GABAergic dysfunction in Parkinson’s disease: Insights from in vivo proton magnetic resonance spectroscopy

GABAergic dysfunction in Parkinson’s disease: Insights from in vivo proton magnetic resonance spectroscopy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review GABAergic dysfunction in Parkinson’s disease: Insights from in vivo proton magnetic resonance spectroscopy Shweta Prasad, Dinesh Kumar Deelchand, Manoj Kumar, Ravi Yadav, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8407027/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract The pathogenesis of Parkinson’s disease (PD) includes neurotransmitters beyond dopamine with suggestions of serotonergic, noradrenergic, cholinergic and GABAergic involvement. In this context advanced methods of magnetic resonance spectroscopy (MRS) permit the in-vivo quantification of GABA. This article aims to systematically review the existing literature on GABAergic alterations in PD as quantified by in-vivo proton MRS with a focus on ascertaining the influence of GABA on motor and non-motor symptoms, motor subtypes, effect of medication status and methodological variations across studies. A systematic search of PubMed and Scopus was carried out in April 2025 with a relevant Boolean phrase. A total of 22 studies met the inclusion criteria. From a methodological perspective, there was variability in magnetic field strengths, pulse sequences, voxel location, voxel size, quantification reference, and methods of processing. Review of reported GABA levels revealed a very heterogenous set of alterations, with gross variations in GABA observed across studies, regions of interest and clinical phenotypes. These observations suggest a multifaceted dysregulation of GABA related neurotransmission that extends the concepts of PD pathogenesis beyond the traditionally implicated canonical dopaminergic framework. GABA plays a definite modulatory role in the pathogenesis of PD, and complex, distinct regional alterations contribute to the development of motor and non-motor symptoms in PD. Standardisation of GABA spectroscopy methods and ideal patient selection is crucial to identify definite patterns of alterations. Health sciences/Diseases Health sciences/Neurology Biological sciences/Neuroscience GABA PD Spectroscopy Motor Non-motor Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Parkinson’s disease (PD) is a neurodegenerative disorder characterised by bradykinesia, rigidity, rest tremor and postural instability 1 and non-motor symptoms (NMS) such as sleep disturbances, olfactory dysfunction, mood disturbances, cognitive deficits, autonomic dysfunction, etc 2 , 3 . Dopaminergic loss in the substantia nigra pars compacta (SNpc) and widespread accumulation of α-synuclein is considered pathognomonic in PD 4 , with dopamine replacement therapy being the therapeutic mainstay. However, this dopaminergic-centric view has been challenged by accumulating evidence highlighting the role of other neurotransmitter systems beyond the nigrostriatal dopaminergic pathway. Primary evidence of this arises from the fact that unlike bradykinesia and rigidity, tremor does not correlate with striatal dopaminergic depletion 5 ; rather serotonergic 6 , 7 , noradrenergic 8 abnormalities, and pallidal rather than striatal dopaminergic depletion 9 , 10 are suggested. The role of other neurotransmitter systems is further exemplified by NMS in PD, for instance serotonergic dysfunction in depression 11 , noradrenergic alterations in autonomic dysfunction 12 , cholinergic deficits in cognitive impairment 13 , etc. Gamma-aminobutyric acid (GABA) is the most prevalent inhibitory neurotransmitter which intricately regulates excitatory-inhibitory balance across the basal ganglia thalamocortical (BGTC) and cerebello thalamocortical (CTC) networks 14 . Dopaminergic neurons from the SNpc exert modulatory effects in the BGTC, i.e., via direct and indirect pathways using GABA from the inhibitory projection neurons 15 , 16 , with disruptions contributing to motor and non-motor in PD 17 . Non-dopaminergic systems interact with GABAergic and dopaminergic pathways to create a complex excitatory-inhibitory balance that perhaps form the basis for the diverse profile of symptoms observed in PD 18 . Understanding the alterations of GABA in PD and its influence on PD symptomatology is crucial to develop a comprehensive understanding of the pathophysiology of PD and open avenues for newer therapeutic strategies. Attempts have been made to indirectly evaluate synaptic GABAergic and glutamatergic activity in PD using transcranial magnetic stimulation (TMS), particularly the measures of short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI) and cortical silent period (CSP) 19 . These studies have consistently reported reduced LICI (mediated by GABA B ), altered SICI-LICI interactions and occasionally reduced SICI in PD, supporting the concept of GABAergic dysfunction in PD 20,21 . Magnetic resonance spectroscopy (MRS) is a non-invasive imaging modality that permits in-vivo quantification of brain metabolite concentrations. Although proton MRS ( 1 H MRS) is routinely performed, GABA spectroscopy is challenging owing to its low concentrations and more importantly spectral overlaps with more abundant metabolites such as creatine 22 . To mitigate this, spectral editing techniques, such as the MEscher-GArwood Point RESolved Spectroscopy (MEGA-PRESS) 23 or MEGA-semi Localized Adiabatic SElective Refocusing (MEGA-semiLASER) which employ frequency-selective editing pulses to isolate the GABA signal at 3.0ppm 24 or alternatively short echo-time STimulated Echo Acquisition Mode (STEAM) sequence at ultra-high field (> 3T) can be used. Several studies have attempted to quantify GABA in PD and ascertain correlations between symptoms, drug responsiveness, etc. However, it is difficult to develop a comprehensive understanding of the influence of GABA owing to significant variability on several fronts including but not restricted to patient selection, magnetic field strength, MRS localization sequence, voxel location, voxel size, quantification method, etc. The current study aims to systematically review the existing literature on GABAergic alterations in PD as quantified by 1 H MRS with a focus on ascertaining the influence of GABA on motor and non-motor symptoms, motor subtypes, effect of medication status and methodological variations across studies. 2. Methodology 2.1. Search strategy This review was conducted in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement (PRISMA) 25 . A systematic search of databases (PubMed, Scopus) was carried out in April 2025 using the Boolean phrase - ("magnetic resonance" AND "spectroscopy") AND ("parkinson's disease" OR "parkinsons disease” OR “Parkinson disease") AND ("GABA" OR "gamma-aminobutyric acid" OR "gamma-amino-butyric acid" OR" γ-Amino-butyric acid" OR "γ-aminobutyric acid"). Reference lists of included studies were also searched to ensure key studies were not overlooked. 2.2. Criteria for inclusion and exclusion Studies that met the following criteria were included (1) Population: Human subjects (2) Disease: PD (3) MRS method: Field strength of 3T or higher, pulse sequences established to measure GABA (MEGA-PRESS, STEAM, etc), single-voxel MRS. Except review articles, and studies investigating GABA spectroscopy in animal models of PD, all other study designs were considered. Only articles written in English were considered. 2.3. Study selection and data extraction process All articles obtained from PubMed and Scopus were screened and duplicates were excluded. Following this, titles and abstracts were assessed to establish eligibility. When the titles and abstract were inconclusive, the full texts were reviewed. Full texts of all eligible articles were obtained and data was extracted. All screening and data extraction was carried out by the first author, SP. Data was extracted based on suggestions in the Minimum Reporting Standards for in vivo Magnetic Resonance Spectroscopy (MRSinMRS) guidelines 26 . (1) Bibliometric data Authors, year of publication (2) Demographic and clinical details Sample size, gender, age at assessment, duration of illness, Movement Disorder Society-Unified Parkinson’s Disease Rating Scale part III (MDS-UPDRS-III) or UPDRS-III OFF and ON state scores, and levodopa equivalent daily dose (LEDD); (3) Hardware and acquisition details : Field strength, manufacturer, model, radiofrequency (RF) coil, medication state while scanning (OFF or ON), pulse sequence, location of voxel-of-interest (VOI), VOI size, repetition time (TR), echo time (TE), water suppression method; (4) Data quality metrics Signal-to-noise ratio (SNR), line width (LW), quantification precision (Cramer-Rao minimum lower bounds (CRLB), GABA fit error). (5) Data analysis Software, output measures, quantification reference, GABA/GABA + levels. One of the limitations of spectral editing at 3T is that the GABA signal is contaminated with macromolecules 27 . This is referred to as GABA+, and is commonly reported in literature. In this review, both GABA and GABA + have been considered and interpreted similarly. 