Whole-brain mapping of increased manganese levels in welders and its association with exposure and motor function.

Although manganese (Mn) is a trace metal essential for humans, chronic exposure to Mn can cause accumulation of this metal ion in the brain leading to an increased risk of neurological and neurobehavioral health effects. This is a concern for welders exposed to Mn through welding fumes. While brain Mn accumulation in occupational settings has mostly been reported in the basal ganglia, several imaging studies also revealed elevated Mn in other brain areas. Since Mn functions as a magnetic resonance imaging (MRI) T1 contrast agent, we developed a whole-brain MRI approach to map in vivo Mn deposition differences in the brains of non-exposed factory controls and exposed welders. This is a cross-sectional analysis of 23 non-exposed factory controls and 36 exposed full-time welders from the same truck manufacturer. We collected high-resolution 3D MRIs of brain anatomy and R1 relaxation maps to identify regional differences using voxel-based quantification (VBQ) and statistical parametric mapping. Furthermore, we investigated the associations between excess Mn deposition and neuropsychological and motor test performance. Our results indicate that: (1) Using whole-brain MRI relaxometry methods we can generate excess Mn deposition maps in vivo, (2) excess Mn accumulation due to occupational exposure occurs beyond the basal ganglia in cortical areas associated with motor and cognitive functions, (3) Mn likely diffuses along white matter tracts in the brain, and (4) Mn deposition in specific brain regions is associated with exposure (cerebellum and frontal cortex) and motor metrics (cerebellum and hippocampus).

Striatal and thalamic GABA level concentrations play differential roles for the modulation of response selection processes by proprioceptive information.

The selection of appropriate responses is a complex endeavor requiring the integration of many different sources of information in fronto-striatal-thalamic circuits. An often neglected but relevant piece of information is provided by proprioceptive inputs about the current position of our limbs. This study examines the importance of striatal and thalamic GABA levels in these processes using GABA-edited magnetic resonance spectroscopy (GABA-MRS) and a Simon task featuring proprioception-induced interference in healthy subjects. As a possible model of deficits in the processing of proprioceptive information, we also included Parkinson's disease (PD) patients in this study. The results show that proprioceptive information about unusual postures complicates response selection processes in controls, but not in PD patients. The well-known deficits of PD patients in processing proprioceptive information can turn into a benefit when altered proprioceptive information would normally complicate response selection processes. Striatal and thalamic GABA levels play dissociable roles in the modulation of response selection processes by proprioceptive information: Striatal GABA levels seem to be important for the general speed of responding, most likely because striatal GABA promotes response selection. In contrast, the modulation of response conflict by proprioceptive information is closely related to thalamic GABA concentrations with higher concentration being related to a smaller response conflict effect. The most likely explanation for this finding is that the thalamus is involved in the integration of sensorimotor, attentional, and cognitive information for the purpose of response formation. Yet, this effect in the thalamus vanishes when controls and PD patients were analyzed separately.

Interaction of synchronized dynamics in cortex and basal ganglia in Parkinson's disease.

Parkinson's disease pathophysiology is marked by increased oscillatory and synchronous activity in the beta frequency band in cortical and basal ganglia circuits. This study explores the functional connections between synchronized dynamics of cortical areas and synchronized dynamics of subcortical areas in Parkinson's disease. We simultaneously recorded neuronal units (spikes) and local field potentials (LFP) from subthalamic nucleus (STN) and electroencephalograms (EEGs) from the scalp in parkinsonian patients, and analysed the correlation between the time courses of the spike-LFP synchronization and inter-electrode EEG synchronization. We found the (non-invasively obtained) time course of the synchrony strength between EEG electrodes and the (invasively obtained) time course of the synchrony between spiking units and LFP in STN to be weakly, but significantly, correlated with each other. This correlation is largest for the bilateral motor EEG synchronization, followed by bilateral frontal EEG synchronization. Our observations suggest that there may be multiple functional modes by which the cortical and basal ganglia circuits interact with each other in Parkinson's disease: not only may synchronization be observed between some areas in cortex and the basal ganglia, but also synchronization within cortex and within basal ganglia may be related, suggesting potentially a more global functional interaction. More coherent dynamics in one brain region may modulate or activate the dynamics of another brain region in a more powerful way, causing correlations between changes in synchrony strength in the two regions.

