Mark Hallett

Pennsylvania State University, University Park, Maryland, United States

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Publications (590)3052.39 Total impact

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    Tao Wu · Jiarong Zhang · Mark Hallett · Tao Feng · Yanan Hou · Piu Chan ·
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    ABSTRACT: Micrographia is a common symptom in Parkinson's disease, which manifests as either a consistent or progressive reduction in the size of handwriting or both. Neural correlates underlying micrographia remain unclear. We used functional magnetic resonance imaging to investigate micrographia-related neural activity and connectivity modulations. In addition, the effect of attention and dopaminergic administration on micrographia was examined. We found that consistent micrographia was associated with decreased activity and connectivity in the basal ganglia motor circuit; while progressive micrographia was related to the dysfunction of basal ganglia motor circuit together with disconnections between the rostral supplementary motor area, rostral cingulate motor area and cerebellum. Attention significantly improved both consistent and progressive micrographia, accompanied by recruitment of anterior putamen and dorsolateral prefrontal cortex. Levodopa improved consistent micrographia accompanied by increased activity and connectivity in the basal ganglia motor circuit, but had no effect on progressive micrographia. Our findings suggest that consistent micrographia is related to dysfunction of the basal ganglia motor circuit; while dysfunction of the basal ganglia motor circuit and disconnection between the rostral supplementary motor area, rostral cingulate motor area and cerebellum likely contributes to progressive micrographia. Attention improves both types of micrographia by recruiting additional brain networks. Levodopa improves consistent micrographia by restoring the function of the basal ganglia motor circuit, but does not improve progressive micrographia, probably because of failure to repair the disconnected networks.
    Brain 11/2015; DOI:10.1093/brain/awv319 · 9.20 Impact Factor