2.4. Quality assessment Quality of included studies was evaluated using MRS-Q (v1.1, http://doi.org/10.17605/OSF.IO/8S7J9 ) - a quality appraisal tool specifically designed for the systematic review of MRS studies 28 . 3. Results The initial search returned 114 studies (Figure-1). After removal of duplicates and preliminary screening, 66 studies were eligible for abstract screening. Forty-four studies were excluded based on exclusion criteria of animal studies, other movement disorders (not PD), review articles, or magnetic resonance spectroscopic imaging (MRSI), i.e., not single voxel spectroscopy. Finally, a total of 22 articles were included in this systematic review 29 – 50 3.1. Demographic and clinical characteristics All except one study 46 included patients with PD and HC, with the sample sizes ranging from 10–60 subjects per group, and most subjects were between the ages of 50–70 (Table-1). With the exception of one study 37 , all others had a relatively equal gender distribution . Duration of illness ranged from early PD ( 10 years). Disease severity was reported by 19 studies, using with the UPDRS-III(n = 12) 30,33,34,36,38,40–43,45,51 and MDS-UPDRS III(n = 6) 32,35,37,39,44,46,50 (total UPDRS-III values not reported by van Nuland et al 39 ). Of this only OFF state scores (n = 9) 30,31,34,36,37,41,43,45,50 , ON state scores (n = 4) 32,35,38,40 , and both OFF and ON scores(n = 4) 42,44,46,48 , where the ON state assessment by Trujillo et al 46 was with only dopamine agonists (DA). The mean of OFF state scores ranged from 13.6-55.9 36,40 , and ON state scores-13.8-27.95 32,40 . The minimum mean ON score is higher than the minimum OFF state score as they were different studies and did not report scores for both states. Levodopa equivalent daily dose (LEDD) was reported by ten studies. Nine studies included subgroups with motor subtypes 34 , 37 , additional NMS 36 , 40 , 45 , 46 , 48 , altered levodopa responsiveness to tremor 39 or intervention-deep brain stimulation (DBS) 35 . Gong et al 34 , included tremor dominant PD (TDPD), and the postural instability and gait disturbance (PIGD) variant, while Pesch et al 37 included akinetic-rigid and the mixed subtypes. PD with somatic syndrome disorder (SSD) was evaluated in two studies 40 , 45 , PD with impulse control disorder (ICD) 46 in one and PD with depression in one 48 . Patients with dopamine resistant tremor were evaluated by van Nuland et al 39 , and patients pre and post DBS were evaluated by O’Gormon Tuura et al 35 . 3.2. Acquisition Magnetic field strengths included − 3 Tesla (T) (n = 19), 4T scanner (n = 1) 29 , and 7T scanner (n = 2) 30,44 (Table-2). Majority used a standard 32 channel receive coil or 8 channel radiofrequency (RF) coil, while 16 channel and dual tuned 1 H/ 31 P transmit and receive coils were used in single studies. An early study by Oz et al, used a transverse electromagnetic (TEM) volume coil 29 . MEGA-PRESS was the most common sequence used to measure GABA, followed by STEAM in 3 studies 29 , 30 , 44 . All MEGA-PRESS studies used a TE of 68ms, except 2 with TE = 69ms 32,35 , and 1 with TE = 120ms 47 . Acquisitions ranged from 128–256 for MEGA-PRESS voxels. Voxels were placed in a total of 14 regions (Table-2) -thalamus(n = 5), basal ganglia/striatum(n = 5), SN (n = 3), occipital cortex, motor cortex (MC), putamen, medial prefrontal cortex (mPFC) – 2 studies each, dorsolateral prefrontal cortex (DLPFC), sensory motor cortex (SMC), PFC, midbrain, brainstem, pons, cerebellum- 1 study each. The voxel sizes varied between location, and only 5 studies 32 , 35 , 36 , 38 , 49 reported volumes above or at the recommended 27mL for MEGA-PRESS 27 . Details pertaining to water suppression were reported in 13 studies, and VAriable Power radiofrequency pulses with Optimized Relaxation (VAPOR)(n = 7) was the most common method followed by chemical shift selective saturation (CHESS)(n = 4) and Multiple optimizations insensitive suppression train (MOIST)(n = 2). Quality metrics in the form of LW, FWHM, SNR or CRLB were reported in 14 studies. Medication state during acquisition of spectroscopy data was reported in all except one study 47 . Most acquired in the OFF state (n = 13), followed by ON state(n = 4), and both OFF and ON state data(n = 4). 3.3. Data analysis Edited spectral data was processed using Gannet(n = 12), followed by Linear combination of MODEL spectra (LCModel) (n = 4), Gannet + Advanced method for accurate, robust, and efficient spectral editing (AMARES)(n = 1), Free induction decay-Appliance (FID-A) + LCModel(n = 1), and KALPANA(n = 1). GABA+, i.e., combined signal contributions of GABA, macromolecules and homocarnisine was reported by most studies (n = 15), while GABA, i.e., without macromolecules and homocarnisine, was reported by the rest (n = 7). The quantification reference for GABA varied, wherein most reported GABA using water(n = 11), followed by total creatine (tCr)(n = 7). One study reported both methods tCr and water 48 , and only one study reported absolute GABA 47 . 3.4. Results of GABA spectroscopy There were numerous domains of variability between studies, ranging from motor subtypes, NMS, medication states and voxel locations (Table-3, Figure-2, Figure-3). The results are categorised to reflect each domain. 3.4.1. Difference between PD and HC based on location of voxel Thalamus Thalamic alterations were evaluated by 4 studies 31 , 37 , 39 , 48 . Dharmadhikari et al 31 and van Nuland et al 39 evaluated PD in the OFF state and reported contradictory results – lower GABA in PD, and no difference. No difference was reported between PD-ON state and HC by all three studies that performed this comparison 37 , 39 , 48 . Basal ganglia, striatum Significant variations were observed in results reported for variations of GABA between PD OFF state and HC. Of the 5 studies, 2 reported higher GABA in PD 32,35 , while 2 reported lower GABA 33 , 34 and 1 reported no difference 37 . Putamen Emir et al 30 and Seger et al 44 reported GABA in PD-OFF and PD-ON states respectively. In comparison to HC, both reported higher levels of GABA in PD. Prefrontal cortex O’Gormon Tuura found no difference between PD-OFF state and HC 32 . Medial prefrontal cortex Delli Pizzi et al, reported no difference between PD-OFF and HC 40,45 Dorsolateral prefrontal cortex PD-OFF state was found to have a lower GABA level in comparison to HC 41 . Motor cortex In both the OFF and ON state, van Nuland et al, reported no difference between patients with PD and HC 39 . Sensory motor cortex Tian et al, reported lower GABA in PD-OFF state compared to HC 49 . Occipital cortex No difference was found between patients PD-OFF 39 or PD-ON 36,39 compared to HC . Cerebellum Piras et al, found no difference between PD-ON state and HC for either right cerebellar hemisphere, left cerebellar hemisphere or the mean cerebellar GABA level 38 . Midbrain No difference was reported between PD-OFF state and HC 50 . Brainstem Song et al, consistently reported a lower brainstem GABA in PD-Off state compared to HC 42,43 , with no difference between PD-ON state and HC 42 . Pons Higher pontine GABA was reported by Emir et al, in PD-OFF state 30 . Substantia nigra Both Oz et al, and Emir et al reported no difference between PD-ON state and HC 29,30 . Shukla et al, also reported a similar observation, however, the medication state during acquisition was uncertain 47 . 