Susceptibility-Weighted MRI Approximates Intraoperative Microelectrode Recording During Deep Brain Stimulation of the Subthalamic Nucleus for Parkinson's Disease.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN-DBS) for Parkinson's disease can be performed with intraoperative neurophysiological and radiographic guidance. Conventional T2-weighted magnetic resonance imaging sequences, however, often fail to provide definitive borders of the STN. Novel magnetic resonance imaging sequences, such as susceptibility-weighted imaging (SWI), might better localize the STN borders and facilitate radiographic targeting. We compared the radiographic location of the dorsal and ventral borders of the STN using SWI with intraoperative microelectrode recording (MER) during awake STN-DBS for Parkinson's disease. METHODS: Thirteen consecutive patients who underwent placement of 24 STN-DBS leads for Parkinson's disease were analyzed retrospectively. Preoperative targeting was performed with SWI, and MER data were obtained from intraoperative electrophysiology records. The boundaries of the STN on SWI were identified by a blinded investigator. RESULTS: The final electrode position differed significantly from the planned coordinates in depth but not in length or width, indicating that MER guided the final electrode depth. When we compared the boundaries of the STN by MER and SWI, SWI accurately predicted the entry into the STN but underestimated the length and ventral boundary of the STN by 1.2 mm. This extent of error approximates the span of a DBS contact and could affect the placement of directional contacts within the STN. CONCLUSIONS: MER might continue to have a role in STN-DBS. This could potentially be mitigated by further refinement of imaging protocols to better image the ventral boundary of the STN.

Bilateral Deep Brain Stimulation of the Ventral Intermediate Nucleus of the Thalamus Improves Objective Acoustic Measures of Essential Vocal Tremor.

BACKGROUND AND OBJECTIVES: Deep brain stimulation of the ventral intermediate nucleus of the thalamus (VIM-DBS) is an established treatment for medically refractory essential tremor. However, the effect of VIM-DBS on vocal tremor remains poorly understood, with results varying by method of vocal tremor assessment and stimulation laterality. This single-center study measures the effect of bilateral VIM-DBS on essential vocal tremor using blinded objective acoustic voice analysis. METHODS: Ten patients with consecutive essential tremor with comorbid vocal tremor receiving bilateral VIM-DBS underwent voice testing before and after implantation of DBS in this prospective cohort study. Objective acoustic measures were extracted from the middle one second of steady-state phonation including cepstral peak prominence, signal-to-noise ratio, percentage voicing, tremor rate, extent of fundamental frequency modulation, and extent of intensity modulation. DBS surgery was performed awake with microelectrode recording and intraoperative testing. Postoperative voice testing was performed after stable programming. RESULTS: Patients included 6 female and 4 male, with a mean age of 67 ± 6.7 years. The VIM was targeted with the following coordinates relative to the mid-anterior commissure:posterior commissure point: 13.2 ± 0.6 mm lateral, 6.2 ± 0.7 mm posterior, and 0.0 mm below. Mean programming parameters were amplitude 1.72.0 ± 0.6 mA, pulse width 63.0 ± 12.7 µs, and rate 130.6 ± 0.0 Hz. VIM-DBS significantly improved tremor rate from 4.43 ± 0.8 Hz to 3.2 ± 0.8 Hz (P = .001) CI (0.546, 1.895), jitter from 1 ± 0.94 to 0.53 ± 0.219 (P = .02) CI (-0.124, 1.038), cepstral peak prominence from 13.6 ± 3.9 to 18.8 ± 2.9 (P = .016) CI (-4.100, -0.235), signal-to-noise ratio from 15.7 ± 3.9 to 18.5 ± 3.7 (P = .02) CI (-5.598, -0.037), and articulation rate from 0.77 ± 0.2 to 0.82 ± .14 (P = .04) CI (-0.097, 0.008). There were no major complications in this series. CONCLUSION: Objective acoustic voice analyses suggest that bilateral VIM-DBS effectively reduces vocal tremor rate and improves voicing. Further studies using objective acoustic analyses and laryngeal imaging may help refine surgical and stimulation techniques and evaluate the effect of laterality on vocal tremor.

Globus Pallidus Interna and Ventral Intermediate Nucleus of the Thalamus Deep Brain Stimulation for Adductor Laryngeal Dystonia: a Case Report of Blinded Analyses of Objective Voice Outcomes in 2 Patients.