  • 09/2015; DOI:10.1001/jamaneurol.2015.1954
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    ABSTRACT: Restless legs syndrome (RLS) is a common sleep disorder that may be associated with pregnancy. Studies have found that the prevalence of RLS among pregnant women ranged from 10 to 34%. Typically there is complete remission of symptoms soon after parturition; however, in some patients they may continue postpartum. RLS has been shown to be associated with a number of complications in pregnancy including preeclampsia and increased incidence of caesarian sections. Although multiple hypotheses have been proposed to explain this association, each individual hypothesis cannot completely explain the whole pathogenesis. Present understanding suggests that a strong family history, low serum iron and ferritin level and high estrogen level during pregnancy might play important roles. Vitamin D deficiency and calcium metabolism may also play a role. Medical treatment of RLS during pregnancy is difficult and challenging considering the risks to mother and fetus. However, in some cases the disease may be severe enough to require treatment.
    Acta Neurologica Scandinavica 09/2015; DOI:10.1111/ane.12520 · 2.40 Impact Factor
  • Mark Hallett ·
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    ABSTRACT: Functional or psychogenic movement disorders are common and disabling, and sometime difficult to diagnose. The history and physical exam can give positive features that will support the diagnosis, which should not be based solely on exclusion. Some clues in the history are sudden onset, intermittent time course, variability of manifestation over time, childhood trauma, history of other somatic symptom and secondary gain. Anxiety and depression are common, but not necessarily more than the general population. On examination, distraction and suggestibility may be present. There are specific signs that should be looked for with different types of movements. For example, with tremor, change in frequency over time and entrainment are common features. With myoclonus, the movements might be complex in type with long latencies to stimulus induced jerks. Gait disorders show good balance despite claims to the contrary. Functional dystonia still remains a challenging diagnosis in many circumstances, although fixed dystonia is one sign more likely to be functional.
    Parkinsonism & Related Disorders 09/2015; 22 Suppl 1. DOI:10.1016/j.parkreldis.2015.08.036 · 3.97 Impact Factor
  • Simon Mitchell · Jennifer Gao · Mark Hallett · Valerie Voon ·
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    ABSTRACT: sec> Aims Novelty preference or sensation seeking is an important trait related to initiating and maintaining risky behaviours, including substance abuse. Here we introduce a novel or familiar prime (image) preceding a risk choice and focus on behavioural and imaging correlates to the prime that might predict risk seeking in healthy volunteers. We aim to investigate whether novel or familiar primes affect judgments of risk. We hypothesize that subjects would be more risk seeking following a novel relative to familiar stimulus and that subjects who are more novelty seeking will have increased striatal and hippocampal activity to the novel stimulus. Methods We adapted a risk-taking task involving acceptance or rejection of a 50:50 choice of gain or loss which was preceded by a familiar (pre-test familiarization) or novel face prime. Neutral expression faces of males and females from The Karolinska Directed Emotional Faces database were used as primes. Subjects were tested behaviourally and scanned using functional MRI as they were performing a different version of the same task. Results Twenty-four healthy volunteers were recruited for the behavioral study and eighteen for the fMRI study. We show enhanced risk taking following novel relative to familiar images and particularly for the low gain condition. Subjects had faster reaction times to the prime when accepting rather than rejecting the risky choice. We further show that right putamen activity to novel versus familiar primes were positively correlated with risk taking choices. Conclusions Novelty appears to have a contextually enhancing effect on augmenting risky choices possibly mediated via putaminal activity. These findings highlight the role of context in risk taking and have important implications for a wide range of behaviours including substance abuse. </sec
    Journal of Neurology Neurosurgery & Psychiatry 09/2015; 86(9). DOI:10.1136/jnnp-2015-311750.54 · 6.81 Impact Factor
  • Brian Johnson · Mark Hallett · Semyon Slobounov ·
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    ABSTRACT: To expand on our previous study by performing a follow-up testing session in the subacute phase of injury for participants recently diagnosed with a concussion. A battery of oculomotor tests were administered to participants 30 days postconcussion while simultaneous fMRI was performed. Three of the 7 oculomotor tasks (antisaccade, self-paced saccade, and memory-guided saccade) administered showed significant differences between the recently concussed group compared with normal volunteers. However, performance in these 3 tasks did show improvement from the acute phase of injury. The fMRI analysis revealed significant differences in brain activation patterns compared with normal volunteers, with the concussed group still demonstrating increased and larger areas of activation. Similar to the oculomotor performance, the fMRI analysis showed that at 30 days postinjury, the concussed group more closely mirrored that of the normal volunteer group compared with at 7 days following insult. Even at 30 days postinjury, and despite being clinically asymptomatic, advanced techniques are able to detect subtle lingering alterations in the concussed brain. Therefore, progressive neuroimaging techniques such as fMRI in conjunction with assessment of oculomotor performance may be beneficial in clinical management of concussion. © 2015 American Academy of Neurology.
    Neurology 08/2015; DOI:10.1212/WNL.0000000000001968 · 8.29 Impact Factor
  • David H. Benninger · Mark Hallett ·
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    ABSTRACT: Background and purpose: In advanced Parkinson's disease (PD), the emergence of symptoms refractory to conventional therapy poses a therapeutic challenge. The success of deep brain stimulation (DBS) and advances in the understanding of the pathophysiology of PD have raised interest in non-invasive brain stimulation as an alternative therapeutic tool. The rationale for its use draws from the concept that reversing abnormalities in brain activity and physiology thought to cause the clinical deficits may restore normal functioning. Currently the best evidence in support of this concept comes from DBS, which improves motor deficits, and modulates brain activity and motor cortex physiology, though whether a causal interaction exists remains largely undetermined. Conclusion: Most trials of non-invasive brain stimulation in PD have applied repetitive transcranial magnetic stimulation (rTMS) targeting the primary motor cortex and cortical areas of the motor circuit. Published studies suggest a possible therapeutic potential of rTMS and transcranial direct current stimulation (tDCS), but clinical effects so far have been small and negligible regarding functional independence and quality of life. Approaches to potentiate the efficacy of rTMS, including increasing stimulation intensity and novel stimulation parameters, derive their rationale from studies of brain physiology. These novel parameters simulate normal firing patterns or act on the hypothesized role of oscillatory activity in the motor cortex and basal ganglia in motor control. There may also be diagnostic potential of TMS in characterizing individual traits for personalized medicine.
    Neurorehabilitation 08/2015; 37(1):11-24. DOI:10.3233/NRE-151237 · 1.12 Impact Factor
  • Jung E Park · Katharine Alter · Mark Hallett ·