3.4.2. GABA in relation to motor symptoms of PD Motor symptoms Gong et al, evaluated the TDPD and PIGD variants and reported distinct GABAergic profiles - TDPD had lower basal ganglia GABA levels than PIGD 34 . GABA and UPDRS scores were inversely correlated in the complete PD group, and the PIGD subtype. No correlation was observed for TDPD. Axial symptoms Basal ganglia GABA positively correlated with gait disturbance, gait summary scores, and difficulty standing up from a chair in akinetic-rigid PD 32 . PFC GABA negatively correlated with postural stability in akinetic-rigid PD. Dopamine-resistant tremor Van Nuland et al, evaluated thalamic, MC, occipital cortex GABA in dopamine-resistant and dopamine-responsive PD tremor and found no influence of clinical phenotype 39 . MC GABA inversely correlated with OFF and ON rigidity and tremor scores. Negative correlations were reported between disease severity and GABA in TDPD. 3.4.3. GABA in relation to non-motor symptoms of PD Depression Liu et al, reported higher mPFC GABA and equal thalamic GABA in PD with depression compared to PD without depression 48 . However, no correlations were observed between GABA levels and Hamilton depression rating scale (HAM-D) and Hamilton Anxiety Rating Scale (HAM-A). Somatic symptom disorder A higher mPFC GABA was consistently reported in PD + SSD in comparison to PD- SSD and HC 40,45 . Similar observations were reported in subjects of SSD, suggestive that higher GABA is an SSD trait rather than associated with PD. Impulse control disorders Patients with PD + ICD were had lower thalamic GABA and equal MC GABA in comparison to PD-ICD 46 . Difference between OFF and ON DA thalamic GABA (∆GABA) significantly correlated with impulsivity scores as measured by Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale. Visual hallucinations Firbank et al, reported lower occipital cortex GABA in PD with visual hallucinations (VH) 36 . No correlations were observed between GABA and neuropsychiatric inventory hallucination score but positive correlations were reported between GABA and visual acuity. Cognition Piras et al, reported positive correlations between mean cerebellar GABA and Stroop Word-Color Test short form error interference effect (SWCT- IE-E) and Stroop Word-Color Test short form time interference effect (SWCT- IE-T) 38 . Hemispheric differences were reported with the left hemisphere positively correlating with the SWCT-IE-E, and right hemisphere negatively correlating with SWCT-IE-T. NMS severity score Song et al, reported no correlations between brainstem GABA and total NMS severity questionnaire scores, or individual domains 43 . 3.4.4. GABA in relation to medication/ surgical intervention (DBS) Three studies reported a direct comparison of OFF and ON state GABA levels 39 , 42 , 48 . Liu et al reported no difference between mPFC OFF and ON GABA 48 , and Song et al reported higher ON state brainstem GABA 42 . Van Nuland et al, reported no differences between thalamic, MC and occipital cortex OFF and ON state GABA levels 39 . No correlations were reported by Gong et al, between levodopa responsiveness and ∆GABA 42 . Seger et al, reported inverse correlations between ON state putaminal GABA with response to dopaminergic treatment. O’Gormon Tuura et al attempted to evaluate if pre-DBS basal ganglia and striatal GABA could predict response to DBS 35 . GABA was considered to be a significant predictor of outcome however; this correlation was lost after removing an outlier. 3.5. Quality assessment Quality assessment was based on MRS-Q 28 (Figure-4). High quality studies were based on Domain 2 and 3, i.e., sequence and scan parameters. Only Firbank et al, and Tian et al met required parameters 36 , 49 . A high-quality sequence was used in 86.3%(n = 19), 63.6%(n = 14) had the required number of averages, and only 22.7%(n = 5) had adequate a voxel size. 77.27%(n = 17) had an appropriate TE, however, 4 studies that did not comply used a different sequence. These criteria were recently established and several of the included studies are almost up to 2 decades old. Moreover, lack of reporting does not imply poor quality. Discussion The current systematic review examined the role of GABA in PD as measured by single-voxel GABA spectroscopy. Across 22 included studies, a range of patterns of GABAergic alterations were noted in PD which suggest a multifaceted, region specific dysregulation of GABA related neurotransmission that extends the concepts of PD pathogenesis beyond the traditionally implicated canonical dopaminergic framework. Alterations in levels of GABA (or GABA+) were reported across numerous cortical and subcortical regions, with either increase, decrease of no change in comparison to controls. This heterogeneity reflects the complex neurochemical landscape in PD. Although methodological inconsistencies limit the possibility of carrying out a meta-analysis, patterns do emerge. Collectively, the observations provide evidence of GABAergic dysfunction in PD that is intricately associated with motor and non-motor symptoms. The need for standardisation from clinical and technical aspects of spectroscopy acquisition was also revealed. Direct and indirect pathways, are the primary networks related to motor functioning which are tightly linked to PD pathogenesis and highly reliant on GABA as the key modulatory neurotransmitter(Figure-5). Dopamine is responsible for modulation of these pathways via excitatory D1 receptors - direct(facilitatory) pathway, and inhibitory D2 receptors -indirect(inhibitory) pathway 15 . Degeneration of dopaminergic neurons and subsequent dopaminergic deficit leads to an imbalance, producing excessive inhibition of the ventral lateral thalamic nucleus and in turn reduced facilitation of the MC. This model explains rigidity and bradykinesia; however, it does not necessarily explain tremor 52 . Rest tremor is suggested to arise from a tremor network comprised of the basal ganglia-thalamocortical, and cerebello-thalamocortical circuit 9 , 16 , 53 . The ‘dimmer-switch’ hypothesis suggests the GPi triggers tremor activity, and the cerebello-thalamocortical circuit modulates tremor amplitude 53 . Thalamocortical communication is modulated by dopamine-dependent thalamic self-inhibition of the ventral intermediate nucleus (VIM) by the thalamic reticulate nucleus via D4 receptors 54 . Dyskinesia is also associated with GABA wherein, loss of dopaminergic neurons leads to a reduction in postsynaptic activation of GABA receptors resulting in hyperexcitability of striatal neurons and subsequent dyskinesia 55 . Beyond modulation, GABA also has a neuroprotective role. The GABA collapse hypothesis suggests that neurons are protected from calcium-based neurotoxicity by GABAergic inputs 56 . Dopaminergic neurons are particularly affected owing to their high energy requirements and dependence on slow calcium-based pacemaker activity 57 . A reduction in GABA is known to dysregulate calcium voltage gated channels leading to calcium related excitotoxicity and oxidative stress which can lead to ɑ-synuclein aggregation and further injury to dopaminergic neurons 58 . Alterations in GABA metabolism, i.e., synthesis, reuptake, or changes in GABA receptor expression can also contribute to dysfunction. For instance, glutamic acid decarboxylase (GAD) is the main enzyme in GABA synthesis for conversion of glutamate to GABA, and a reduction of GAD expression in the PFC has been reported 59 . It is imperative to understand that GABA is not restricted to only the above-described networks, rather GABAergic neurons are widespread including other critical cortical and subcortical networks. Alterations of GABA in these areas may significantly contribute toward the development of NMS in PD 17 . It is evident that GABA plays a crucial physiological role and alterations may contribute to PD symptomatology. However, previous studies evaluating GABA in PD present a very heterogenous image of alterations, with gross variations in results across studies, regions of interest and clinical phenotypes (Figure-2, Figure-3). Hence it is challenging to provide a definite response regarding GABA alterations in PD and if MRS consistently replicates concepts put forth by classical models of PD pathogenesis. For instance, based on the reviewed studies, significant inter-regional and intra-regional variability was observed for GABA in PD-OFF state. With the exception of mPFC 40 , 45 , brainstem 42 , 43 and SN 29,30 , where no difference was observed, no other voxel with multiple studies reported consistent results. Within the basal ganglia which is the primary area of interest to PD, significant heterogeneity exists – with equal observations of high 32 , 35 , equal 31 , 37 and low levels 33 , 34 of GABA in PD. In this context, MRS sensitivity to GABA varies between compartments, and has reduced sensitivity in subcortical structures. MRS is particularly sensitive to extracellular, unbound GABA which is involved in tonic inhibition 60 , 61 . Extracellular GABA depends on accumulation of GABA spill over from synaptic transmission along with a small percentage of GABA that is released by local glia cells 62 , 63 . Intracellular GABA is present in limited quantities as it is converted from glutamate on demand at the axon terminal, hence contributes minimally to the spectroscopy signal 64 , 65 . Furthermore, it is imperative to understand that the thalamus is not a single function, single