Effect of Primidone on Dentate Nucleus γ-Aminobutyric Acid Concentration in Patients With Essential Tremor

OBJECTIVES: It is not known whether current use of the medication primidone affects brain γ-aminobutyric acid (GABA) concentrations. This is an important potential confound in studies of the pathophysiology of essential tremor (ET), one of the most common neurological diseases. We compared GABA concentrations in the dentate nucleus in 6 ET patients taking primidone versus 26 ET patients not taking primidone. METHODS: (1)H magnetic resonance spectroscopy was performed using a 3.0-T Siemens Tim Trio scanner. The MEGA-PRESS J-editing sequence was used for GABA detection in 2 cerebellar volumes of interest (left and right) that included the dentate nucleus. RESULTS: The right dentate GABA concentration was similar in the 2 groups (2.21 ± 0.46 [on primidone] vs 1.93 ± 0.39 [not on primidone], P = 0.15), as was the left dentate GABA concentration (1.61 ± 0.35 [on primidone] vs 1.67 ± 0.34 [not on primidone], P = 0.72). The daily primidone dose was not associated with either right or left dentate GABA concentrations (P = 0.89 and 0.76, respectively). CONCLUSIONS: We did not find a difference in dentate GABA concentrations between 6 ET patients taking daily primidone and 26 ET patients not taking primidone. Furthermore, there was no association between daily primidone dose and dentate GABA concentration. These data suggest that it is not necessary to exclude ET patients on primidone from magnetic resonance spectroscopy studies of dentate GABA concentration, and if assessment of these concentrations was to be developed as a biomarker for ET, primidone usage would not confound interpretation of the results

In Vivo Dentate Nucleus Gamma-aminobutyric Acid Concentration in Essential Tremor vs. Controls

Despite its high prevalence, essential tremor (ET) is among the most poorly understood neurological diseases. The presence and extent of Purkinje cell (PC) loss in ET is the subject of controversy. PCs are a major storehouse of central nervous system gamma-aminobutyric acid (GABA), releasing GABA at the level of the dentate nucleus. It is therefore conceivable that cerebellar dentate nucleus GABA concentration could be an in vivo marker of PC number. We used in vivo 1H magnetic resonance spectroscopy (MRS) to quantify GABA concentrations in two cerebellar volumes of interest, left and right, which included the dentate nucleus, comparing 45 ET cases to 35 age-matched controls. 1H MRS was performed using a 3.0-T Siemens Tim Trio scanner. The MEGA-PRESS J-editing sequence was used for GABA detection in two cerebellar volumes of interest (left and right) that included the dentate nucleus. The two groups did not differ with respect to our primary outcome of GABA concentration (given in institutional units). For the right dentate nucleus, [GABA] in ET cases = 2.01 ± 0.45 and [GABA] in controls = 1.86 ± 0.53, p = 0.17. For the left dentate nucleus, [GABA] in ET cases = 1.68 ± 0.49 and [GABA] controls = 1.80 ± 0.53, p = 0.33. The controls had similar dentate nucleus [GABA] in the right vs. left dentate nucleus (p = 0.52); however, in ET cases, the value on the right was considerably higher than that on the left (p = 0.001). We did not detect a reduction in dentate nucleus GABA concentration in ET cases vs. CONTROLS: One interpretation of the finding is that it does not support the existence of PC loss in ET; however, an alternative interpretation is the observed pattern could be due to the effects of terminal sprouting in ET (i.e., collateral sprouting from surviving PCs making up for the loss of GABA-ergic terminals from PC degeneration). Further research is needed

Reproducibility and effect of tissue composition on cerebellar GABA MRS in an elderly population.

Magnetic resonance spectroscopy (MRS) provides a valuable tool to non-invasively detect brain gamma-amino butyric acid (GABA) in vivo. GABAergic dysfunction has been observed in the aging cerebellum. Studying cerebellar GABA changes is of considerable interest in understanding certain age-related motor disorders. However, little is known about the reproducibility of GABA MRS in an aged population. Therefore, this study aimed to explore the feasibility and reproducibility of GABA MRS in the aged cerebellum at 3.0 Tesla and to examine the effect of differing tissue composition on GABA measurements. MRI and 1H MRS exams were performed on 10 healthy elderly volunteers (mean age 75.2 years ± 6.5 years) using a 3.0 Tesla Siemens Tim Trio scanner. Among them, 5 subjects were scanned twice to assess short-term reproducibility. The MEGA-PRESS J-editing sequence was used for GABA detection in two volumes of interest (VOIs) in left and right cerebellar dentate. MRS data processing and quantification were performed with LCModel 6.3-0L using two separate basis sets, generated from density matrix simulations using published values for chemical shifts an

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 (GABAMRS) 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

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 ± 0.1 mg/m3; High: N = 13; mean air Mn = 0.23 ± 0.18 mg/m3), as well as unexposed control workers (N = 22, mean air Mn = 0.002 ± 0.001 mg/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

Relationship of Auditory Electrophysiological Responses to Magnetic Resonance Spectroscopy Metabolites in Early Phase Psychosis