    08/2015; DOI:10.1001/jamaneurol.2015.1456
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    ABSTRACT: The resting sensory discomfort transiently relieved upon movement of the affected area in restless legs syndrome suggests that sensorimotor integration mechanisms, specifically gating, may be altered in the disease. The authors sought to determine the effects of prepulse auditory and tactile stimulation applied to lower limbs on the blink reflex of patients with restless legs syndrome and healthy subjects. Seventeen patients with restless legs syndrome and 17 age- and sex-matched healthy controls were investigated. Auditory stimuli and tactile lower limb stimulation were applied as prepulses. The R2 response of the blink reflex induced by electrical stimulation applied to the right supraorbital nerve was selected as the test stimulus. Time intervals between prepulses and response-eliciting stimuli were 40, 70, 90, 110, and 200 milliseconds. There were no differences in either the auditory or tactile prepulse conditions between patients and controls and no differences between these measures within subject groups. We concluded that the tactile lower limb and the auditory prepulse effects on the brainstem interneurons mediating the blink reflex share common neural pathways. Because forebrain interneurons mediate these prepulse effects, they are likely not involved in the disordered sensorimotor interaction of restless legs syndrome.
    Journal of clinical neurophysiology: official publication of the American Electroencephalographic Society 08/2015; 32(4):369-374. DOI:10.1097/WNP.0000000000000196 · 1.43 Impact Factor
  • Mark Hallett ·
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    ABSTRACT: While the steps in the action of botulinum neurotoxin (BoNT) are well known, the factors underlying the timing of these steps are not fully understood. After toxin is injected into a muscle, it resides in the extracellular space and must be taken up into the nerve terminals. More toxin will be taken up if near the endplate. Toxin is distributed mainly by convection and there is likely little diffusion. Toxin that is not taken up will go into the general circulation where it may have a slight systemic effect. The uptake is activity and temperature dependent. Encouraging the unwanted muscle contractions after injection should be helpful. Cooling will decrease the uptake. The times for washout from the extracellular space and uptake of the toxin are not well established, but are likely measured in minutes. Toxin in the general circulation has a long half time. The time from injection to weakness is determined by how long it takes to get sufficient damage of the SNARE proteins to interfere with synaptic release. Toxins are zinc dependent proteases, and supplemental zinc may produce a greater effect. There will be weakness as long as there is residual toxin in the nerve ending. Copyright © 2015. Published by Elsevier Ltd.
    Toxicon 07/2015; 93. DOI:10.1016/j.toxicon.2015.07.013 · 2.49 Impact Factor
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    ABSTRACT: Functional imaging studies have shown that control of planned movement involves a distributed network that involves the premotor (PMv) and posterior parietal cortices (PPC). Similarly, anatomical studies show that these regions are densely interconnected via white matter tracts. We therefore hypothesized that the PPC influence over the motor cortex is partly via a connection with the PMv. Using a novel three-pulse ipsilateral transcranial magnetic stimulation technique, we preconditioned the PPC (80% RMT) at ISIs from 4-15ms prior to stimulating the PMv and M1 at ISIs of 4 and 6ms. As previously shown, PMv-M1 paired-pulse stimulation resulted in inhibition of the MEP (90% RMT, 4-6ms) and PPC-M1 paired-pulse stimulation resulted in facilitation of the MEP (90% RMT, 4-8ms). PPC-M1 paired-pulse stimulation at 80% RMT preconditioning had no effect on M1. PPC-PMv-M1 stimulation resulted in reversal of inhibition observed with PMv-M1 stimulation at ISIs ranging from 6 to 15ms. The reversal of inhibition observed with PPC-PMv-M1 stimulation suggests that the parietal connection to the PMv plays a role in the modulation of M1. This is the first study to stimulate three intrahemispheric regions in order to test a disynaptic connection with M1. The described network may be important in a variety of movement disorders. Published by Elsevier Ireland Ltd.
    Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 07/2015; DOI:10.1016/j.clinph.2015.06.031 · 3.10 Impact Factor
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    ABSTRACT: Functional reaching is impaired in dystonia. Here, we analyze upper extremity kinematics to quantify timing and coordination abnormalities during unimanual reach-to-grasp movements in individuals with childhood-onset unilateral wrist dystonia. Kinematics were measured during movements of both upper limbs in a patient group (n = 11, age = 17.5 ± 5 years), and a typically developing control group (n = 9, age = 16.6 ± 5 years). Hand aperture was computed to study the coordination of reach and grasp. Time-varying joint synergies within one upper limb were calculated using a novel technique based on principal component analysis to study intra-limb coordination. In the non-dominant arm, results indicate reduced coordination between reach and grasp in patients who could not lift the grasped object compared to those who could lift it. Lifters exhibit incoordination in distal upper extremity joints later in the movement and non-lifters lacked coordination throughout the movement and in the whole upper limb. The amount of atypical coordination correlates with dystonia severity in patients. Reduced coordination during movement may reflect deficits in the execution of simultaneous movements, motor planning, or muscle activation. Rehabilitation efforts can focus on particular time points when kinematic patterns deviate abnormally to improve functional reaching in individuals with childhood-onset dystonia.