connection structure. Rather a hub of afferent and efferent connections with varied functionality of each nuclei. This is relevant in context of evaluating motor symptoms in PD, wherein the ventral oralis anterior, i.e., ventral lateral nucleus is linked with the BGTC, whereas the VIM is linked with the CTC. It is plausible that results obtained from thalamic voxels may not be specific, and different influences and functions may nullify specific results. In the same vein, it is also pertinent to state that a larger voxel size is a methodological limitation of GABA editing spectroscopy owing to which specificity may be lost in attempting to evaluate brain regions, and significant overlaps exist, for e.g., the basal ganglia voxel is very large, and covers the putamen, globus pallidus externa and GPi, and each region probably has specific changes which cannot be evaluated. In contrast, almost all studies comparing patients in the ON state to HC consistently reported equal levels of GABA irrespective of region of interest. Only a single study reported higher putaminal ON state GABA compared to HC 44 . This is a crucial observation as it highlights levodopa induced normalisation of neurotransmitters in PD. The elevated putaminal GABA may be due to striatal GABAergic neurons, rather than GABAergic afferents, as primary striatal afferents are dopaminergic and glutamatergic, whereas medium sized GABAergic spiny neurons are the predominant cells in the striatum. Animal models suggest that nigrostriatal pathway lesions lead to elevated striatal GABA, and this may be observed in PD 66 . Very few studies evaluated medication induced variations, and majority reported no differences. While intriguing, it is plausible and implores further evaluation of directionality of change, i.e., toward or away from normal. van Nuland et al 39 , evaluated this in the thalamus, motor and occipital cortex, however, they reported no influence of disease subtype or medication state. In contrast, Song et al 42 , reported lower brain stem GABA in PD-OFF state compared to HC and PD-ON state, suggesting levodopa induced normalisation of GABA. Numerous factors can affect observations of the impact of levodopa between and within studies. These can include dose of levodopa, time point in the ON state when data was acquired, individual variations in pharmacodynamics and pharmacokinetics of levodopa, stage of disease, dopamine reserve, etc. The exploration of GABAergic influences is inadequately and inconsistently explored. However, there are relevant observations within the limited studies. For instance, Gong et al, compared TDPD and PIGD PD 34 . Their observation of higher basal ganglia GABA in PIGD supports the classical model of PD pathogenesis, as it indicates the possibility of higher basal ganglia inhibition producing reduced excitation of the MC and subsequent reduction in movement. Axial symptoms of PD are often poorly responsive to dopaminergic treatment, and indicates the possibility of non-dopaminergic influences. The basal ganglia is a crucial hub for sensorimotor integration and descending projections toward the midbrain play a role in postural control and gait 15 . O’Gormon Tuura et al reported a positive association between basal ganglia GABA and gait disturbance scores in akinetic-rigid PD, and PFC GABA and postural stability 32 . However, they did not directly compare akinetic-rigid PD and TDPD. Only van Nuland et al 39 , focused on PD tremor and implications of dopaminergic medication. They reported an inverse relationship between MC GABA and tremor, suggesting that a reduction in cortical GABA produces higher tremor severity which is in line with current concepts and role of the CTC in tremor modulation. An attempt was also made to evaluate if basal ganglia GABA could predict response to subthalamic nucleus DBS. The study had limitations in sample size and moreover, the observed results of GABA being a good predictor were nullified after removal of a significant outlier 35 . However, this is an interesting concept and deserves to be evaluated by future studies. Several studies have focused on evaluating NMS in PD as these extend beyond the conventional understanding of PD pathogenesis. The motor network is one of many roles of the basal ganglia as it is well established that limbic and associative/cognitive loops also exist 67 , 68 . This implies that dopaminergic deficit or even excess can strongly influence the development of NMS. Almost all studies evaluating GABA and NMS have focused on neuropsychiatric domain of NMS–depression, SSD, ICD, hallucinations, and cognition. Perhaps this is supported by the corpus of previous studies evaluating spectroscopic alterations in psychiatric disorders 69 , 70 . The presence of existing information helps form parallels between pure psychiatric disorders and the psychiatric NMS seen in PD, aiding in ascertaining the basis for NMS. Depression occurs secondary to an imbalance in excitation and inhibition in the PFC secondary to altered inhibitory transmission to key glutamatergic regions 71 leading to suppressed excitatory neurotransmission. This observation was also made by Liu et al 48 who reported higher mPFC GABA in PD depression. The study designs by Delli Pizzi et al 40,45 to evaluate PD with SSD is ideal to dissect the exact changes. They included four groups – PD with SSD, PD without SSD, pure SSD and HC. These comparisons revealed that higher mPFC GABA was seen in both PD with SSD and pure SSD, indicating that higher GABA was a SSD trait rather than associated with PD. Such a design would also be helpful to understand other crucial NMS like ICD and psychosis which often tend to be medication related. Trujillo et al 46 , reported a reduction in thalamic GABA in PD with ICD, further substantiating the complex regional interplay and impaired inhibitory mechanisms in thalamocortical circuits. Psychosis in PD is an important NMS, and Firbank et al suggested that low GABA levels may predispose development of hallucinations, however, the occurrence of visual hallucinations is controlled by other factors such as visual environment and attention 36 . These observations open therapeutic avenues for attempting to use other groups of medication. Interestingly, cognitive alterations were evaluated in relation to cerebellar GABA levels by Piras et al 38 , and significant role of GABA in producing decreased efficiency in filtering task-irrelevant information. Although this is not the traditional choice for studying cognition, it significantly expands the scope of regions associated with cognition. There are several reasons to explain the heterogeneity of results across the observed studies. From a methodological perspective, there was variability in field strengths, pulse sequences, voxel location, voxel size, quantification reference, and methods of processing. Majority of the evaluated studies used MEGA-PRESS, however, this sequence although robust has limitations due to sensitivity to motion, frequency shifts and a large chemical shift displacement error (CSDE) 22 . This may impede the specificity of data acquired from the voxel, particularly in crowded subcortical area of the basal ganglia and thalamus. Several studies have reported GABA/tCr ratios however there is lack of consensus about the stability of tCr concentrations and if it is truly unaltered in patients with PD for use as an internal reference. Altered tCr levels have been reported in the PD basal ganglia but not in other regions, and some studies report altered level following administration of levodopa 34 , 72 . Hence, it may be inappropriate to use tCr as a reference especially for the basal ganglia. Perhaps, studies should consider reporting absolute values to permit better interpretation and uniformity. This is emphasised by the observation that within voxels similar observations of GABA alterations were often reported by the same group who probably followed relatively uniform methods. For e.g. both observations of high GABA in the basal ganglia were by the same group 32 , 35 , or even the mPFC 40 , 45 , brainstem 42 , 43 and SN 29,30 . Another confounder in interpretation is the interchangeable use of GABA + and GABA. Both measures have different implications and authors should be careful in stating whether the reported GABA concentration includes macromolecules and homocarnosine or if the used TE permitted the measurement of GABA rather than GABA+. Finally, lack of complete reporting of details further confounds the problem. Future studies should consider including details suggested in the MRSinMRS guidelines 26 , this would permit replication and interpretation of