Examiners (NBME) subject examinations are used as a standardized metric for performance in required clerkships for third-year medical students. While several medical schools have implemented a review session to help consolidate knowledge acquired during the clerkship, the effects of such an intervention are not yet well-established. An improvement in NBME psychiatry examination scores has previously been reported with a single end-of-clerkship review session, but this was limited by a small sample size and the fact that attendance at the review session was optional, leading to likely selection bias.
Methods:
A 1.5-hour structured review session was conducted for medical students in the last week of each 4-week psychiatry clerkship between September 2014 and July 2015. Students were required to attend unless excused due to scheduling conflicts. Scores on the NBME psychiatry subject exam were compared with those of students taking the examination in the corresponding time period in each of the previous two academic years.
Results:
83 students took the exam during the experimental period, while 176 took the exam during the control period. Statistically significant improvements were found in mean score (p=0.03), mean for the two lowest scores in each group (p<0.0007), and percentage of students scoring 70 or less (p=0.03). Percentage of students achieving the maximum possible score (99) was higher in the experimental group, but did not reach significance (p=0.06).
Conclusions:
An end-of-clerkship review session led to increased mean scores on the NBME psychiatry subject examination, particularly for students at the lower end of the score range. Future research should investigate the impact of such an intervention in other specialties and other institutions.
The National Board of Medical Examiners (NBME) subject examinations are used as a standardized metric for performance in required clerkships for third-year medical students. While several medical schools have implemented a review session to help consolidate knowledge acquired during the clerkship, the effects of such an intervention are not yet well-established. An improvement in NBME psychiatry examination scores has previously been reported with a single end-of-clerkship review session, but this was limited by a small sample size and the fact that attendance at the review session was optional, leading to likely selection bias.
Methods:
A 1.5-hour structured review session was conducted for medical students in the last week of each 4-week psychiatry clerkship between September 2014 and July 2015. Students were required to attend unless excused due to scheduling conflicts. Scores on the NBME psychiatry subject exam were compared with those of students taking the examination in the corresponding time period in each of the previous two academic years.
Results:
83 students took the exam during the experimental period, while 176 took the exam during the control period. Statistically significant improvements were found in mean score (p=0.03), mean for the two lowest scores in each group (p<0.0007), and percentage of students scoring 70 or less (p=0.03). Percentage of students achieving the maximum possible score (99) was higher in the experimental group, but did not reach significance (p=0.06).
Conclusions:
An end-of-clerkship review session led to increased mean scores on the NBME psychiatry subject examination, particularly for students at the lower end of the score range. Future research should investigate the impact of such an intervention in other specialties and other institutions.
Research Interests:
Research Interests:
Tourette syndrome (TS) is a developmental neuropsychiatric disorder characterized by motor and vocal tics. Individuals with TS would benefit greatly from advances in prediction of symptom timecourse and treatment effectiveness. As a first... more
Tourette syndrome (TS) is a developmental neuropsychiatric disorder characterized by motor and vocal tics. Individuals with TS would benefit greatly from advances in prediction of symptom timecourse and treatment effectiveness. As a first step, we applied a multivariate method – support vector machine (SVM) classification – to test whether patterns in brain network activity, measured with resting state functional connectivity (RSFC) MRI, could predict diagnostic group membership for individuals. RSFC data from 42 children with TS (8-15yrs) and 42 unaffected controls (age, IQ, in-scanner movement matched) were included. While univariate tests identified no significant group differences, SVM classified group membership with ~70% accuracy (p < 0.001). We also report a novel adaptation of SVM binary classification that, in addition to an overall accuracy rate for the SVM, provides a confidence measure for the accurate classification of each individual. Our results support the contention that multivariate methods can better capture the complexity of some brain disorders, and hold promise for predicting prognosis and treatment outcome for individuals with TS.
Research Interests:
A variety of approaches has been used to minimize head movement during functional brain imaging studies in awake laboratory animals. Many laboratories expend substantial effort and time training animals to remain essentially motionless... more
A variety of approaches has been used to minimize head movement during functional brain imaging studies in awake laboratory animals. Many laboratories expend substantial effort and time training animals to remain essentially motionless during such studies. We could not locate an “off-the-shelf” automated training system that suited our needs.
We developed a time- and labor-saving automated system to train animals to hold still for extended periods of time. The system uses a personal computer and modest external hardware to provide stimulus cues, monitor movement using commercial video surveillance components, and dispense rewards. A custom computer program automatically increases the motionless duration required for rewards based on performance during the training session but allows changes during sessions. This system was used to train cynomolgus monkeys (Macaca fascicularis) for awake neuroimaging studies using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI).
The automated system saved the trainer substantial time, presented stimuli and rewards in a highly consistent manner, and automatically documented training sessions. We have limited data to prove the training system's success, drawn from the automated records during training sessions, but we believe others may find it useful. The system can be adapted to a range of behavioral training/recording activities for research or commercial applications, and the software is freely available for non-commercial use.
We developed a time- and labor-saving automated system to train animals to hold still for extended periods of time. The system uses a personal computer and modest external hardware to provide stimulus cues, monitor movement using commercial video surveillance components, and dispense rewards. A custom computer program automatically increases the motionless duration required for rewards based on performance during the training session but allows changes during sessions. This system was used to train cynomolgus monkeys (Macaca fascicularis) for awake neuroimaging studies using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI).
The automated system saved the trainer substantial time, presented stimuli and rewards in a highly consistent manner, and automatically documented training sessions. We have limited data to prove the training system's success, drawn from the automated records during training sessions, but we believe others may find it useful. The system can be adapted to a range of behavioral training/recording activities for research or commercial applications, and the software is freely available for non-commercial use.
Research Interests:
Objective: To compile a comprehensive summary of published human experience with levodopa given intravenously, with a focus on information required by regulatory agencies. Background: While safe intravenous (IV) use of levodopa has been... more
Objective: To compile a comprehensive summary of published human experience
with levodopa given intravenously, with a focus on information required by regulatory
agencies.
Background: While safe intravenous (IV) use of levodopa has been documented for
over 50 years, regulatory supervision for pharmaceuticals given by a route other than
that approved by the U.S. Food and Drug Administration (FDA) has become increasingly
cautious. If delivering a drug by an alternate route raises the risk of adverse events, an
investigational new drug (IND) application is required, including a comprehensive review
of toxicity data.
Methods: Over 200 articles referring to IV levodopa were examined for details of
administration, pharmacokinetics, benefit, and side effects.
Results: We identified 142 original reports describing IVLD use in humans, beginning
with psychiatric research in 1959–1960 before the development of peripheral
decarboxylase inhibitors. At least 2760 subjects have received IV levodopa, and reported
outcomes include parkinsonian signs, sleep variables, hormone levels, hemodynamics,
CSF amino acid composition, regional cerebral blood flow, cognition, perception and
complex behavior. Mean pharmacokinetic variables were summarized for 49 healthy
subjects and 190 with Parkinson’s disease. Side effects were those expected from clinical
experience with oral levodopa and dopamine agonists. No articles reported deaths or
induction of psychosis.