BACKGROUND: Adductor laryngeal dystonia (ADLD) is a substantially debilitating focal progressive neurological voice disorder. Current standard of care is symptomatic treatment with repeated injections of botulinum toxin into specific intrinsic laryngeal muscles with extremely variable and temporary benefits. We report the use of bilateral deep brain stimulation (DBS) of globus pallidus (GPi) for long-term improvement of ADLD voice symptoms. OBJECTIVE: To investigate the effects of bilateral DBS of the GPi and ventral intermediate nucleus (VIM) of the thalamus on vocal function in 2 patients with ADLD associated with voice and hand tremor. METHODS: Blinded objective and quantitative analyses of voice were conducted before and after treatment in 2 female patients (70 and 69 years). Paired t-tests were conducted to compare voice measurements pre-GPi and post-GPi and VIM-DBS. A 2-way analysis of variance was conducted to determine the interaction between target (GPi/VIM) and time (pre/post) for each voice measure. RESULTS: Although the follow-up period differed between patients, the GPi-DBS implanted patient had notable improvement in vowel voicing (%), extent of tremor intensity (%), and overall speech intelligibility (%), compared with preoperative status. GPi-DBS also resulted in significant improvement in cepstral peak prominence (dB). VIM-DBS resulted in a significantly greater change in the tremor rate (Hz). CONCLUSION: Changes in phonatory function provide preliminary support for the use of bilateral GPi-DBS for treatment of ADLD and bilateral VIM-DBS for vocal tremor predominant ADLD. Future studies with larger sample sizes and standardized follow-up periods are needed to better assess the role of DBS for ADLD.

The association of bone and blood manganese with motor function in Chinese workers.

Manganese (Mn) is an essential element. However, Mn overexposure is associated with motor dysfunction. This cross-sectional study assessed the association between bone Mn (BnMn) and whole blood Mn (BMn) with motor function in 59 Chinese workers. BnMn and BMn were measured using a transportable in vivo neutron activation analysis system and inductively coupled plasma mass spectrometry, respectively. Motor function (manual coordination, postural sway, postural hand tremor, and fine motor function) was assessed using the Coordination Ability Test System (CATSYS) and the Purdue Pegboard. Relationships between Mn biomarkers and motor test scores were analyzed with linear regression models adjusted for age, education, current employment, and current alcohol consumption. BMn was significantly inversely associated with hand tremor intensity (dominant hand (ß=-0.04, 95 % confidence interval (CI):-0.07, -0.01; non-dominant hand ß=-0.05, 95 % CI:-0.08, -0.01) hand tremor center frequency (non-dominant hand ß=-1.61, 95 % CI:-3.03, -0.19) and positively associated with the Purdue Pegboard Assembly Score (ß = 4.58, 95 % CI:1.08, 8.07). BnMn was significantly inversely associated with finger-tapping performance (non-dominant hand ß=-0.02, 95 % CI:-0.04,-0.004), mean sway (eyes closed and foam ß=-0.68, 95 % CI:-1.31,-0.04), and positively associated with hand tremor center frequency (dominant hand, ß = 0.40, 95 % CI:0.002, 0.80). These results suggest BMn is related to better postural hand tremor and fine motor control and BnMn is related to worse motor coordination and postural hand tremor but better (i.e., less) postural sway. The unexpected positive results might be explained by choice of biomarker or confounding by work-related motor activities. Larger, longitudinal studies in this area are recommended.

Stimulation-induced parkinsonism after posteroventral deep brain stimulation of the globus pallidus internus for craniocervical dystonia.

The authors report on a patient with craniocervical dystonia who was treated with bilateral GPi stimulation, with excellent improvement in dystonia but at the cost of stimulation-induced, reversible parkinsonism. Stimulation through ventral contacts resulted in maximal relief of craniocervical dystonia but induced considerable hypophonia, bradykinesia, rigidity, freezing, and impaired postural reflexes. Stimulation through dorsal contacts alleviated parkinsonism, but resulted in the return of dystonia. No stimulation parameters could alleviate the dystonia without inducing parkinsonism over the course of his 4-year follow-up.

Reversibility of Neuroimaging Markers Influenced by Lifetime Occupational Manganese Exposure.