studies. Considering the fact that motor subtypes, NMS and medication can contribute to specific changes in GABA levels, clinical phenotyping is critical to outcomes. Numerous studies reported no difference between PD and HC, however it is possible that the admixture of multiple phenotypes in a single PD group led to nullifying of specific alterations in comparison to HC. These may have become evident if patient selection and groups were more specific. The dosage of levodopa used to induce an ON state for scanning was also not clearly described in most studies. It is evident that levodopa may have a strong modulatory influence and variations in dosing across subjects even within the same study will lead to variations. In addition, use of the other medication, caffeine, other stimulants, was not consistently reported and this can often confound results. Perhaps similar to the MRSinMRS guidelines, clinical reporting guidelines are also required to ensure transparency and increase interpretability. Conclusions GABA plays a significant role in balancing numerous processes. At a neuronal level it prevents calcium related neurotoxicity, and at a circuit-based level it has the significant role in preventing dysfunctional motor hyperactivity. GABA plays a definite role in the pathogenesis of PD, and complex, distinct regional alterations contribute to the development of motor and non-motor symptoms in PD. This area of research has immense potential and there is scope for significant improvement and exploration in future studies. Methodological uniformity and upgradation to more optimised sequences with low CSDE such as MEGA-semiLASER or scanning at higher field strengths may yield more precise information. Spectroscopy should be integrated with other methods of evaluating GABA metabolism such as 11 C-Flumazenil imaging, and a bimodal approach using TMS. Considering the possibility of synchronous alterations in excitation and inhibition, levels of excitatory neurotransmitters, i.e., glutamate, glutamate + glutamine (Glx), the corresponding alterations in GABA, and change in excitatory-inhibitory balance should also be evaluated. Of higher importance is the requirement for detailed clinical phenotyping, longitudinal studies and assessment of other domains of NMS such as sleep dysfunction. This is essential if any attempts need to made at exploring newer, non-dopaminergic therapeutic options. Finally, the evaluation of prodromal PD, and at-risk populations, mutation carriers may perhaps aid in developing imaging biomarkers for PD. Declarations Source of funding DBT/ Wellcome Trust India Alliance Early Career Fellowship (IA/CPHE/21/1/505953) – awarded to SP. Financial Disclosure/Conflict of Interest None of the authors have any financial disclosure to make or have any conflict of interest. Declaration of generative AI in scientific writing No generative AI tool was used in the preparation of this manuscript Author Contribution (1) Research project: A. Conception, B. Organization, C. Execution; (2) Analysis: A. Design, B. Execution, C. Review and critique; (3) Manuscript: A. Writing of the first draft, B. Review and critique.SP: 1A, 1B, 1C, 2A, 2B, 3ADKD: 2C, 3BMK: 2C, 3BRY: 2C, 3BPKP: 2C, 3BJS: 2C, 3B Acknowledgements: All figures were created by SP using BioRender Data Availability Statement: Data sharing not applicable to this article as no datasets were generated or analysed during the current study. Author Roles (1) Research project: A. Conception, B. Organization, C. Execution; (2) Analysis: A. Design, B. Execution, C. Review and critique; (3) Manuscript: A. Writing of the first draft, B. Review and critique. 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16:30:42","extension":"xml","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":247522,"visible":true,"origin":"","legend":"","description":"","filename":"d8515b1d8c5f4105a90271d94c6742dc1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/9723394223cd65332cc4f888.xml"},{"id":99223892,"identity":"d30c80c2-7448-4a99-9d52-e5645d81e7ba","added_by":"auto","created_at":"2025-12-30 10:02:22","extension":"jpeg","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":832393,"visible":true,"origin":"","legend":"","description":"","filename":"Figure1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/c680731c8818fd0ede8fada8.jpeg"},{"id":99223889,"identity":"88e48c69-767a-4981-8216-5804d152df6b","added_by":"auto","created_at":"2025-12-30 10:02:22","extension":"jpeg","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3973010,"visible":true,"origin":"","legend":"","description":"","filename":"Figure2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/4afdbeaaaa7b1ab28665e09b.jpeg"},{"id":99223905,"identity":"313a84b3-28e6-48ec-8242-f9ecdb0bc131","added_by":"auto","created_at":"2025-12-30 10:02:22","extension":"jpeg","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5658718,"visible":true,"origin":"","legend":"","description":"","filename":"Figure3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/27438460b5e549f58665de14.jpeg"},{"id":99317718,"identity":"e13c55c7-1334-421b-b3c3-971602cee800","added_by":"auto","created_at":"2025-12-31 16:30:38","extension":"jpeg","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4099287,"visible":true,"origin":"","legend":"","description":"","filename":"Figure4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/12cc7072d7f54851c8a7dc62.jpeg"},{"id":99223900,"identity":"854c75e8-82dd-4579-ab88-70d445c69390","added_by":"auto","created_at":"2025-12-30 10:02:22","extension":"jpeg","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5447521,"visible":true,"origin":"","legend":"","description":"","filename":"Figure5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/9a2f3f11ad49f377efffa45d.jpeg"},{"id":99318413,"identity":"99e3ee50-7122-4bd5-94a2-b141c60827b4","added_by":"auto","created_at":"2025-12-31 16:33:07","extension":"png","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":124589,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/8bb1ec939cf80be77b506a0e.png"},{"id":99223902,"identity":"8c1b978d-9425-4a2e-a0b7-ee5f82765876","added_by":"auto","created_at":"2025-12-30 10:02:22","extension":"png","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":549369,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/634d38227283b0fb1825b37d.png"},{"id":99223896,"identity":"073e4ad4-0462-4010-8c83-1dcbc0b12b25","added_by":"auto","created_at":"2025-12-30 10:02:22","extension":"png","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":431307,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/4210a67a911282f3eaabe9ac.png"},{"id":99317728,"identity":"ed8314c9-113c-4843-9117-a0d9eff0788a","added_by":"auto","created_at":"2025-12-31 16:30:39","extension":"png","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":472778,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/c590acb43b05a053ccf03001.png"},{"id":99317581,"identity":"06df9592-6b24-4433-9aa7-0a94cc009d89","added_by":"auto","created_at":"2025-12-31 16:30:24","extension":"png","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":493281,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure5.png","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/c14c14f2bd30a91a3c3b0adb.png"},{"id":99318907,"identity":"3ee08d2b-3108-4ff0-82bc-2e328a89f81b","added_by":"auto","created_at":"2025-12-31 16:35:44","extension":"xml","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":244808,"visible":true,"origin":"","legend":"","description":"","filename":"d8515b1d8c5f4105a90271d94c6742dc1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/c3fe122bc584759a467c32c1.xml"},{"id":99223898,"identity":"1bfb5d3a-c7a6-4a94-89b8-10c09e24e7e8","added_by":"auto","created_at":"2025-12-30 10:02:22","extension":"html","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":258929,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/779d9b691badd960d2e8ae14.html"},{"id":99223878,"identity":"b4cd5159-e320-4cc2-b753-ffc444192146","added_by":"auto","created_at":"2025-12-30 10:02:22","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":832393,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow diagram\u003c/p\u003e","description":"","filename":"Figure1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/ba5c04a77b67f79353b508ee.jpeg"},{"id":99317624,"identity":"5b429625-ab6a-4518-884a-ba9bc23c41cf","added_by":"auto","created_at":"2025-12-31 16:30:30","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3973010,"visible":true,"origin":"","legend":"\u003cp\u003eVoxels of interest evaluated and obtained results. Note: The location of voxels were generalised to optimise inclusion and may not be completely anatomically