Conclusion: At least 2760 patients have received IV levodopa with a safety profile
comparable to that seen with oral administration.
with levodopa given intravenously, with a focus on information required by regulatory
agencies.
Background: While safe intravenous (IV) use of levodopa has been documented for
over 50 years, regulatory supervision for pharmaceuticals given by a route other than
that approved by the U.S. Food and Drug Administration (FDA) has become increasingly
cautious. If delivering a drug by an alternate route raises the risk of adverse events, an
investigational new drug (IND) application is required, including a comprehensive review
of toxicity data.
Methods: Over 200 articles referring to IV levodopa were examined for details of
administration, pharmacokinetics, benefit, and side effects.
Results: We identified 142 original reports describing IVLD use in humans, beginning
with psychiatric research in 1959–1960 before the development of peripheral
decarboxylase inhibitors. At least 2760 subjects have received IV levodopa, and reported
outcomes include parkinsonian signs, sleep variables, hormone levels, hemodynamics,
CSF amino acid composition, regional cerebral blood flow, cognition, perception and
complex behavior. Mean pharmacokinetic variables were summarized for 49 healthy
subjects and 190 with Parkinson’s disease. Side effects were those expected from clinical
experience with oral levodopa and dopamine agonists. No articles reported deaths or
induction of psychosis.
Conclusion: At least 2760 patients have received IV levodopa with a safety profile
comparable to that seen with oral administration.
Research Interests:
Human neuroimaging, specifically magnetic resonance imaging (MRI), is being used with increasing popularity to study brain structure and function in development and disease. When applying these methods to developmental and clinical... more
Human neuroimaging, specifically magnetic resonance imaging (MRI), is being used with increasing popularity to study brain structure and function in development and disease. When applying these methods to developmental and clinical populations, careful consideration must be taken with regard to study design and implementation. In this article, we discuss two major considerations particularly pertinent to brain research in special populations. First, we discuss considerations for subject selection and characterization, including issues related to comorbid conditions, medication status, and clinical assessment. Second, we discuss methods and considerations for acquisition of adequate, useable MRI data. Given that children and patients may experience anxiety with the scanner environment, preventing participation, and that they have a higher risk of motion artifact, resulting in data loss, successful subject compliance and data acquisition are not trivial tasks. We conclude that, as researchers, we must consider a number of issues when using neuroimaging tools to study children and patients, and we should thoughtfully justify our choices of methods and study design.
Research Interests: Developmental Psychology, Developmental Biology, Developmental Psychopathology, Research Methodology, ADHD, and 13 moreMRI, Cognitive Neuroscience, Tourette's Syndrome, Comorbidity, FMRI, OCD, Resting State, Default Mode Networks, Tourette Syndrome, Obsessive Compulsive Disorder (OCD), Study design, fMRI (BOLD, resting state fMRI, and Resting State Functional Connectivity
Tics are repeated, usually suppressible movements or vocalizations. They are the defining features of tic disorders including Tourette syndrome, but many people have them for shorter durations at some point in childhood. This editorial... more
Tics are repeated, usually suppressible movements or vocalizations. They are the defining features of tic disorders including Tourette syndrome, but many people have them for shorter durations at some point in childhood. This editorial marks the beginning of the F1000Research: Tics specialty section, an effort to provide a single portal to modern research on tics and tic disorders. Publications in F1000Research: Tics benefit from F1000Research’s novel approach to publishing, in which articles can be published within days of submission. Peer review happens after publication and is fully open. When the submitted article or a revision is approved, it is promptly submitted to repositories including NIH’s PubMed Central. In addition to research articles and reviews, F1000Research: Tics will publish study protocols, clinical practice articles, case reports, and data notes. The home page will also provide links to expert recommendations of articles that have appeared elsewhere, and to relevant posters from scientific meetings (http://f1000.com/posters/). F1000Research’s approach is enabled by the capabilities of internet publication, including space to publish the full results of a study rather than just a few graphs selected from the data. Publishing methodologically sound studies without requiring subjective editorial judgments of novelty or broad appeal brings numerous advantages, including minimizing publication bias and shining the light of openness on peer review. To celebrate the launch of the Tics section, F1000Research is offering discounted article processing charges for manuscripts submitted by March 1st 2015. I have had good experiences publishing in F1000Research, and look forward to seeing a wide range of tic-related manuscripts submitted.
Research Interests:
Parkinson's disease (PD) patients commonly develop fluctuations in their motor responses to levodopa within several years of initiation of treatment; some also develop nonmotor fluctuations. The authors performed a case-control study... more
Parkinson's disease (PD) patients commonly develop fluctuations in their motor responses to levodopa within several years of initiation of treatment; some also develop nonmotor fluctuations. The authors performed a case-control study comparing the frequency of comorbid symptoms in 70 PD patients who experienced clinically apparent mood changes during their motor "on" or "off" states with two control groups with no mood fluctuations. Mood fluctuators had significantly younger age at onset and longer disease duration and were significantly more likely to have dementia, psychosis, clinical depression, and motor complications. This association remained after removing effects of age and disease duration.
Research Interests:
The putamen has a somatotopic organization of neurons identified by correspondence of firing rates with selected body part movements, as well as by complex, but organized, differential cortical projections onto putamen. In isolated focal... more
The putamen has a somatotopic organization of neurons identified by correspondence of firing rates with selected body part movements, as well as by complex, but organized, differential cortical projections onto putamen. In isolated focal dystonia, whole putaminal binding of dopamine D2-like receptor radioligands is quantitatively decreased, but it has not been known whether selected parts of the putamen are differentially affected depending upon the body part affected by dystonia. The radioligand [18F]spiperone binds predominantly to D2-like receptors in striatum. We hypothesized that the spatial location of [18F]spiperone binding within the putamen would differ in patients with dystonia limited to the hand versus the face, and we tested that hypothesis using positron emission tomography and magnetic resonance imaging. To address statistical and methodological concerns, we chose a straightforward but robust image analysis method. An automated algorithm located the peak location of [18F]spiperone binding within the striatum, relative to a brain atlas, in each of 14 patients with cranial dystonia and 8 patients with hand dystonia. The mean (left and right) |x|, y, and z coordinates of peak striatal binding for each patient were compared between groups by t test. The location of peak [18F]spiperone binding within the putamen differed significantly between groups (cranial dystonia z<hand dystonia z, p = 0.016). We conclude that in isolated focal dystonia, dopamine D2-like receptors are distributed differently in the putamen depending on the body part manifesting dystonia.
Research Interests:
Background. This study’s goal was to provide dose–response data for a dopamine agonist in the baboon using standard methods (replicate measurements at each dose, across a range of doses), as a standard against which to subsequently... more
Background. This study’s goal was to provide dose–response data for a dopamine agonist in the baboon using standard methods (replicate measurements at each dose, across a range of doses), as a standard against which to subsequently validate a novel pharmacological MRI (phMRI) method. Dependent variables were functional MRI (fMRI) data from brain regions selected a priori, and systemic prolactin release. Necessary first steps included estimating the magnitude and time course of prolactin response to anesthesia alone and to various doses of agonist. These first steps (“time course studies”) were performed with three agonists, and the results were used to select promising agonists and to guide design details for the single-dose studies needed to generate dose–response curves.
