Browsing by Author "Dharmadhikari, Shalmali"

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    Association of exposure to manganese and iron with striatal and thalamic GABA and other neurometabolites - Neuroimaging results from the WELDOX II study
    (Elsevier, 2018-01) Casjens, Swaantje; Dydak, Urike; Dharmadhikari, Shalmali; Lotz, Anne; Lehnert, Martin; Quetscher, Clara; Stewig, Christoph; Glaubitz, Benjamin; Schmidt-Wilcke, Tobias; Edmondson, David; Yeh, Chien-Lin; Weiss, Tobias; van Thriel, Christoph; Herrmann, Lennard; Muhlack, Siegfried; Woitalla, Dirk; Aschner, Michael; Brüning, Thomas; Pesch, Beate; Radiology and Imaging Sciences, School of Medicine
    OBJECTIVE: Magnetic resonance spectroscopy (MRS) is a non-invasive method to quantify neurometabolite concentrations in the brain. Within the framework of the WELDOX II study, we investigated the association of exposure to manganese (Mn) and iron (Fe) with γ-aminobutyric acid (GABA) and other neurometabolites in the striatum and thalamus of 154 men. MATERIAL AND METHODS: GABA-edited and short echo-time MRS at 3T was used to assess brain levels of GABA, glutamate, total creatine (tCr) and other neurometabolites. Volumes of interest (VOIs) were placed into the striatum and thalamus of both hemispheres of 47 active welders, 20 former welders, 36 men with Parkinson's disease (PD), 12 men with hemochromatosis (HC), and 39 male controls. Linear mixed models were used to estimate the influence of Mn and Fe exposure on neurometabolites while simultaneously adjusting for cerebrospinal fluid (CSF) content, age and other factors. Exposure to Mn and Fe was assessed by study group, blood concentrations, relaxation rates R1 and R2* in the globus pallidus (GP), and airborne exposure (active welders only). RESULTS: The median shift exposure to respirable Mn and Fe in active welders was 23μg/m3 and 110μg/m3, respectively. Airborne exposure was not associated with any other neurometabolite concentration. Mn in blood and serum ferritin were highest in active and former welders. GABA concentrations were not associated with any measure of exposure to Mn or Fe. In comparison to controls, tCr in these VOIs was lower in welders and patients with PD or HC. Serum concentrations of ferritin and Fe were associated with N-acetylaspartate, but in opposed directions. Higher R1 values in the GP correlated with lower neurometabolite concentrations, in particular tCr (exp(β)=0.87, p<0.01) and choline (exp(β)=0.84, p=0.04). R2* was positively associated with glutamate-glutamine and negatively with myo-inositol. CONCLUSIONS: Our results do not provide evidence that striatal and thalamic GABA differ between Mn-exposed workers, PD or HC patients, and controls. This may be due to the low exposure levels of the Mn-exposed workers and the challenges to detect small changes in GABA. Whereas Mn in blood was not associated with any neurometabolite content in these VOIs, a higher metal accumulation in the GP assessed with R1 correlated with generally lower neurometabolite concentrations.
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    Effects of Alcohol Cues on MRS Glutamate Levels in the Anterior Cingulate
    (Oxford University Press, 2018-05-01) Cheng, Hu; Kellar, Derek; Lake, Allison; Finn, Peter; Rebec, George V.; Dharmadhikari, Shalmali; Dydak, Ulrike; Newman, Sharlene; Radiology and Imaging Sciences, School of Medicine
    Growing evidence suggests that glutamate neurotransmission plays a critical role in alcohol addiction. Cue-induced change of glutamate has been observed in animal studies but never been investigated in humans. This work investigates cue-induced change in forebrain glutamate in individuals with alcohol use disorder (AUD). A total of 35 subjects (17 individuals with AUD and 18 healthy controls) participated in this study. The glutamate concentration was measured with single-voxel 1H-MR spectroscopy at the dorsal anterior cingulate. Two MRS sessions were performed in succession, the first to establish basal glutamate levels and the second to measure the change in response to alcohol cues. The changes in glutamate were quantified for both AUD subjects and controls. A mixed model ANOVA and t-tests were performed for statistical analysis. ANOVA revealed a main effect of cue-induced decrease of glutamate level in the anterior cingulate cortex (ACC). A significant interaction revealed that only AUD subjects showed significant decrease of glutamate in the ACC. There were no significant group differences in the level of basal glutamate. However, a negative correlation was found between the basal glutamate level and the number of drinking days in the past 2 weeks for the AUD subjects. Collectively, our results indicate that glutamate in key areas of the forebrain reward circuit is modulated by alcohol cues in early alcohol dependence.