Both auditory evoked responses and metabolites measured by magnetic resonance spectroscopy (MRS) are altered in schizophrenia and other psychotic disorders, but the relationship between electrophysiological and metabolic changes are not well characterized. We examined the relation of MRS metabolites to cognitive and electrophysiological measures in individuals during the early phase of psychosis (EPP) and in healthy control subjects. The mismatch negativity (MMN) of the auditory event-related potential to duration deviant tones and the auditory steady response (ASSR) to 40 Hz stimulation were assessed. MRS was used to quantify glutamate+glutamine (Glx), N-Acetylasparate (NAA), creatine (Cre), myo-inositol (Ins) and choline (Cho) at a voxel placed medially in the frontal cortex. MMN amplitude and ASSR power did not differ between groups. The MRS metabolites Glx, Cre and Cho were elevated in the psychosis group. Partial least squares analysis in the patient group indicated that elevated levels of MRS metabolites were associated with reduced MMN amplitude and increased 40 Hz ASSR power. There were no correlations between the neurobiological measures and clinical measures. These data suggest that elevated neurometabolites early in psychosis are accompanied by altered auditory neurotransmission, possibly indicative of a neuroinflammatory or excitotoxic disturbance which disrupts a wide range of metabolic processes in the cortex

Mapping in Vivo Neurotransmitter Concentrations in the Human Brain with 3D MR Spectroscopic Imaging: Alterations in Manganese-induced Movement Disorders

Gamma-aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the brain. It plays vital roles in the basal ganglia direct and indirect pathways, which modulate various motor and cognitive functions by relaying signals to the thalamus and then projecting to the cortical area for the execution. The basal ganglia pathways have been observed to be disrupted in movement disorders such as idiopathic Parkinson’s disease (IPD) and manganese (Mn)-induced parkinsonism. Previous work from our group demonstrated elevated thalamic GABA levels in IPD patients as well as in a group of workers with high exposure to manganese (Mn). There is a gap in human in vivo research to find biomarkers of neurotoxic effect that can inform occupationally safe levels of exposure to Mn. Therefore, following our previous research, investigating the human GABAergic and glutamergic system under Mn exposure, as well as its association with motor and cognitive functions would help with both understanding the mechanism of how Mn intoxication disturbs the neurotransmitter system and finding a marker for the early detection Mn neurotoxicity. Using both single voxel MEGA-PRESS and MEGA-LASER 3-dimentional magnetic resonance spectroscopic imaging (MRSI) techniques, the dissertation work, for the first time, is able to study Mn neurotoxicty by investigating in vivo GABA concentration maps in the central brain area. This in return allows to study the association between neurotransmitter levels in different brain areas and i) individual exposure levels, ii) brain Mn deposition and iii) motor functions that have been observed to be impaired in IPD patients. The dissertation work has been accomplished in three steps. First, two subgroups of welders with different exposure levels, as well as unexposed control workers were recruited. The group of welders with higher exposure showed a significant increase of thalamic GABA levels by 45%, as well as significantly worse performance in general motor function. 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. Second, to move the neurotransmitter measurement from a localized single-voxel MEGA-PRESS acquisition to a larger brain coverage with higher resolution using MEGA-LASER 3D MRSI, an automated brain-structure-specific approach for the quantification of the MRSI-measured brain metabolite levels from structures of interest was developed. To cross-validate this approach with the single voxel MRS technique, MRSI data from a central brain area and single voxel MRS data from the thalamus were acquired on 21 healthy subjects. The main metabolites measured by the two techniques are highly correlated between the two techniques. Finally, the MEGA-LASER 3D MRSI technique combined with the brain-structure-specific approach was then applied to a pilot study with 10 controls and 11 welders, with the structures of interest including the thalamus, putamen, caudate and globus pallidus. Individual exposure levels, brain Mn deposition and general motor function were examined. Further, a more specific motor function known as response selection, which is deeply involved with the GABAergic system in the basal ganglia and has been found to be affected in IPD patients, was tested through a modified version of the Simon task. In addition, a longitudinal study was performed to follow up the welders we recruited for step 1 with the same measurements as described in step 1. Due to more usage of respirators and increased ventilation at the factory, the exposure levels of welders recruited in this step were significantly reduced. Further, no difference in GABA levels or R1 values in any brain region was found in this study. The general motor function and response selection function did not differ either between welders and controls. These findings from the pilot study are in line with our main longitudinal study. However, Mn potentially affects the response selection function by a subtle modulation of GABA levels in the putamen, reflected by partial regression between Simon task and GABA levels from several all measured brain regions after multiple comparison correction. In conclusion, my dissertation work, for the first time, enabled studying the effect of Mn neurotoxicity using in vivo GABA mapping in several brain structures of the human brain. The feasibility and user-friendliness of this new methodology is enhanced with an automatic brain-structure-specific approach for the quantification of brain metabolite levels from structures of interest. (Abstract shortened by ProQuest.

Electroassisted Propane Dehydrogenation at Low Temperatures : Far beyond the Equilibrium Limitation

Propylene production by propane dehydrogenation (PDH) generally requires high temperatures due to thermodynamic equilibrium limitations. This study developed a novel type of catalytic system for low-temperature PDH by combining a surface protonics methodology with intermetallic active sites. By application of an electric current, the intermetallic Pt-In/TiO2 catalyst gave a propylene yield of 10.2% with high selectivity, even at 250 degrees C, where the thermodynamic equilibrium yield was only 0.15%. Electroassisted proton collisions with propane allowed an unusual reaction pathway for low-temperature PDH. Alloying of Pt with In drastically enhanced the activity and selectivity due to the increased electron density of Pt