Methods. We studied 6 male baboons (Papio anubis) under low-dose isoflurane anesthesia after i.m. ketamine. Time course studies charted the changes in plasma prolactin levels over time after anesthesia alone or after an intravenous (i.v.) dose of the dopamine D1-like agonists SKF82958 and SKF38393 or the D2-like agonist pramipexole. In the single-dose dopamine agonist studies, one dose of SKF38393 (ranging from 0.0928–9.28 mg/kg, N = 5 animals) or pramipexole (0.00928–0.2 mg/kg, N = 1) was given i.v. during a 40-min blood oxygen level dependent (BOLD) fMRI session, to determine BOLD and plasma prolactin responses to different drug concentrations. BOLD response was quantified as the area under the time-signal curve for the first 15 min after the start of the drug infusion, compared to the linearly predicted signal from the baseline data before drug. The ED50 (estimated dose that produces 50% of the maximal possible response to drug) for SKF38393 was calculated for the serum prolactin response and for phMRI responses in hypothalamus, pituitary, striatum and midbrain.
Results. Prolactin rose 2.4- to 12-fold with anesthesia alone, peaking around 50–90 min after ketamine administration and gradually tapering off but still remaining higher than baseline on isoflurane 3–5 h after ketamine. Baseline prolactin level increased with age. SKF82958 0.1 mg/kg i.v. produced no noticeable change in plasma prolactin concentration. SKF38393 produced a substantial increase in prolactin release that peaked at around 20–30 min and declined to pre-drug levels in about an hour. Pramipexole quickly reduced prolactin levels below baseline, reaching a nadir 2–3 h after infusion. SKF38393 produced clear, dose-responsive BOLD signal changes, and across the four regions, ED50 was estimated at 2.6–8.1 mg/kg.
Conclusions. In the baboon, the dopamine D1 receptor agonist SKF38393 produces clear plasma prolactin and phMRI dose–response curves. Variability in age and a modest sample size limit the precision of the conclusions.
Methods. We studied 6 male baboons (Papio anubis) under low-dose isoflurane anesthesia after i.m. ketamine. Time course studies charted the changes in plasma prolactin levels over time after anesthesia alone or after an intravenous (i.v.) dose of the dopamine D1-like agonists SKF82958 and SKF38393 or the D2-like agonist pramipexole. In the single-dose dopamine agonist studies, one dose of SKF38393 (ranging from 0.0928–9.28 mg/kg, N = 5 animals) or pramipexole (0.00928–0.2 mg/kg, N = 1) was given i.v. during a 40-min blood oxygen level dependent (BOLD) fMRI session, to determine BOLD and plasma prolactin responses to different drug concentrations. BOLD response was quantified as the area under the time-signal curve for the first 15 min after the start of the drug infusion, compared to the linearly predicted signal from the baseline data before drug. The ED50 (estimated dose that produces 50% of the maximal possible response to drug) for SKF38393 was calculated for the serum prolactin response and for phMRI responses in hypothalamus, pituitary, striatum and midbrain.
Results. Prolactin rose 2.4- to 12-fold with anesthesia alone, peaking around 50–90 min after ketamine administration and gradually tapering off but still remaining higher than baseline on isoflurane 3–5 h after ketamine. Baseline prolactin level increased with age. SKF82958 0.1 mg/kg i.v. produced no noticeable change in plasma prolactin concentration. SKF38393 produced a substantial increase in prolactin release that peaked at around 20–30 min and declined to pre-drug levels in about an hour. Pramipexole quickly reduced prolactin levels below baseline, reaching a nadir 2–3 h after infusion. SKF38393 produced clear, dose-responsive BOLD signal changes, and across the four regions, ED50 was estimated at 2.6–8.1 mg/kg.
Conclusions. In the baboon, the dopamine D1 receptor agonist SKF38393 produces clear plasma prolactin and phMRI dose–response curves. Variability in age and a modest sample size limit the precision of the conclusions.
Research Interests:
Levodopa has several advantages as a pharmacological challenge agent for human neuroscience research. Exogenous levodopa changes striatal neuronal activity and increases extracellular dopamine concentrations, and with adequate inhibition... more
Levodopa has several advantages as a pharmacological challenge agent for human neuroscience research. Exogenous levodopa changes striatal neuronal activity and increases extracellular dopamine concentrations, and with adequate inhibition of peripheral metabolism levodopa does not change mean cerebral blood flow. For neuroimaging studies of Parkinson disease (PD) and Tourette syndrome, we sought to rapidly produce a biologically relevant steady-state levodopa concentration and then maintain that concentration for at least an hour. We also wished to minimize side effects, even in individuals without prior levodopa treatment. We designed a two-stage intravenous infusion protocol based on published levodopa pharmacokinetic data. We report results of 125 infusions in 106 subjects, including healthy volunteers, PD patients, and people with chronic tics. At higher doses (target steady-state levodopa concentrations of 2,169 and 1,200 ng/ml), treatment-naive volunteers had unacceptably frequent side effects. The final infusion protocol, with a target steady-state concentration of 600 ng/ml, was well-tolerated (mild nausea in 11% of subjects was the only side effect occurring significantly more than in single-blind saline infusions), produced the desired plasma levodopa concentration (612+/-187 ng/ml, mean+/-S.D.), and produced statistically significant antiparkinsonian benefit (16% mean reduction in a standard rating of parkinsonian motor signs, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0005).
Research Interests:
Purpose: Our goals were to (a) develop and validate a sensitive measure of image registration, applicable between as well as within imaging modalities; and (b) quantify the accuracy of the automated image registration (AIR) algorithm in... more
Purpose: Our goals were to (a) develop and validate a sensitive measure of image registration, applicable between as well as within imaging modalities; and (b) quantify the accuracy of the automated image registration (AIR) algorithm in retrospectively registering MR and PET images of baboon brain.
Method: We studied five monkeys, each with a surgically implanted “cap” that was bolted to an acrylic headholder containing fiducial markers. Anatomic MRI and PET H215O blood flow images were aligned using AIR (ignoring the fiducials).
Results: (a) Fiducial points were localized to about one-tenth the voxel size. Distances computed from the fiducial points were correct to within 0.2% (MRI) and 1.4% (PET). (b) The mean error remaining after AIR, measured at the five fiducial points, varied from 2.9 to 5.3 mm. The average registration error within the brain was calculated to be 2.20 mm (maximum, 3.57 mm). This error was not primarily rotational about the center of the brain and was worsened by heavy smoothing of the PET images.
Conclusion: (a) We have defined a reliable, sensitive metric that can stringently test the accuracy of various image registration techniques. (b) The AIR algorithm leaves modest error after aligning PET blood flow and anatomic MR images of baboon brain.
Method: We studied five monkeys, each with a surgically implanted “cap” that was bolted to an acrylic headholder containing fiducial markers. Anatomic MRI and PET H215O blood flow images were aligned using AIR (ignoring the fiducials).