correct\u003c/p\u003e","description":"","filename":"Figure2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/325d5aef106dddec32bf2135.jpeg"},{"id":99318567,"identity":"95b2fc4d-de28-49d9-87f4-380a1adfeafa","added_by":"auto","created_at":"2025-12-31 16:33:37","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":5658718,"visible":true,"origin":"","legend":"\u003cp\u003eSummary of results of included studies\u003c/p\u003e","description":"","filename":"Figure3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/dfdcf238d693cac451fe0779.jpeg"},{"id":99223887,"identity":"25460ef3-e235-4876-baea-20d61071432f","added_by":"auto","created_at":"2025-12-30 10:02:22","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":4099287,"visible":true,"origin":"","legend":"\u003cp\u003eMRS-Q assessment of included studies\u003c/p\u003e","description":"","filename":"Figure4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/28137caf7364eefa2d0ce1f7.jpeg"},{"id":99317648,"identity":"ce3abc99-99a3-49d3-9206-6508b34b292b","added_by":"auto","created_at":"2025-12-31 16:30:31","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":5447521,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic representation demonstrating the role of GABA in basal ganglia thalamocortical and cerebello thalamocortical networks. A. Normal connectivity B. Parkinson’s disease.\u003c/p\u003e","description":"","filename":"Figure5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/05f17c7a8045f587d6ac3deb.jpeg"},{"id":99324041,"identity":"15edc8dc-dc0c-42f6-88b8-f2e86d2d39b3","added_by":"auto","created_at":"2025-12-31 16:46:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":21071237,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/40b45ef4-62f2-4095-b4c3-3353dad43ded.pdf"},{"id":99317903,"identity":"18d6786e-e4bd-4ee0-8864-c379b255da4b","added_by":"auto","created_at":"2025-12-31 16:30:55","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":21076,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/4d0f8d63f2ec66ac8795e364.docx"},{"id":99320237,"identity":"799812a3-873c-4340-bd77-b5c871a59132","added_by":"auto","created_at":"2025-12-31 16:38:25","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":21129,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/e51d4d69b33cab1f51bdf033.docx"},{"id":99223882,"identity":"fc3d087d-72ab-424b-9317-00612547461d","added_by":"auto","created_at":"2025-12-30 10:02:22","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":24962,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8407027/v1/c5da70f39f7ce81dffaa1517.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"GABAergic dysfunction in Parkinson’s disease: Insights from in vivo proton magnetic resonance spectroscopy","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eParkinson\u0026rsquo;s disease (PD) is a neurodegenerative disorder characterised by bradykinesia, rigidity, rest tremor and postural instability\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e and non-motor symptoms (NMS) such as sleep disturbances, olfactory dysfunction, mood disturbances, cognitive deficits, autonomic dysfunction, etc\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Dopaminergic loss in the substantia nigra pars compacta (SNpc) and widespread accumulation of α-synuclein is considered pathognomonic in PD\u003csup\u003e4\u003c/sup\u003e, with dopamine replacement therapy being the therapeutic mainstay. However, this dopaminergic-centric view has been challenged by accumulating evidence highlighting the role of other neurotransmitter systems beyond the nigrostriatal dopaminergic pathway. Primary evidence of this arises from the fact that unlike bradykinesia and rigidity, tremor does not correlate with striatal dopaminergic depletion\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e; rather serotonergic\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, noradrenergic\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e abnormalities, and pallidal rather than striatal dopaminergic depletion\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e are suggested. The role of other neurotransmitter systems is further exemplified by NMS in PD, for instance serotonergic dysfunction in depression\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, noradrenergic alterations in autonomic dysfunction\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, cholinergic deficits in cognitive impairment\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, etc.\u003c/p\u003e \u003cp\u003eGamma-aminobutyric acid (GABA) is the most prevalent inhibitory neurotransmitter which intricately regulates excitatory-inhibitory balance across the basal ganglia thalamocortical (BGTC) and cerebello thalamocortical (CTC) networks\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Dopaminergic neurons from the SNpc exert modulatory effects in the BGTC, i.e., via direct and indirect pathways using GABA from the inhibitory projection neurons\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, with disruptions contributing to motor and non-motor in PD\u003csup\u003e17\u003c/sup\u003e. Non-dopaminergic systems interact with GABAergic and dopaminergic pathways to create a complex excitatory-inhibitory balance that perhaps form the basis for the diverse profile of symptoms observed in PD\u003csup\u003e18\u003c/sup\u003e. Understanding the alterations of GABA in PD and its influence on PD symptomatology is crucial to develop a comprehensive understanding of the pathophysiology of PD and open avenues for newer therapeutic strategies. Attempts have been made to indirectly evaluate synaptic GABAergic and glutamatergic activity in PD using transcranial magnetic stimulation (TMS), particularly the measures of short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI) and cortical silent period (CSP)\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. These studies have consistently reported reduced LICI (mediated by GABA\u003csub\u003eB\u003c/sub\u003e), altered SICI-LICI interactions and occasionally reduced SICI in PD, supporting the concept of GABAergic dysfunction in PD\u003csup\u003e20,21\u003c/sup\u003e .\u003c/p\u003e \u003cp\u003eMagnetic resonance spectroscopy (MRS) is a non-invasive imaging modality that permits in-vivo quantification of brain metabolite concentrations. Although proton MRS (\u003csup\u003e1\u003c/sup\u003eH MRS) is routinely performed, GABA spectroscopy is challenging owing to its low concentrations and more importantly spectral overlaps with more abundant metabolites such as creatine\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. To mitigate this, spectral editing techniques, such as the MEscher-GArwood Point RESolved Spectroscopy (MEGA-PRESS)\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e or MEGA-semi Localized Adiabatic SElective Refocusing (MEGA-semiLASER) which employ frequency-selective editing pulses to isolate the GABA signal at 3.0ppm\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e or alternatively short echo-time STimulated Echo Acquisition Mode (STEAM) sequence at ultra-high field (\u0026gt;\u0026thinsp;3T) can be used. Several studies have attempted to quantify GABA in PD and ascertain correlations between symptoms, drug responsiveness, etc. However, it is difficult to develop a comprehensive understanding of the influence of GABA owing to significant variability on several fronts including but not restricted to patient selection, magnetic field strength, MRS localization sequence, voxel location, voxel size, quantification method, etc.\u003c/p\u003e \u003cp\u003eThe current study aims to systematically review the existing literature on GABAergic alterations in PD as quantified by \u003csup\u003e1\u003c/sup\u003eH MRS with a focus on ascertaining the influence of GABA on motor and non-motor symptoms, motor subtypes, effect of medication status and methodological variations across studies.\u003c/p\u003e"},{"header":"2. Methodology","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Search strategy\u003c/h2\u003e \u003cp\u003eThis review was conducted in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement (PRISMA)\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. A systematic search of databases (PubMed, Scopus) was carried out in April 2025 using the Boolean phrase - (\"magnetic resonance\" AND \"spectroscopy\") AND (\"parkinson's disease\" OR \"parkinsons disease\u0026rdquo; OR \u0026ldquo;Parkinson disease\") AND (\"GABA\" OR \"gamma-aminobutyric acid\" OR \"gamma-amino-butyric acid\" OR\" γ-Amino-butyric acid\" OR \"γ-aminobutyric acid\"). Reference lists of included studies were also searched to ensure key studies were not overlooked.