    IEEE transactions on neural systems and rehabilitation engineering: a publication of the IEEE Engineering in Medicine and Biology Society 07/2015; DOI:10.1109/TNSRE.2015.2458293 · 3.19 Impact Factor
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    ABSTRACT: The cerebellum is involved in sensorimotor operations, cognitive tasks and affective processes. Here, we revisit the concept of the cerebellar syndrome in the light of recent advances in our understanding of cerebellar operations. The key symptoms and signs of cerebellar dysfunction, often grouped under the generic term of ataxia, are discussed. Vertigo, dizziness, and imbalance are associated with lesions of the vestibulo-cerebellar, vestibulo-spinal, or cerebellar ocular motor systems. The cerebellum plays a major role in the online to long-term control of eye movements (control of calibration, reduction of eye instability, maintenance of ocular alignment). Ocular instability, nystagmus, saccadic intrusions, impaired smooth pursuit, impaired vestibulo-ocular reflex (VOR), and ocular misalignment are at the core of oculomotor cerebellar deficits. As a motor speech disorder, ataxic dysarthria is highly suggestive of cerebellar pathology. Regarding motor control of limbs, hypotonia, a- or dysdiadochokinesia, dysmetria, grasping deficits and various tremor phenomenologies are observed in cerebellar disorders to varying degrees. There is clear evidence that the cerebellum participates in force perception and proprioceptive sense during active movements. Gait is staggering with a wide base, and tandem gait is very often impaired in cerebellar disorders. In terms of cognitive and affective operations, impairments are found in executive functions, visual-spatial processing, linguistic function, and affective regulation (Schmahmann's syndrome). Nonmotor linguistic deficits including disruption of articulatory and graphomotor planning, language dynamics, verbal fluency, phonological, and semantic word retrieval, expressive and receptive syntax, and various aspects of reading and writing may be impaired after cerebellar damage. The cerebellum is organized into (a) a primary sensorimotor region in the anterior lobe and adjacent part of lobule VI, (b) a second sensorimotor region in lobule VIII, and (c) cognitive and limbic regions located in the posterior lobe (lobule VI, lobule VIIA which includes crus I and crus II, and lobule VIIB). The limbic cerebellum is mainly represented in the posterior vermis. The cortico-ponto-cerebellar and cerebello-thalamo-cortical loops establish close functional connections between the cerebellum and the supratentorial motor, paralimbic and association cortices, and cerebellar symptoms are associated with a disruption of these loops.
    The Cerebellum 06/2015; DOI:10.1007/s12311-015-0687-3 · 2.72 Impact Factor
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    ABSTRACT: While the presence of co-existing psychological stressors has historically been used as a supportive factor in the diagnosis of functional neurological disorders, many patients with functional neurological disorders deny the presence of these stressors. The stress response circuitry in these patients remains largely unexplored. We performed an observational study examining biological stress levels in patients with functional movement disorders as compared with matched healthy controls. Specifically, we compared levels of circulating cortisol, the end-product of the hypothalamic-pituitary-adrenal axis. Salivary cortisol samples were collected from patients with "clinically definite" functional movement disorders (n = 33) and their age- and sex-matched controls (n = 33). Collections were performed at five standardized time points, reflecting participants' diurnal cortisol cycles. To rule out confounders, participants also underwent extensive psychological assessment including Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Hamilton Anxiety Rating Scale, and Hamilton Rating Scale for Depression. Patients with functional movement disorders did not differ from matched controls with respect to levels of circulating cortisol. We demonstrate that current stress levels are not altered in patients with functional movement disorders. Our results warrant careful review of current management of patients with functional neurological symptoms, and suggest that the insistence on heightened stress levels in these patients is unjustified. Published by Elsevier Ltd.
    Parkinsonism & Related Disorders 06/2015; 21(9). DOI:10.1016/j.parkreldis.2015.06.017 · 3.97 Impact Factor
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    Tao Wu · Mark Hallett · Piu Chan ·
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    ABSTRACT: Bradykinesia is the most important feature contributing to motor difficulties in Parkinson's disease (PD). However, the pathophysiology underlying bradykinesia is not fully understood. One important aspect is that PD patients have difficulty in performing learned motor skills automatically, but this problem has been generally overlooked. Here we review motor automaticity associated motor deficits in PD, such as reduced arm swing, decreased stride length, freezing of gait, micrographia and reduced facial expression. Recent neuroimaging studies have revealed some neural mechanisms underlying impaired motor automaticity in PD, including less efficient neural coding of movement, failure to shift automated motor skills to the sensorimotor striatum, instability of the automatic mode within the striatum, and use of attentional control and/or compensatory efforts to execute movements usually performed automatically in healthy people. PD patients lose previously acquired automatic skills due to their impaired sensorimotor striatum, and have difficulty in acquiring new automatic skills or restoring lost motor skills. More investigations on the pathophysiology of motor automaticity, the effect of L-dopa or surgical treatments on automaticity, and the potential role of using measures of automaticity in early diagnosis of PD would be valuable. Copyright © 2015. Published by Elsevier Inc.
    Neurobiology of Disease 06/2015; 82. DOI:10.1016/j.nbd.2015.06.014 · 5.08 Impact Factor