Results: (a) Fiducial points were localized to about one-tenth the voxel size. Distances computed from the fiducial points were correct to within 0.2% (MRI) and 1.4% (PET). (b) The mean error remaining after AIR, measured at the five fiducial points, varied from 2.9 to 5.3 mm. The average registration error within the brain was calculated to be 2.20 mm (maximum, 3.57 mm). This error was not primarily rotational about the center of the brain and was worsened by heavy smoothing of the PET images.
Conclusion: (a) We have defined a reliable, sensitive metric that can stringently test the accuracy of various image registration techniques. (b) The AIR algorithm leaves modest error after aligning PET blood flow and anatomic MR images of baboon brain.
Research Interests:
Background: Prior brain imaging and autopsy studies have suggested that structural abnormalities of the basal ganglia (BG) nuclei may be present in Tourette Syndrome (TS). These studies have focused mainly on the volume differences of the... more
Background: Prior brain imaging and autopsy studies have suggested that structural abnormalities of the basal ganglia (BG) nuclei may be present in Tourette Syndrome (TS). These studies have focused mainly on the volume differences of the BG structures and not their anatomical shapes. Shape differences of various brain structures have been demonstrated in other neuropsychiatric disorders using large-deformation, high dimensional brain mapping (HDBM-LD). A previous study of a small sample of adult TS patients demonstrated the validity of the method, but did not find significant differences compared to controls. Since TS usually begins in childhood and adult studies may show structure differences due to adaptations, we hypothesized that differences in BG and thalamus structure geometry and volume due to etiological changes in TS might be better characterized in children.
Objective: Pilot the HDBM-LD method in children and estimate effect sizes.
Methods: In this pilot study, T1-weighted MRIs were collected in 13 children with TS and 16 healthy, tic-free, control children. The groups were well matched for age. The primary outcome measures were the first 10 eigenvectors which are derived using HDBM-LD methods and represent the majority of the geometric shape of each structure, and the volumes of each structure adjusted for whole brain volume. We also compared hemispheric right/left asymmetry and estimated effect sizes for both volume and shape differences between groups.
Results: We found no statistically significant differences between the TS subjects and controls in volume, shape, or right/left asymmetry. Effect sizes were greater for shape analysis than for volume.
Conclusion: This study represents one of the first efforts to study the shape as opposed to the volume of the BG in TS, but power was limited by sample size. Shape analysis by the HDBM-LD method may prove more sensitive to group differences.
- See more at: http://f1000research.com/articles/2-207/v1#sthash.57Uc4Yz5.dpuf
Objective: Pilot the HDBM-LD method in children and estimate effect sizes.
Methods: In this pilot study, T1-weighted MRIs were collected in 13 children with TS and 16 healthy, tic-free, control children. The groups were well matched for age. The primary outcome measures were the first 10 eigenvectors which are derived using HDBM-LD methods and represent the majority of the geometric shape of each structure, and the volumes of each structure adjusted for whole brain volume. We also compared hemispheric right/left asymmetry and estimated effect sizes for both volume and shape differences between groups.
Results: We found no statistically significant differences between the TS subjects and controls in volume, shape, or right/left asymmetry. Effect sizes were greater for shape analysis than for volume.
Conclusion: This study represents one of the first efforts to study the shape as opposed to the volume of the BG in TS, but power was limited by sample size. Shape analysis by the HDBM-LD method may prove more sensitive to group differences.
- See more at: http://f1000research.com/articles/2-207/v1#sthash.57Uc4Yz5.dpuf
Research Interests:
Background: Psychosis is a common and debilitating side effect of long-term dopaminergic treatment of Parkinson disease (PD). While clozapine is an effective treatment, the need for blood monitoring has limited its first-line use.... more
Background: Psychosis is a common and debilitating side effect of long-term dopaminergic treatment of Parkinson disease (PD). While clozapine is an effective treatment, the need for blood monitoring has limited its first-line use.
Objective: Since olanzapine shows similar receptor affinity to clozapine, we hypothesized that it might be an effective alternative to clozapine for treatment of drug-induced psychosis (DIP) in PD, and that lower doses than usual might make it tolerable.
Methods: In 1998-2003 we conducted a four-week, double-blind, placebo-controlled, parallel group, fixed-dose trial of olanzapine (0, 2.5mg, or 5mg) in 23 PD patients with DIP while allowing for clinically realistic dose adjustments of dopaminomimetic mid-study. The primary outcome measures were Brief Psychiatric Rating Scale (BPRS) ratings scored from videotaped interviews after study termination by an observer blinded to dose assignment and to interview timing, and CGI (Clinical Global Impression). The Unified Parkinson’s Disease Rating Scale motor subscale (UPDRS) was the primary measure of tolerability.
Results: Intention-to-treat analysis found no significant differences among treatment groups in study completion or serious adverse events. However, a disproportionate number of olanzapine vs. placebo subjects reported mild side effects (p<0.04), many citing motor worsening. Fourteen patients completed the study (seven on placebo, two on 2.5mg olanzapine, five on 5mg olanzapine). In study completers, analysis by repeated measures ANOVA revealed no significant difference between olanzapine and placebo groups in BPRS psychosis reduction (p=0.536), parkinsonism (p=0.608), or any other measured parameters (CGI, MMSE, Beck Depression Inventory, Hamilton Depression score, PDQ‑39, Schwab-England ADL assessment, and sleep scores).
Conclusion: This study adds to other evidence that olanzapine is ineffective in treating medication-induced psychosis in Parkinson disease.
- See more at: http://f1000research.com/articles/2-150/v1#sthash.TT7DCx1Y.dpuf
Objective: Since olanzapine shows similar receptor affinity to clozapine, we hypothesized that it might be an effective alternative to clozapine for treatment of drug-induced psychosis (DIP) in PD, and that lower doses than usual might make it tolerable.
Methods: In 1998-2003 we conducted a four-week, double-blind, placebo-controlled, parallel group, fixed-dose trial of olanzapine (0, 2.5mg, or 5mg) in 23 PD patients with DIP while allowing for clinically realistic dose adjustments of dopaminomimetic mid-study. The primary outcome measures were Brief Psychiatric Rating Scale (BPRS) ratings scored from videotaped interviews after study termination by an observer blinded to dose assignment and to interview timing, and CGI (Clinical Global Impression). The Unified Parkinson’s Disease Rating Scale motor subscale (UPDRS) was the primary measure of tolerability.
Results: Intention-to-treat analysis found no significant differences among treatment groups in study completion or serious adverse events. However, a disproportionate number of olanzapine vs. placebo subjects reported mild side effects (p<0.04), many citing motor worsening. Fourteen patients completed the study (seven on placebo, two on 2.5mg olanzapine, five on 5mg olanzapine). In study completers, analysis by repeated measures ANOVA revealed no significant difference between olanzapine and placebo groups in BPRS psychosis reduction (p=0.536), parkinsonism (p=0.608), or any other measured parameters (CGI, MMSE, Beck Depression Inventory, Hamilton Depression score, PDQ‑39, Schwab-England ADL assessment, and sleep scores).
Conclusion: This study adds to other evidence that olanzapine is ineffective in treating medication-induced psychosis in Parkinson disease.