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Criteria for inclusion and exclusion\u003c/h2\u003e \u003cp\u003eStudies that met the following criteria were included (1) Population: Human subjects (2) Disease: PD (3) MRS method: Field strength of 3T or higher, pulse sequences established to measure GABA (MEGA-PRESS, STEAM, etc), single-voxel MRS.\u003c/p\u003e \u003cp\u003eExcept review articles, and studies investigating GABA spectroscopy in animal models of PD, all other study designs were considered. Only articles written in English were considered.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Study selection and data extraction process\u003c/h2\u003e \u003cp\u003eAll articles obtained from PubMed and Scopus were screened and duplicates were excluded. Following this, titles and abstracts were assessed to establish eligibility. When the titles and abstract were inconclusive, the full texts were reviewed. Full texts of all eligible articles were obtained and data was extracted. All screening and data extraction was carried out by the first author, SP.\u003c/p\u003e \u003cp\u003eData was extracted based on suggestions in the Minimum Reporting Standards for in vivo Magnetic Resonance Spectroscopy (MRSinMRS) guidelines\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003e(1) Bibliometric data\u003c/strong\u003e \u003cp\u003eAuthors, year of publication\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003e(2) Demographic and clinical details\u003c/strong\u003e \u003cp\u003eSample size, gender, age at assessment, duration of illness, Movement Disorder Society-Unified Parkinson\u0026rsquo;s Disease Rating Scale part III (MDS-UPDRS-III) or UPDRS-III OFF and ON state scores, and levodopa equivalent daily dose (LEDD);\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003e(3) Hardware and acquisition details\u003c/em\u003e: Field strength, manufacturer, model, radiofrequency (RF) coil, medication state while scanning (OFF or ON), pulse sequence, location of voxel-of-interest (VOI), VOI size, repetition time (TR), echo time (TE), water suppression method;\u003c/p\u003e \u003cp\u003e \u003cstrong\u003e(4) Data quality metrics\u003c/strong\u003e \u003cp\u003eSignal-to-noise ratio (SNR), line width (LW), quantification precision (Cramer-Rao minimum lower bounds (CRLB), GABA fit error).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003e(5) Data analysis\u003c/strong\u003e \u003cp\u003eSoftware, output measures, quantification reference, GABA/GABA\u0026thinsp;+\u0026thinsp;levels.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eOne of the limitations of spectral editing at 3T is that the GABA signal is contaminated with macromolecules\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. This is referred to as GABA+, and is commonly reported in literature. In this review, both GABA and GABA\u0026thinsp;+\u0026thinsp;have been considered and interpreted similarly.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Quality assessment\u003c/h2\u003e \u003cp\u003eQuality of included studies was evaluated using MRS-Q (v1.1, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://doi.org/10.17605/OSF.IO/8S7J9\u003c/span\u003e\u003cspan address=\"10.17605/OSF.IO/8S7J9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) - a quality appraisal tool specifically designed for the systematic review of MRS studies\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eThe initial search returned 114 studies (Figure-1). After removal of duplicates and preliminary screening, 66 studies were eligible for abstract screening. Forty-four studies were excluded based on exclusion criteria of animal studies, other movement disorders (not PD), review articles, or magnetic resonance spectroscopic imaging (MRSI), i.e., not single voxel spectroscopy. Finally, a total of 22 articles were included in this systematic review\u003csup\u003e\u003cspan additionalcitationids=\"CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38 CR39 CR40 CR41 CR42 CR43 CR44 CR45 CR46 CR47 CR48 CR49\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Demographic and clinical characteristics\u003c/h2\u003e \u003cp\u003eAll except one study\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e included patients with PD and HC, with the sample sizes ranging from 10\u0026ndash;60 subjects per group, and most subjects were between the ages of 50\u0026ndash;70 (Table-1). With the exception of one study\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e, all others had a relatively equal gender distribution .\u003c/p\u003e \u003cp\u003eDuration of illness ranged from early PD (\u0026lt;\u0026thinsp;1 year) to advanced PD (\u0026gt;\u0026thinsp;10 years). Disease severity was reported by 19 studies, using with the UPDRS-III(n\u0026thinsp;=\u0026thinsp;12)\u003csup\u003e30,33,34,36,38,40\u0026ndash;43,45,51\u003c/sup\u003e and MDS-UPDRS III(n\u0026thinsp;=\u0026thinsp;6)\u003csup\u003e32,35,37,39,44,46,50\u003c/sup\u003e (total UPDRS-III values not reported by van Nuland et al\u003csup\u003e39\u003c/sup\u003e). Of this only OFF state scores (n\u0026thinsp;=\u0026thinsp;9)\u003csup\u003e30,31,34,36,37,41,43,45,50\u003c/sup\u003e, ON state scores (n\u0026thinsp;=\u0026thinsp;4)\u003csup\u003e32,35,38,40\u003c/sup\u003e, and both OFF and ON scores(n\u0026thinsp;=\u0026thinsp;4)\u003csup\u003e42,44,46,48\u003c/sup\u003e, where the ON state assessment by Trujillo et al\u003csup\u003e46\u003c/sup\u003e was with only dopamine agonists (DA). The mean of OFF state scores ranged from 13.6-55.9\u003csup\u003e36,40\u003c/sup\u003e, and ON state scores-13.8-27.95\u003csup\u003e32,40\u003c/sup\u003e. The minimum mean ON score is higher than the minimum OFF state score as they were different studies and did not report scores for both states. Levodopa equivalent daily dose (LEDD) was reported by ten studies.\u003c/p\u003e \u003cp\u003eNine studies included subgroups with motor subtypes\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e, additional NMS\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e,\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e,\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e, altered levodopa responsiveness to tremor\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e or intervention-deep brain stimulation (DBS)\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. Gong et al\u003csup\u003e34\u003c/sup\u003e, included tremor dominant PD (TDPD), and the postural instability and gait disturbance (PIGD) variant, while Pesch et al\u003csup\u003e37\u003c/sup\u003e included akinetic-rigid and the mixed subtypes. PD with somatic syndrome disorder (SSD) was evaluated in two studies\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e, PD with impulse control disorder (ICD)\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e in one and PD with depression in one\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e. Patients with dopamine resistant tremor were evaluated by van Nuland et al\u003csup\u003e39\u003c/sup\u003e, and patients pre and post DBS were evaluated by O\u0026rsquo;Gormon Tuura et al\u003csup\u003e35\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Acquisition\u003c/h2\u003e \u003cp\u003eMagnetic field strengths included \u0026minus;\u0026thinsp;3 Tesla (T) (n\u0026thinsp;=\u0026thinsp;19), 4T scanner (n\u0026thinsp;=\u0026thinsp;1)\u003csup\u003e29\u003c/sup\u003e, and 7T scanner (n\u0026thinsp;=\u0026thinsp;2)\u003csup\u003e30,44\u003c/sup\u003e (Table-2). Majority used a standard 32 channel receive coil or 8 channel radiofrequency (RF) coil, while 16 channel and dual tuned \u003csup\u003e1\u003c/sup\u003eH/\u003csup\u003e31\u003c/sup\u003eP transmit and receive coils were used in single studies. An early study by Oz et al, used a transverse electromagnetic (TEM) volume coil\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. MEGA-PRESS was the most common sequence used to measure GABA, followed by STEAM in 3 studies\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. All MEGA-PRESS studies used a TE of 68ms, except 2 with TE\u0026thinsp;=\u0026thinsp;69ms\u003csup\u003e32,35\u003c/sup\u003e, and 1 with TE\u0026thinsp;=\u0026thinsp;120ms\u003csup\u003e47\u003c/sup\u003e. Acquisitions ranged from 128\u0026ndash;256 for MEGA-PRESS voxels.