  • Nineteenth International Congress of Parkinson's Disease and Movement Disorders; 06/2015
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    ABSTRACT: Surround inhibition (SI) is a feature of motor control in which activation of task-related muscles is associated with inhibition of neighboring, non-protagonist muscles, allowing selective motor control. The physiological basis for SI still remains unknown. In all previous studies, SI in the motor system was measured during movement initiation using transcranial magnetic stimulation (TMS) to deliver a postero-anterior current at single supra-threshold intensity. To expand our understanding of SI, we explored this phenomenon at a wide range of intensities and by stimulating motor cortex with currents along antero-posterior and latero-medial directions. Fifteen healthy volunteers performed a brief isometric index finger flexion on hearing a tone. Electromyography was recorded from the synergist and surround finger muscles. Single-pulse TMS was applied to stimulate the surround muscle at different intensities at rest or movement initiation. The motor evoked potential (MEP) amplitudes were then plotted against stimulation intensities to obtain the MEP recruitment curves for the rest and movement initiation conditions, and for the three current directions for every subject. From the recruitment curves, we found that surround inhibition could be elicited only by the postero-anterior current. Hence we postulate that surround inhibition is mediated by intracortical circuits in the motor cortex. Also, for the first time we observed surround facilitation when the motor cortex was stimulated with antero-posterior current. Further studies are needed to investigate the mechanisms underlying both these phenomena individually in healthy subjects and patients with dystonia and other movement disorders. Copyright © 2014, Journal of Neurophysiology.
    Journal of Neurophysiology 06/2015; 114(2):jn.00791.2014. DOI:10.1152/jn.00791.2014 · 2.89 Impact Factor
  • Sanjay Pandey · Debra L. Byler · Mark Hallett ·