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    GABA and Glutamate Levels in Occlusal Splint-Wearing Males with Possible Bruxism
    (Elsevier B.V., 2015-07) Dharmadhikari, Shalmali; Romito, Laura M.; Dzemidzic, Mario; Dydak, Ulrike; Xu, Jun; Bodkin, Cynthia L.; Manchanda, Shalini; Byrd, Kenneth E.; Department of Oral Biology, IU School of Dentistry
    Objective The inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays an important role in the pathophysiology of anxiety behavioural disorders such as panic disorder and post-traumatic stress disorder and is also implicated in the manifestation of tooth-grinding and clenching behaviours generally known as bruxism. In order to test whether the stress-related behaviours of tooth-grinding and clenching share similar underlying mechanisms involving GABA and other metabolites as do anxiety-related behavioural disorders, we performed a Magnetic Resonance Spectroscopy (MRS) study for accurate, in vivo metabolite quantification in anxiety-related brain regions. Design MRS was performed in the right hippocampus and right thalamus involved in the hypothalamic−pituitary−adrenal axis system, together with a motor planning region (dorsal anterior cingulate cortex/pre-supplementary motor area) and right dorsolateral prefrontal cortex (DLPFC). Eight occlusal splint-wearing men (OCS) with possible tooth-grinding and clenching behaviours and nine male controls (CON) with no such behaviour were studied. Results Repeated-measures ANOVA showed significant Group × Region interaction for GABA+ (p = 0.001) and glutamate (Glu) (p = 0.031). Between-group post hoc ANOVA showed significantly lower levels of GABA+ (p = 0.003) and higher levels of Glu (p = 0.002) in DLPFC of OCS subjects. These GABA+ and Glu group differences remained significant (GABA+, p = 0.049; Glu, p = 0.039) after the inclusion of anxiety as a covariate. Additionally, GABA and Glu levels in the DLPFC of all subjects were negatively related (Pearson's r = −0.75, p = 0.003). Conclusions These findings indicate that the oral behaviours of tooth-grinding and clenching, generally known as bruxism, may be associated with disturbances in brain GABAergic and glutamatergic systems.
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    Impairment of Motor Function Correlates with Neurometabolite and Brain Iron Alterations in Parkinson’s Disease
    (MDPI, 2019-01-29) Pesch, Beate; Casjens, Swaantje; Woitalla, Dirk; Dharmadhikari, Shalmali; Edmondson, David A.; Zella, Maria Angela Samis; Lehnert, Martin; Lotz, Anne; Herrmann, Lennard; Muhlack, Siegfried; Kraus, Peter; Yeh, Chien-Lin; Glaubitz, Benjamin; Schmidt-Wilcke, Tobias; Gold, Ralf; van Thriel, Christoph; Brüning, Thomas; Tönges, Lars; Dydak, Ulrike; Department of Radiology and Imaging Sciences, Indiana University School of Medicine
    We took advantage of magnetic resonance imaging (MRI) and spectroscopy (MRS) as non-invasive methods to quantify brain iron and neurometabolites, which were analyzed along with other predictors of motor dysfunction in Parkinson's disease (PD). Tapping hits, tremor amplitude, and the scores derived from part III of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS3 scores) were determined in 35 male PD patients and 35 controls. The iron-sensitive MRI relaxation rate R2* was measured in the globus pallidus and substantia nigra. γ-aminobutyric acid (GABA)-edited and short echo-time MRS was used for the quantification of neurometabolites in the striatum and thalamus. Associations of R2*, neurometabolites, and other factors with motor function were estimated with Spearman correlations and mixed regression models to account for repeated measurements (hands, hemispheres). In PD patients, R2* and striatal GABA correlated with MDS-UPDRS3 scores if not adjusted for age. Patients with akinetic-rigid PD subtype (N = 19) presented with lower creatine and striatal glutamate and glutamine (Glx) but elevated thalamic GABA compared to controls or mixed PD subtype. In PD patients, Glx correlated with an impaired dexterity when adjusted for covariates. Elevated myo-inositol was associated with more tapping hits and lower MDS-UPDRS3 scores. Our neuroimaging study provides evidence that motor dysfunction in PD correlates with alterations in brain iron and neurometabolites.