- See more at: http://f1000research.com/articles/2-150/v1#sthash.TT7DCx1Y.dpuf
Research Interests:
PURPOSE: We report the residual anatomic error after a nine parameter visually guided registration of MR images with a baboon brain atlas to validate a stereotactic method for use in PET studies. METHOD: MPRAGE images of brain in six... more
PURPOSE:
We report the residual anatomic error after a nine parameter visually guided registration of MR images with a baboon brain atlas to validate a stereotactic method for use in PET studies.
METHOD:
MPRAGE images of brain in six baboons and one nemestrina monkey were placed in atlas space using internal landmarks and proportional measurements. An expert noted the location of 23 subcortical test points in the transformed images and in the atlas.
RESULTS:
The average absolute error at the test points was 1.62 mm. At the extremes of the brain surface, there was more variability. PET images could be combined across animals in a common atlas space.
CONCLUSION:
There is minimal subcortical error attributable to anatomic variability after this method of transforming MR images of baboon to stereotactic space. This method provides a useful tool for intrasubject PET baboon studies as well as "bootstrapping" for more refined methods.
We report the residual anatomic error after a nine parameter visually guided registration of MR images with a baboon brain atlas to validate a stereotactic method for use in PET studies.
METHOD:
MPRAGE images of brain in six baboons and one nemestrina monkey were placed in atlas space using internal landmarks and proportional measurements. An expert noted the location of 23 subcortical test points in the transformed images and in the atlas.
RESULTS:
The average absolute error at the test points was 1.62 mm. At the extremes of the brain surface, there was more variability. PET images could be combined across animals in a common atlas space.
CONCLUSION:
There is minimal subcortical error attributable to anatomic variability after this method of transforming MR images of baboon to stereotactic space. This method provides a useful tool for intrasubject PET baboon studies as well as "bootstrapping" for more refined methods.
Research Interests:
Research Interests:
BACKGROUND: Several lines of evidence suggest that dopamine (DA)-influenced neuronal pathways may malfunction in Tourette Syndrome (TS). A dopamine-responsive abnormality of brain function in TS could be either presynaptic or... more
BACKGROUND: Several lines of evidence suggest that dopamine (DA)-influenced neuronal pathways may malfunction in Tourette Syndrome (TS). A dopamine-responsive abnormality of brain function in TS could be either presynaptic or postsynaptic. Some PET studies support the hypothesis of presynaptic abnormalities in levodopa uptake, dopamine synthesis, or dopamine release. Alternatively, presynaptic dopaminergic function could be normal in TS but dopamine-sensitive abnormalities could exist in striatum, pallidum, thalamus, or cortex. METHODS: In this study we directly tested the presynaptic hypothesis using a new approach. We used positron emission tomography (PET) and [11C]raclopride (RAC*) to measure synaptic dopamine release in response to levodopa and placebo infusions (with carbidopa) in 5 neuroleptic-naïve adults with TS and 5 matched control subjects. The primary analysis examined RAC* binding potential (BPND) in predefined volumes of interest (VOIs). A secondary analysis compared BPND voxel by voxel over the entire brain. RESULTS: (1) Overall, baseline RAC* BPND did not differ significantly between groups, though nucleus accumbens BPND was higher in TS (16%, p=0.051). (2) Across regions, DA release declined from before to during infusion (p=0.014), including with placebo. (3) This decline was smaller in TS (p=0.080). (4) Levodopa’s effect on BPND differed significantly in right midbrain (p=0.002, corrected), where levodopa displaced RAC* by 59% in control subjects but increased BPND by 74% in TS subjects, and in parahippocampal gyrus (p=0.02, corrected). DISCUSSION: Our finding that a before/after RAC* design is confounded by time and/or expectation effects has implications for other RAC* PET studies. The smaller magnitude of the decrease with time in TS may be attributable to impaired habituation to the scan environment. Levodopa’s opposite effect on RAC* binding in TS dopaminergic midbrain was not predicted, but may signify an abnormal response to dopaminergic stimulation in TS. These findings invite confirmation in a larger sample.
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Background. Normally one habituates rapidly to steady, faint sensations. People with sensory hypersensitivity (SH), by contrast, continue to attend to such stimuli and find them noxious. SH is common in Tourette syndrome (TS) and autism,... more
Background. Normally one habituates rapidly to steady, faint sensations. People with sensory hypersensitivity (SH), by contrast, continue to attend to such stimuli and find them noxious. SH is common in Tourette syndrome (TS) and autism, and methods to quantify SH may lead to better understanding of these disorders. In an attempt to objectively quantify SH severity, the authors tested whether a choice reaction time (CRT) task was a sensitive enough measure to detect significant distraction from a steady tactile stimulus, and to detect significantly greater distraction in subjects with more severe SH.
Methods. Nineteen ambulatory adult volunteers with varying scores on the Adult Sensory Questionnaire (ASQ), a clinical measure of SH, completed a CRT task in the alternating presence and absence of tactile stimulation.
Results. Tactile stimulation interfered with attention (i.e., produced longer reaction times), and this effect was significantly greater in participants with more SH (higher ASQ scores). Accuracy on the CRT was high in blocks with and without stimulation. Habituation within stimulation blocks was not detected.
Conclusion. This approach can detect distraction from a cognitive task by a steady, faint tactile stimulus that does not degrade response accuracy. The method was also sensitive to the hypothesized enhancement of this effect by SH. These results support the potential utility of this approach to quantifying SH, and suggest possible refinements for future studies.
Methods. Nineteen ambulatory adult volunteers with varying scores on the Adult Sensory Questionnaire (ASQ), a clinical measure of SH, completed a CRT task in the alternating presence and absence of tactile stimulation.
Results. Tactile stimulation interfered with attention (i.e., produced longer reaction times), and this effect was significantly greater in participants with more SH (higher ASQ scores). Accuracy on the CRT was high in blocks with and without stimulation. Habituation within stimulation blocks was not detected.
Conclusion. This approach can detect distraction from a cognitive task by a steady, faint tactile stimulus that does not degrade response accuracy. The method was also sensitive to the hypothesized enhancement of this effect by SH. These results support the potential utility of this approach to quantifying SH, and suggest possible refinements for future studies.
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Research Interests: Research Design, Diabetes, Magnetic Resonance Imaging, Adolescent, Brain development, and 15 moreHippocampus, Humans, Child, Hyperglycemia, Female, Male, Hypoglycemia, Magnetic Resonance, Siblings, Human Brain, Type 2 Diabetes Mellitus, Reference Values, Age of Onset, Functional Laterality, and Magnetic resonance image
Some of the most important unanswered questions about PD include: What is the etiology? and Can one predict the risk of developing PD before any clinical signs are apparent? The study by Piccini et al. has relevance to both questions.... more
Some of the most important unanswered questions about PD include: What is the etiology? and Can one predict the risk of developing PD before any clinical signs are apparent? The study by Piccini et al. has relevance to both questions.