    JAMA Neurology 05/2015; 72(5):606-607. · 7.42 Impact Factor
  • Sanjay Pandey · Debra L Byler · Mark Hallett ·

    05/2015; 72(5):606-607. DOI:10.1001/jamaneurol.2015.0147
  • Jung E. Park · Carine W. Maurer · Mark Hallett ·
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    ABSTRACT: Making the diagnosis of functional movement disorders can be challenging. Identifying positive physical signs and diagnostic maneuvers is critical to this process. Distractibility, entrainability, and variability are examples of classic physical findings in these patients. In this case series, we identify and characterize another phenomenon observed in some of these patients. In this phenomenon, movement suppression of one body part is followed by immediate reemergence of movement in another. We propose that this phenomenon be referred to as the “whack-a-mole” sign. This name is derived from the arcade game whack-a-mole, in which a mole, when hit into its original hole, re-emerges elsewhere. We present a case series of 4 patients with functional movement disorders who exhibit this sign.
    05/2015; 2(3). DOI:10.1002/mdc3.12177

Publication Stats

34k Citations
3,052.39 Total Impact Points


  • 2015
    • Pennsylvania State University
      • Department of Kinesiology
      University Park, Maryland, United States
  • 1986-2015
    • National Institutes of Health
      • • Division of Intramural Research (Dental Research)
      • • Division of Functional and Molecular Imaging
      • • Branch of Neurogenetics
      베서스다, Maryland, United States
  • 2014
    • Govind Ballabh Pant Hospital
      New Dilli, NCT, India
  • 2013
    • Xuanwu hospital
      Peping, Beijing, China
  • 2012-2013
    • George Washington University
      • • Department of Neurology
      • • School of Medicine and Health Sciences
      Washington, Washington, D.C., United States
  • 2011-2013
    • National Eye Institute
      베서스다, Maryland, United States
  • 1991-2013
    • National Institute of Neurological Disorders and Strokes
      Chicago, Illinois, United States
  • 1999-2010
    • University of Toronto
      • Division of Neurology
      Toronto, Ontario, Canada
  • 2009
    • Baylor College of Medicine
      • Department of Neurology
      Houston, Texas, United States
  • 2008
    • Università degli Studi di Milano-Bicocca
      Milano, Lombardy, Italy
  • 2007
    • Sungkyunkwan University
      • Samsung Medical Center
      Seoul, Seoul, South Korea
    • Sapienza University of Rome
      Roma, Latium, Italy
  • 1992-2005
    • Northern Inyo Hospital
      BIH, California, United States
  • 2002
    • University of Oxford
      • Department of Experimental Psychology
      Oxford, England, United Kingdom
  • 2001
    • The National Institute of Diabetes and Digestive and Kidney Diseases
      베서스다, Maryland, United States
  • 1995-1997
    • National Institute of Mental Health (NIMH)
      • • Laboratory of Systems Neuroscience
      • • Laboratory of Brain And Cognition
      베서스다, Maryland, United States
  • 1994
    • University of Freiburg
      • Center for Data Analysis and Modeling (FDM)
      Freiburg, Baden-Württemberg, Germany
    • IMSA Amsterdam
      Amsterdamo, North Holland, Netherlands
    • State of Maryland
      Maryland City, Maryland, United States
  • 1990
    • Howard University
      • Department of Physics & Astronomy
      Вашингтон, West Virginia, United States
  • 1989
    • Bulgarian Academy of Sciences
      Ulpia Serdica, Sofia-Capital, Bulgaria