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    An Investigation of Neurochemical Changes in Chronic Cannabis Users
    (Frontiers Media, 2019-09-19) Newman, Sharlene D.; Cheng, Hu; Martin, Ashley Schnakenberg; Dydak, Ulrike; Dharmadhikari, Shalmali; Hetrick, William; O’Donnell, Brian; Radiology and Imaging Sciences, School of Medicine
    With the legalization of recreational cannabis (CB) the characterization of how it may impact brain chemistry is essential. Magnetic resonance spectroscopy (MRS) was used to examine neurometabolite concentrations in the dorsal anterior cingulate (dACC) in chronic CB users (N = 26; 10 females) and controls (N = 24; 10 females). The concentrations of glutamate (Glu), total creatine (tCr), choline (Cho), total N-acetylaspartate (tNAA), and myo-inositol (mI) were estimated using LCModel. The ANCOVAs failed to show significant differences between controls and CB users. Regression analyses were then performed on the CB group to model each neurometabolite to determine its relationship to monthly CB use, sex, the interaction between CB use and sex. tCr was found to be predicted by both monthly CB use and sex. While the regression model was not significant the relationship between monthly CB use and Glu appears to be modulated by sex with the effect of monthly use (dose) being stronger in males. tNAA failed to show an effect of CB use but did reveal an effect of sex with females showing larger tNAA levels. Although the results presented are preliminary due to the small sample size they do guide future research. The results presented provide direction for further studies as they suggest that dose may significantly influence the observance of CB effects and that those effects may be modulated by sex. Studies with significantly larger sample sizes designed specifically to examine individuals with varying usage as well as sex effects are necessary.
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    An investigation of the relationship between glutamate and resting state connectivity in chronic cannabis users
    (SpringerLink, 2020-10) Newman, Sharlene D.; Cheng, Hu; Kim, Dae-Jin; Schnakenberg-Martin, Ashley; Dydak, Ulrike; Dharmadhikari, Shalmali; Hetrick, William; O’Donnell, Brian; Radiology and Imaging Sciences, School of Medicine
    Human and animal studies have shown that heavy cannabis (CB) use interacts with glutamatergic signaling. Additionally, recent studies have suggested that glutamate (Glu) may drive resting state functional connectivity (RSfc). The aims of the current preliminary study were to: 1) determine whether dorsal anterior cingulate cortex (dACC) Glu is related to RSfc between the dACC and two nodes of the reward network, the nucleus accumbens (NAc) and hippocampus (Hp); and 2) determine whether CB use interacts with the relationship between dACC Glu and RSfc. A group of 23 chronic CB users and 23 healthy controls participated in this multimodal MRI study. Glu levels were assessed in the dACC using magnetic resonance spectroscopy (MRS). Linear regression models were used to determine whether dACC Glu and CB use predicts RSfc between the dACC and the NAc and Hp. While the effect size is small, the results showed that the connectivity between the dACC and right NAc was predicted by the interaction between dACC Glu levels and monthly CB use. Additionally, while there is some suggestion that dACC Glu is correlated with dACC-hippocampal connectivity, unlike for dACC/NAc connectivity the relationship between them does not appear to be affected by CB use. These preliminary findings are significant in that they demonstrate the need for future studies with larger sample sizes to better characterize the relationship between resting state connectivity and neurochemistry as well as to characterize how CB use interacts with that relationship.
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    Striatal and thalamic GABA level concentrations play differential roles for the modulation of response selection processes by proprioceptive information.
    (Elsevier, 2015-10-15) Dharmadhikari, Shalmali; Ma, Ruoyun; Yeh, Chien-Lin; Stock, Ann-Kathrin; Snyder, Sandy; Zauber, S. Elizabeth; Dydak, Ulrike; Beste, Christian; Department of Radiology and Imaging Sciences, IU School of Medicine
    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.
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    Striatal GABA-MRS predicts response inhibition performance and its cortical electrophysiological correlates
    (Springer-Verlag, 2015-11) Quetscher, Clara; Yildiz, Ali; Dharmadhikari, Shalmali; Glaubitz, Benjamin; Schmidt-Wilcke, Tobias; Dydak, Ulrike; Beste, Christian; Department of Radiology and Imaging Sciences, IU School of Medicine
    Response inhibition processes are important for performance monitoring and are mediated via a network constituted by different cortical areas and basal ganglia nuclei. At the basal ganglia level, striatal GABAergic medium spiny neurons are known to be important for response selection, but the importance of the striatal GABAergic system for response inhibition processes remains elusive. Using a novel combination of behavior al, EEG and magnetic resonance spectroscopy (MRS) data, we examine the relevance of the striatal GABAergic system for response inhibition processes. The study shows that striatal GABA levels modulate the efficacy of response inhibition processes. Higher striatal GABA levels were related to better response inhibition performance. We show that striatal GABA modulate specific subprocesses of response inhibition related to pre-motor inhibitory processes through the modulation of neuronal synchronization processes. To our knowledge, this is the first study providing direct evidence for the relevance of the striatal GABAergic system for response inhibition functions and their cortical electrophysiological correlates in humans.