Commentary on:
Dopaminergic Function in Familial Parkinson's Disease: A Clinical and 18F-dopa Positron Emission Tomography Study Article by P. Piccini, M.D., P.K. Morrish, M.R.C.P., N. Turjanski, M.D., G.V. Sawle, D.M., D.J. Burn, M.D., R.A. Weeks, M.D., M.H. Mark, M.D., D.M. Maraganore, M.D., A.J. Lees, M.D., and D.J. Brooks, M.D.; Ann Neurol 1997; 41: 222-229
Commentary on:
Dopaminergic Function in Familial Parkinson's Disease: A Clinical and 18F-dopa Positron Emission Tomography Study Article by P. Piccini, M.D., P.K. Morrish, M.R.C.P., N. Turjanski, M.D., G.V. Sawle, D.M., D.J. Burn, M.D., R.A. Weeks, M.D., M.H. Mark, M.D., D.M. Maraganore, M.D., A.J. Lees, M.D., and D.J. Brooks, M.D.; Ann Neurol 1997; 41: 222-229
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Dopamine has been hypothesized to modulate response inhibition. To test this hypothesis, we used functional magnetic resonance imaging (fMRI) to measure the effects of the dopamine prodrug levodopa on the brain responses to a... more
Dopamine has been hypothesized to modulate response inhibition. To test this hypothesis, we used functional magnetic resonance imaging (fMRI) to measure the effects of the dopamine prodrug levodopa on the brain responses to a well-validated response inhibition task (go/no-go, or GNG). Since abnormalities of response inhibition and dopamine have been thought to underlie tics and other symptoms of Tourette syndrome, we studied 8 neuroleptic-naive adults with tic disorders as well as 10 well-matched healthy controls. Subjects were pretreated with the peripheral decarboxylase inhibitor carbidopa, then scanned during GNG and control blocks, both before and during i.v. levodopa infusion. Both groups had similar task performance and task-related regional brain activity before and during levodopa infusion. Levodopa did not affect reaction times or accuracy, so fMRI findings can be interpreted without concern that they simply reflect a performance difference between conditions. Levodopa did affect the magnitude of GNG-related fMRI responses in the right cerebellum and right parietal cortex, significantly reducing both. Pre-levodopa activity in the right cerebellum correlated with reaction times (higher magnitudes associated with faster reaction times), and pre-levodopa activity in the right parietal cortex correlated with false alarm rate (higher magnitudes associated with higher error). In summary, right parietal and cerebellar regions important in mediating specific aspects of the GNG task were modulated by levodopa, suggesting a region-specific role for dopamine in response inhibition.
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Research Interests: Psychopharmacology, Depression, Schizophrenia, Neuropsychopharmacology, Humans, and 13 morePlacebo, Female, Male, Regression Analysis, Statistical Significance, Depressive Disorder, Placebos, Rating Scale, Serotonin Receptors, Adult, Biological markers, Psychiatric Status Rating Scales, and Paroxetine
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The analysis of structural brain asymmetry has been a focal point in anthropological theories of human brain evolution and the development of lateralized behaviors. While physiological brain asymmetries have been documented for humans and... more
The analysis of structural brain asymmetry has been a focal point in anthropological theories of human brain evolution and the development of lateralized behaviors. While physiological brain asymmetries have been documented for humans and animals presenting with pathological conditions or under certain activation tasks, published studies on baseline asymmetries in healthy individuals have produced conflicting results. We tested for the presence of cerebral blood flow asymmetries in 7 healthy, sedated baboons using positron emission tomography, a method of in vivo autoradiography. Five of the 7 baboons exhibited hemispheric asymmetries in which left-sided flow was significantly greater than right-sided flow. Furthermore, the degree of asymmetry in 8 of 24 brain regions was found to be significantly correlated with age; older individuals exhibited a higher degree of asymmetry than younger individuals. Cerebral blood flow itself was uncorrelated with age, and differences between males and females were not significant. Am J Phys Anthropol, 2003. © 2003 Wiley-Liss, Inc.
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Exposure and response prevention (ERP) is a first-line behavior therapy for obsessive-compulsive disorder, and has also been tested in Tourette syndrome (TS). However, ERP for tic disorders requires intentional tic suppression, which for... more
Exposure and response prevention (ERP) is a first-line behavior therapy for obsessive-compulsive disorder, and has also been tested in Tourette syndrome (TS). However, ERP for tic disorders requires intentional tic suppression, which for some patients is difficult even for brief periods. Additionally, practical access to behavior therapy is difficult for many patients, especially those in rural areas. The authors present a simple, working web platform (TicTrainer) that implements a strategy called reward-enhanced exposure and response prevention (RE–ERP). This strategy sacrifices most expert therapist components of ERP, focusing only on increasing the duration of time for which the user can suppress tics through automated differential reinforcement of tic-free periods (DRO). RE–ERP requires an external tic monitor, such as a parent, during training sessions. The user sees increasing digital rewards for longer and longer periods of successful tic suppression, similar to a video game ...
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Background: Motor and vocal tics are common in childhood. The received wisdom among clinicians is that for most children the tics are temporary, disappearing within a few months. However, that common clinical teaching is based largely on... more
Background: Motor and vocal tics are common in childhood. The received wisdom among clinicians is that for most children the tics are temporary, disappearing within a few months. However, that common clinical teaching is based largely on biased and incomplete data. The present study was designed to prospectively assess outcome of children with what the current nomenclature calls Persistent Tic Disorder. Methods: We identified 43 children with recent onset tics (mean tic onset 3.3 months prior to baseline study visit) by advertising in addition to clinical sources and characterized them using extensive clinical measures. At baseline, tic symptoms were mild on average (YGTSS total tic score = 17.23 ± 6.15). We re-examined 39 of these children on the 12-month anniversary of their first tic (mean 1 year + 8 days after onset). Results: We found that tic symptoms improved on a group level at the 12-month follow-up (YGTSS total tic score = 14.15 ± 6.63), more than 90% of children had no or...
Background Tourette syndrome (TS) is a neuropsychiatric disorder characterized by motor and vocal tics that typically change over development. Whether and how brain function in TS also differs across development has been largely... more
Background Tourette syndrome (TS) is a neuropsychiatric disorder characterized by motor and vocal tics that typically change over development. Whether and how brain function in TS also differs across development has been largely understudied. Here, we used functional connectivity MRI to examine whole brain functional networks in children and adults with TS. Methods Multivariate classification methods were used to find patterns among functional connections that distinguish TS from controls separately for children and adults (total N = 202). We tested whether the patterns of connections that classify diagnosis in one age group (e.g., children) could classify diagnosis in another age group (e.g., adults). We also tested whether the developmental trajectory of these connections were altered in TS. Results Patterns of functional connections that distinguished TS from controls were generalizable to an age-matched independent test set, but not to other age groups. While diagnostic classifi...
Tic suppression is the primary target of tic disorder treatment, but factors that influence voluntary tic inhibition are not well understood. Several studies using the Tic Suppression Task have demonstrated significant inter-individual... more
Tic suppression is the primary target of tic disorder treatment, but factors that influence voluntary tic inhibition are not well understood. Several studies using the Tic Suppression Task have demonstrated significant inter-individual variability in tic suppressibility but have individually been underpowered to address correlates of tic suppression. The present study explored patterns and clinical correlates of reward-enhanced tic suppression in youth with tic disorders using a large, pooled dataset. Individual-level data from nine studies using the Tic Suppression Task were pooled, yielding a sample of 99 youth with tic disorders. Analyses examined patterns of tic suppressibility and the relationship between tic suppressibility and demographic and clinical characteristics. A large majority of youth demonstrated a high degree of tic suppression, but heterogeneous patterns of tic suppressibility were also observed. Better tic suppressibility was related to older age and more frequen...