Manganese (Mn) is a neurotoxicant that many workers are exposed to daily. There is limited knowledge about how changes in exposure levels impact measures in magnetic resonance imaging (MRI). We hypothesized that changes in Mn exposure would be reflected by changes in the MRI relaxation rate R1 and thalamic γ-aminobutyric acid (GABAThal). As part of a prospective cohort study, 17 welders were recruited and imaged on 2 separate occasions approximately 2 years apart. MRI relaxometry was used to assess changes of Mn accumulation in the brain. Additionally, GABA was measured using magnetic resonance spectroscopy in the thalamic and striatal regions of the brain. Air Mn exposure ([Mn]Air) and cumulative exposure indexes of Mn (Mn-CEI) for the past 3 months (Mn-CEI3M), past year (Mn-CEI12M), and lifetime (Mn-CEILife) were calculated using personal air sampling and a comprehensive work history, whereas toenails were collected for analysis of internal Mn body burden. Finally, welders' motor function was examined using the Unified Parkinson's Disease Rating Scale (UPDRS). Median exposure decreased for all exposure measures between the first and second scan. ΔGABAThal was significantly correlated with ΔMn-CEI3M (ρ = 0.66, adjusted p = .02), ΔMn-CEI12M (ρ = 0.70, adjusted p = .006), and Δ[Mn]Air (ρ = 0.77, adjusted p = .002). ΔGABAThal significantly decreased linearly with ΔMn-CEI3M (quantile regression, ß = 15.22, p = .02) as well as Δ[Mn]Air (ß = 1.27, p = .04). Finally, Mn-CEILife interacted with Δ[Mn]Air in the substantia nigra where higher Mn-CEILife lessened the ΔR1 per Δ[Mn]Air (F-test, p = .005). Although R1 and GABA changed with Mn exposure, UPDRS was unaffected. In conclusion, our study shows that effects from changes in Mn exposure are reflected in thalamic GABA levels and brain Mn levels, as measured by R1, in most brain regions.

The association of bone, fingernail and blood manganese with cognitive and olfactory function in Chinese workers.

Occupational manganese (Mn) exposure has been associated with cognitive and olfactory dysfunction; however, few studies have incorporated cumulative biomarkers of Mn exposure such as bone Mn (BnMn). Our goal was to assess the cross-sectional association between BnMn, blood Mn (BMn), and fingernail Mn (FMn) with cognitive and olfactory function among Mn-exposed workers. A transportable in vivo neutron activation analysis (IVNAA) system was designed and utilized to assess BnMn among 60 Chinese workers. BMn and FMn were measured using inductively coupled plasma mass spectrometry. Cognitive and olfactory function was assessed using Animal and Fruit Naming tests, World Health Organization/University of California-Los Angeles Auditory Verbal Learning Test (AVLT) and the University of Pennsylvania Smell Identification Test (UPSIT). Additional data were obtained via questionnaire. Regression models adjusted for age, education, factory of employment, and smoking status (UPSIT only), were used to assess the relationship between Mn biomarkers and test scores. In adjusted models, increasing BnMn was significantly associated with decreased performance on average AVLT scores [ß (95% confidence interval (CI)) = -0.65 (-1.21, -0.09)] and Animal Naming scores [ß (95% CI) = -1.54 (-3.00, -0.07)]. Increasing FMn was significantly associated with reduced performance measured by the average AVLT [ß (95% CI) = -0.35 (-0.70, -0.006)] and the difference in AVLT scores [ß (95% CI) = -0.40 (-0.77, -0.03)]. BMn was not significantly associated with any test scores; no significant associations were observed with Fruit Naming or UPSIT tests. BnMn and FMn, but not BMn, are associated with cognitive function in Mn-exposed workers. None of the biomarkers were significantly associated with olfactory function.

Thalamic GABA levels and occupational manganese neurotoxicity: Association with exposure levels and brain MRI.