This article presents highlights chosen from research that appeared during 2016 on Tourette syndrome and other tic disorders. Selected articles felt to represent meaningful advances in the field are briefly summarized.
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Woods and Himle developed a standardized tic suppression paradigm (TSP) for the experimental setting, to quantify the effects of intentional tic suppression in Tourette syndrome. The present article describes a Java program that automates... more
Woods and Himle developed a standardized tic suppression paradigm (TSP) for the experimental setting, to quantify the effects of intentional tic suppression in Tourette syndrome. The present article describes a Java program that automates record keeping and reward dispensing during the several experimental conditions of the TSP. The software can optionally be connected to a commercial reward token dispenser to further automate reward delivery to the participant. The timing of all tics, 10-second tic-free intervals, and dispensed rewards is recorded in plain text files for later analysis. Expected applications include research on Tourette syndrome and related disorders.
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Freezing of gait (FOG) is a common, disabling gait disturbance in Parkinson's disease (PD) and other Parkinsonian syndromes. Freezing also occurs during non-gait movements involving the upper limbs. The mechanisms underlying freezing... more
Freezing of gait (FOG) is a common, disabling gait disturbance in Parkinson's disease (PD) and other Parkinsonian syndromes. Freezing also occurs during non-gait movements involving the upper limbs. The mechanisms underlying freezing are complex, likely involving motor, cognitive, and sensory systems that contribute to the episodes. Here, we reported a 60-year-old female with a 24-year history of parkinsonism who experienced significant FOG when ambulatory. Disease progression resulted in her permanent use of a powered wheelchair. While using the power chair, the patient experiences apparent paroxysmal freezing in the hand and arm used to steer and propel the chair. These episodes, some lasting up to several minutes, occur only in circumstances (e.g., entering and leaving an elevator) that are similar to environments known to elicit and exacerbate FOG. Episodes are transient and can be volitionally interrupted by the patient but sometimes require external assistance. Therapeutic...
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Motor and vocal tics are relatively common motor manifestations identified as the core features of Tourette's syndrome (TS). Although traditional descriptions have focused on objective phenomenological observations, such as anatomical... more
Motor and vocal tics are relatively common motor manifestations identified as the core features of Tourette's syndrome (TS). Although traditional descriptions have focused on objective phenomenological observations, such as anatomical location, number and frequency of tics, patients' first-person accounts have consistently reported characteristic subjective correlates. These sensory phenomena are often described as a feeling of mounting inner tension or urge to move ("premonitory urge"), which is transiently relieved by tic expression. This article reviews the existing literature on the clinical and neurobiological aspects of the premonitory urge in patients with TS, with focus on its pathophysiology and possible treatment implications.
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Population-based assessment of Tourette syndrome (TS) and other tic disorders produces a paradox. On one hand, ideally diagnosis of tic disorders requires expert observation. In fact, diagnostic criteria for TS explicitly require expert... more
Population-based assessment of Tourette syndrome (TS) and other tic disorders produces a paradox. On one hand, ideally diagnosis of tic disorders requires expert observation. In fact, diagnostic criteria for TS explicitly require expert assessment of tics for a definite diagnosis. On the other hand, large-scale population surveys with expert assessment of every subject are impracticable. True, several published studies have successfully used expert assessment to find tic prevalence in a representative population (e.g. all students in a school district). However, extending these studies to larger populations is daunting. We created a multimedia tool to demonstrate tics to a lay audience, discuss their defining and common attributes, and address features that differentiate tics from other movements and vocalizations. A first version was modified to improve clarity and to include a more diverse group in terms of age and ethnicity. The result is a tool intended for epidemiological resea...
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A 74-year-old man with a remote history of Sydenham&#39;s chorea but no personal or family history of mood disorder had simultaneous onset of severe, generalized chorea and a mild manic syndrome in clear consciousness. Both chorea and... more
A 74-year-old man with a remote history of Sydenham&#39;s chorea but no personal or family history of mood disorder had simultaneous onset of severe, generalized chorea and a mild manic syndrome in clear consciousness. Both chorea and hypomania improved after treatment with sodium valproate and clonazepam. Agitated delirium or mood lability have been described in Sydenham&#39;s, but this case is the first report of criteria-based secondary mania with probable Sydenham&#39;s chorea, as well as the longest reported remission between symptomatic Sydenham&#39;s episodes. The parallel course of this patient&#39;s hypomania and chorea supports current pathophysiologic theories of idiopathic mania.
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Alterations in dopaminergic circuitry play a critical role in food reward and may contribute to susceptibility to obesity. Ingestion of sweets releases dopamine in striatum, and both sweet preferences and striatal D2 receptors (D2R)... more
Alterations in dopaminergic circuitry play a critical role in food reward and may contribute to susceptibility to obesity. Ingestion of sweets releases dopamine in striatum, and both sweet preferences and striatal D2 receptors (D2R) decline with age and may be altered in obesity. Understanding the relationships between these variables and the impact of obesity on these relationships may reveal insight into the neurobiological basis of sweet preferences. We evaluated sucrose preferences, perception of sweetness intensity, and striatal D2R binding potential (D2R BPND) using PET with a D2R selective radioligand insensitive to endogenous dopamine, (N-[(11)C] methyl)benperidol, in 20 subjects without obesity (BMI 22.6 ±2.5 kg/m(2); age 28.3 ±5.4y) and 24 subjects with obesity (BMI 40.3±5.0 kg/m(2); age 31.2±6.3y). Groups had similar sucrose preferences, sweetness intensity perception, striatal D2R BPND, and age-related D2R BPND declines. However, both striatal D2R BPND and age correlated...
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Levodopa has several advantages as a pharmacological challenge agent for human neuroscience research. Exogenous levodopa changes striatal neuronal activity and increases extracellular dopamine concentrations, and with adequate inhibition... more
Levodopa has several advantages as a pharmacological challenge agent for human neuroscience research. Exogenous levodopa changes striatal neuronal activity and increases extracellular dopamine concentrations, and with adequate inhibition of peripheral metabolism levodopa does not change mean cerebral blood flow. For neuroimaging studies of Parkinson disease (PD) and Tourette syndrome, we sought to rapidly produce a biologically relevant steady-state levodopa concentration and then maintain that concentration for at least an hour. We also wished to minimize side effects, even in individuals without prior levodopa treatment. We designed a two-stage intravenous infusion protocol based on published levodopa pharmacokinetic data. We report results of 125 infusions in 106 subjects, including healthy volunteers, PD patients, and people with chronic tics. At higher doses (target steady-state levodopa concentrations of 2,169 and 1,200 ng/ml), treatment-naive volunteers had unacceptably frequent side effects. The final infusion protocol, with a target steady-state concentration of 600 ng/ml, was well-tolerated (mild nausea in 11% of subjects was the only side effect occurring significantly more than in single-blind saline infusions), produced the desired plasma levodopa concentration (612+/-187 ng/ml, mean+/-S.D.), and produced statistically significant antiparkinsonian benefit (16% mean reduction in a standard rating of parkinsonian motor signs, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0005).
Research Interests: Neuroscience, Cognitive Science, Chromatography, Dopaminergic Neurotransmision, Movement disorders, and 15 moreDopamine, Humans, Female, Male, Levodopa, Clinical Sciences, Aged, Middle Aged, Adult, Neuronal Activity, Cerebral Blood Flow, Neurosciences, Parkinson Disease, Carbidopa, and Neuroscience Methods
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In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R)... more
In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are non-selective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N-[(11) C]methyl)benperidol ([(11) C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in 2 independent samples. Sample 1 (n = 39) was composed of obese and non-obese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers...
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The child with recent onset of tics is a common patient in a pediatrics or child neurology practice. If the child’s first tic was less than a year in the past, the diagnosis is usually Provisional Tic Disorder (PTD). Published reviews by... more
The child with recent onset of tics is a common patient in a pediatrics or child neurology practice. If the child’s first tic was less than a year in the past, the diagnosis is usually Provisional Tic Disorder (PTD). Published reviews by experts reveal substantial consensus on prognosis in this situation: the tics will almost always disappear in a few months, having remained mild while they lasted. Surprisingly, however, the sparse existing data may not support these opinions.PTD may have just as much importance for science as for clinical care. It provides an opportunity to prospectively observe the spontaneous remission of tics. Such prospective studies may aid identification of genes or biomarkers specifically associated with remission rather than onset of tics. A better understanding of tic remission may also suggest novel treatment strategies for Tourette syndrome, or may lead to secondary prevention of tic disorders.This review summarizes the limited existing data on the epide...
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Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;am... more
Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (PD) patients commonly develop fluctuations in their motor responses to levodopa within several years of initiation of treatment; some also develop nonmotor fluctuations. The authors performed a case-control study comparing the frequency of comorbid symptoms in 70 PD patients who experienced clinically apparent mood changes during their motor &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;on&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; or &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;off&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; states with two control groups with no mood fluctuations. Mood fluctuators had significantly younger age at onset and longer disease duration and were significantly more likely to have dementia, psychosis, clinical depression, and motor complications. This association remained after removing effects of age and disease duration.
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This study attempted to determine how often psychiatric residents are exposed to violence, the types of violence they encounter, and what institutional changes might increase their safety. Safety conditions at two private general... more
This study attempted to determine how often psychiatric residents are exposed to violence, the types of violence they encounter, and what institutional changes might increase their safety. Safety conditions at two private general hospitals and one state hospital that served as training sites for a psychiatric residency program were assessed through a survey of psychiatric residents and site visits to the hospitals. The survey asked residents to quantify violent incidents occurring in the emergency rooms, wards, and clinics at each site. The site visits focused on safety issues related to staff training, physical layout, staffing patterns, current policies, and compliance with policies. All 47 residents in the training program responded to the survey. None reported serious injury, although as many as 56 percent had been physically assaulted on the wards of one hospital, and 54 percent of residents had encountered a weapon in one emergency room. Almost all residents had been verbally threatened or had witnessed violence to others. A paradoxical finding of the survey was that the residents felt safest in the hospital that had the highest rate of violence. The site visits revealed that deficiencies in the safety procedures were allowing weapons to be brought into patient care areas. Psychiatric residents are often exposed to dangerous situations, although serious injury is rare. Residents&#39; beliefs about their level of safety seem to be influenced more by how competent they perceive the staff to be than by the frequency of violence. The findings from the site visits pointed to two steps to increase safety: creating a weapon-free environment by searching all patients and finding ways to improve compliance with existing safety measures.
Research Interests: Psychiatry, Violence, Occupational Health, Humans, United States, and 14 moreFemale, Male, Missouri, Data Collection, Mental Disorders, Incidence, Middle Aged, Risk Factor, Security Measures, Adult, Public health systems and services research, Psychiatric Services, Psychiatric, and internship and residency
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Depression following a cerebrovascular accident is common, disabling, and treatable. However, the consequences of a stroke often render the clinical evaluation for depression misleading or difficult to interpret. These factors make a... more
Depression following a cerebrovascular accident is common, disabling, and treatable. However, the consequences of a stroke often render the clinical evaluation for depression misleading or difficult to interpret. These factors make a laboratory test for depression especially desirable in this population. We reviewed and evaluated the literature on the dexamethasone suppression test (DST) as a diagnostic tool for depression in stroke patients. Nine studies were identified. Our findings included (1) substantial variation in both methods and results, (2) a median specificity of 87%, and (3) a median sensitivity of 47%. We show that if these estimates of sensitivity and specificity are supported by future studies with improved methodology, then the DST may be clinically useful for the minority of stroke patients in whom a careful evaluation for depression remains inconclusive.
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Tourette Syndrome (ts) is a developmental neuropsychiatric disorder of the central nervous system defined by the presence of chronic tics. While investigations of the underlying brain mechanisms have provided valuable information, a... more
Tourette Syndrome (ts) is a developmental neuropsychiatric disorder of the central nervous system defined by the presence of chronic tics. While investigations of the underlying brain mechanisms have provided valuable information, a complete understanding of the pathophysiology of ts remains elusive. Neuroimaging methods provide remarkable tools for examining the human brain, and have been used to study brain structure and function in ts. In this article, we review ts neuroimaging studies published in 2014-2015. We highlight a number of noteworthy studies due to their innovative methods and interesting findings. Yet, we note that many of the recent studies share common concerns, specifically susceptibility to motion artifacts and modest sample sizes. Thus, we encourage future work to carefully address potential methodological confounds and to study larger samples to increase the potential for replicable results.
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Levodopa has several advantages as a pharmacological challenge agent for human neuroscience research. Exogenous levodopa changes striatal neuronal activity and increases extracellular dopamine concentrations, and with adequate inhibition... more
Levodopa has several advantages as a pharmacological challenge agent for human neuroscience research. Exogenous levodopa changes striatal neuronal activity and increases extracellular dopamine concentrations, and with adequate inhibition of peripheral metabolism levodopa does not change mean cerebral blood flow. For neuroimaging studies of Parkinson disease (PD) and Tourette syndrome, we sought to rapidly produce a biologically relevant steady-state levodopa concentration and then maintain that concentration for at least an hour. We also wished to minimize side effects, even in individuals without prior levodopa treatment. We designed a two-stage intravenous infusion protocol based on published levodopa pharmacokinetic data. We report results of 125 infusions in 106 subjects, including healthy volunteers, PD patients, and people with chronic tics. At higher doses (target steady-state levodopa concentrations of 2,169 and 1,200 ng/ml), treatment-naive volunteers had unacceptably frequent side effects. The final infusion protocol, with a target steady-state concentration of 600 ng/ml, was well-tolerated (mild nausea in 11% of subjects was the only side effect occurring significantly more than in single-blind saline infusions), produced the desired plasma levodopa concentration (612+/-187 ng/ml, mean+/-S.D.), and produced statistically significant antiparkinsonian benefit (16% mean reduction in a standard rating of parkinsonian motor signs, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0005).