Excessive occupational exposure to Manganese (Mn) has been associated with clinical symptoms resembling idiopathic Parkinson's disease (IPD), impairing cognitive and motor functions. Several studies point towards an involvement of the brain neurotransmitter system in Mn intoxication, which is hypothesized to be disturbed prior to onset of symptoms. Edited Magnetic Resonance Spectroscopy (MRS) offers the unique possibility to measure γ-amminobutyric acid (GABA) and other neurometabolites in vivo non-invasively in workers exposed to Mn. In addition, the property of Mn as Magnetic Resonance Imaging (MRI) contrast agent may be used to study Mn deposition in the human brain. In this study, using MRI, MRS, personal air sampling at the working place, work history questionnaires, and neurological assessment (UPDRS-III), the effects of chronic Mn exposure on the thalamic GABAergic system was studied in a group of welders (N=39) with exposure to Mn fumes in a typical occupational setting. Two subgroups of welders with different exposure levels (Low: N=26; mean air Mn=0.13±0.1mg/m3; High: N=13; mean air Mn=0.23±0.18mg/m3), as well as unexposed control workers (N=22, mean air Mn=0.002±0.001mg/m3) were recruited. The group of welders with higher exposure showed a significant increase of thalamic GABA levels by 45% (p<0.01, F(1,33)=9.55), as well as significantly worse performance in general motor function (p<0.01, F(1,33)=11.35). However, welders with lower exposure did not differ from the controls in GABA levels or motor performance. Further, in welders the thalamic GABA levels were best predicted by past-12-months exposure levels and were influenced by the Mn deposition in the substantia nigra and globus pallidus. Importantly, both thalamic GABA levels and motor function displayed a non-linear pattern of response to Mn exposure, suggesting a threshold effect.

Synchronized Beta-Band Oscillations in a Model of the Globus Pallidus-Subthalamic Nucleus Network under External Input.

Hypokinetic symptoms of Parkinson's disease are usually associated with excessively strong oscillations and synchrony in the beta frequency band. The origin of this synchronized oscillatory dynamics is being debated. Cortical circuits may be a critical source of excessive beta in Parkinson's disease. However, subthalamo-pallidal circuits were also suggested to be a substantial component in generation and/or maintenance of Parkinsonian beta activity. Here we study how the subthalamo-pallidal circuits interact with input signals in the beta frequency band, representing cortical input. We use conductance-based models of the subthalamo-pallidal network and two types of input signals: artificially-generated inputs and input signals obtained from recordings in Parkinsonian patients. The resulting model network dynamics is compared with the dynamics of the experimental recordings from patient's basal ganglia. Our results indicate that the subthalamo-pallidal model network exhibits multiple resonances in response to inputs in the beta band. For a relatively broad range of network parameters, there is always a certain input strength, which will induce patterns of synchrony similar to the experimentally observed ones. This ability of the subthalamo-pallidal network to exhibit realistic patterns of synchronous oscillatory activity under broad conditions may indicate that these basal ganglia circuits are directly involved in the expression of Parkinsonian synchronized beta oscillations. Thus, Parkinsonian synchronized beta oscillations may be promoted by the simultaneous action of both cortical (or some other) and subthalamo-pallidal network mechanisms. Hence, these mechanisms are not necessarily mutually exclusive.

The International Deep Brain Stimulation Registry and Database for Gilles de la Tourette Syndrome: How Does It Work?

Tourette Syndrome (TS) is a neuropsychiatric disease characterized by a combination of motor and vocal tics. Deep brain stimulation (DBS), already widely utilized for Parkinson's disease and other movement disorders, is an emerging therapy for select and severe cases of TS that are resistant to medication and behavioral therapy. Over the last two decades, DBS has been used experimentally to manage severe TS cases. The results of case reports and small case series have been variable but in general positive. The reported interventions have, however, been variable, and there remain non-standardized selection criteria, various brain targets, differences in hardware, as well as variability in the programming parameters utilized. DBS centers perform only a handful of TS DBS cases each year, making large-scale outcomes difficult to study and to interpret. These limitations, coupled with the variable effect of surgery, and the overall small numbers of TS patients with DBS worldwide, have delayed regulatory agency approval (e.g., FDA and equivalent agencies around the world). The Tourette Association of America, in response to the worldwide need for a more organized and collaborative effort, launched an international TS DBS registry and database. The main goal of the project has been to share data, uncover best practices, improve outcomes, and to provide critical information to regulatory agencies. The international registry and database has improved the communication and collaboration among TS DBS centers worldwide. In this paper we will review some of the key operation details for the international TS DBS database and registry.

Movement disorders caused by medical disease.

Movement disorders often occur in the context of medical illness, whether as the presenting sign of the illness, as a related feature of the underlying disease process, or as a complication of treatment. Early recognition of an underlying medical cause for movement disorders is essential because the treatment and prognosis differ significantly depending on the underlying pathophysiology. Parkinsonism, nonparkinsonian tremor, dystonia, and chorea have a wide variety of etiologies, requiring a careful medical history in the evaluation of new-onset movement disorders. The spectrum of medical diseases associated with these four syndromes is reviewed in this article.