\u003c/p\u003e \u003cp\u003eVoxels were placed in a total of 14 regions (Table-2) -thalamus(n\u0026thinsp;=\u0026thinsp;5), basal ganglia/striatum(n\u0026thinsp;=\u0026thinsp;5), SN (n\u0026thinsp;=\u0026thinsp;3), occipital cortex, motor cortex (MC), putamen, medial prefrontal cortex (mPFC) \u0026ndash; 2 studies each, dorsolateral prefrontal cortex (DLPFC), sensory motor cortex (SMC), PFC, midbrain, brainstem, pons, cerebellum- 1 study each. The voxel sizes varied between location, and only 5 studies\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e reported volumes above or at the recommended 27mL for MEGA-PRESS\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Details pertaining to water suppression were reported in 13 studies, and VAriable Power radiofrequency pulses with Optimized Relaxation (VAPOR)(n\u0026thinsp;=\u0026thinsp;7) was the most common method followed by chemical shift selective saturation (CHESS)(n\u0026thinsp;=\u0026thinsp;4) and Multiple optimizations insensitive suppression train (MOIST)(n\u0026thinsp;=\u0026thinsp;2). Quality metrics in the form of LW, FWHM, SNR or CRLB were reported in 14 studies.\u003c/p\u003e \u003cp\u003eMedication state during acquisition of spectroscopy data was reported in all except one study\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. Most acquired in the OFF state (n\u0026thinsp;=\u0026thinsp;13), followed by ON state(n\u0026thinsp;=\u0026thinsp;4), and both OFF and ON state data(n\u0026thinsp;=\u0026thinsp;4).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Data analysis\u003c/h2\u003e \u003cp\u003e Edited spectral data was processed using Gannet(n\u0026thinsp;=\u0026thinsp;12), followed by Linear combination of MODEL spectra (LCModel) (n\u0026thinsp;=\u0026thinsp;4), Gannet\u0026thinsp;+\u0026thinsp;Advanced method for accurate, robust, and efficient spectral editing (AMARES)(n\u0026thinsp;=\u0026thinsp;1), Free induction decay-Appliance (FID-A)\u0026thinsp;+\u0026thinsp;LCModel(n\u0026thinsp;=\u0026thinsp;1), and KALPANA(n\u0026thinsp;=\u0026thinsp;1).\u003c/p\u003e \u003cp\u003eGABA+, i.e., combined signal contributions of GABA, macromolecules and homocarnisine was reported by most studies (n\u0026thinsp;=\u0026thinsp;15), while GABA, i.e., without macromolecules and homocarnisine, was reported by the rest (n\u0026thinsp;=\u0026thinsp;7). The quantification reference for GABA varied, wherein most reported GABA using water(n\u0026thinsp;=\u0026thinsp;11), followed by total creatine (tCr)(n\u0026thinsp;=\u0026thinsp;7). One study reported both methods tCr and water\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e, and only one study reported absolute GABA\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.4. Results of GABA spectroscopy\u003c/h2\u003e \u003cp\u003eThere were numerous domains of variability between studies, ranging from motor subtypes, NMS, medication states and voxel locations (Table-3, Figure-2, Figure-3). The results are categorised to reflect each domain.\u003c/p\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003e3.4.1. Difference between PD and HC based on location of voxel\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eThalamus\u003c/strong\u003e \u003cp\u003eThalamic alterations were evaluated by 4 studies\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e. Dharmadhikari et al\u003csup\u003e31\u003c/sup\u003e and van Nuland et al\u003csup\u003e39\u003c/sup\u003e evaluated PD in the OFF state and reported contradictory results \u0026ndash; lower GABA in PD, and no difference. No difference was reported between PD-ON state and HC by all three studies that performed this comparison\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eBasal ganglia, striatum\u003c/strong\u003e \u003cp\u003eSignificant variations were observed in results reported for variations of GABA between PD OFF state and HC. Of the 5 studies, 2 reported higher GABA in PD\u003csup\u003e32,35\u003c/sup\u003e, while 2 reported lower GABA\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e and 1 reported no difference\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003ePutamen\u003c/strong\u003e \u003cp\u003eEmir et al\u003csup\u003e30\u003c/sup\u003e and Seger et al\u003csup\u003e44\u003c/sup\u003e reported GABA in PD-OFF and PD-ON states respectively. In comparison to HC, both reported higher levels of GABA in PD.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003ePrefrontal cortex\u003c/strong\u003e \u003cp\u003eO\u0026rsquo;Gormon Tuura found no difference between PD-OFF state and HC\u003csup\u003e32\u003c/sup\u003e.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eMedial prefrontal cortex\u003c/strong\u003e \u003cp\u003eDelli Pizzi et al, reported no difference between PD-OFF and HC\u003csup\u003e40,45\u003c/sup\u003e\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eDorsolateral prefrontal cortex\u003c/strong\u003e \u003cp\u003ePD-OFF state was found to have a lower GABA level in comparison to HC\u003csup\u003e41\u003c/sup\u003e.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eMotor cortex\u003c/strong\u003e \u003cp\u003eIn both the OFF and ON state, van Nuland et al, reported no difference between patients with PD and HC\u003csup\u003e39\u003c/sup\u003e.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eSensory motor cortex\u003c/strong\u003e \u003cp\u003eTian et al, reported lower GABA in PD-OFF state compared to HC\u003csup\u003e49\u003c/sup\u003e.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eOccipital cortex\u003c/strong\u003e \u003cp\u003eNo difference was found between patients PD-OFF\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e or PD-ON\u003csup\u003e36,39\u003c/sup\u003e compared to HC .\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCerebellum\u003c/strong\u003e \u003cp\u003ePiras et al, found no difference between PD-ON state and HC for either right cerebellar hemisphere, left cerebellar hemisphere or the mean cerebellar GABA level\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eMidbrain\u003c/strong\u003e \u003cp\u003eNo difference was reported between PD-OFF state and HC\u003csup\u003e50\u003c/sup\u003e.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eBrainstem\u003c/strong\u003e \u003cp\u003eSong et al, consistently reported a lower brainstem GABA in PD-Off state compared to HC\u003csup\u003e42,43\u003c/sup\u003e, with no difference between PD-ON state and HC\u003csup\u003e42\u003c/sup\u003e.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003ePons\u003c/strong\u003e \u003cp\u003eHigher pontine GABA was reported by Emir et al, in PD-OFF state\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eSubstantia nigra\u003c/strong\u003e \u003cp\u003eBoth Oz et al, and Emir et al reported no difference between PD-ON state and HC\u003csup\u003e29,30\u003c/sup\u003e. Shukla et al, also reported a similar observation, however, the medication state during acquisition was uncertain\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003e3.4.2. GABA in relation to motor symptoms of PD\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eMotor symptoms\u003c/strong\u003e \u003cp\u003eGong et al, evaluated the TDPD and PIGD variants and reported distinct GABAergic profiles - TDPD had lower basal ganglia GABA levels than PIGD\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. GABA and UPDRS scores were inversely correlated in the complete PD group, and the PIGD subtype. No correlation was observed for TDPD.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eAxial symptoms\u003c/strong\u003e \u003cp\u003eBasal ganglia GABA positively correlated with gait disturbance, gait summary scores, and difficulty standing up from a chair in akinetic-rigid PD\u003csup\u003e32\u003c/sup\u003e. PFC GABA negatively correlated with postural stability in akinetic-rigid PD.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eDopamine-resistant tremor\u003c/strong\u003e \u003cp\u003eVan Nuland et al, evaluated thalamic, MC, occipital cortex GABA in dopamine-resistant and dopamine-responsive PD tremor and found no influence of clinical phenotype\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. MC GABA inversely correlated with OFF and ON rigidity and tremor scores. Negative correlations were reported between disease severity and GABA in TDPD.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003e3.4.3. GABA in relation to non-motor symptoms of PD\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eDepression\u003c/strong\u003e \u003cp\u003eLiu et al, reported higher mPFC GABA and equal thalamic GABA in PD with depression compared to PD without depression\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e. However, no correlations were observed between GABA levels and Hamilton depression rating scale (HAM-D) and Hamilton Anxiety Rating Scale (HAM-A).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eSomatic symptom disorder\u003c/strong\u003e \u003cp\u003eA higher mPFC GABA was consistently reported in PD\u0026thinsp;+\u0026thinsp;SSD in comparison to PD- SSD and HC\u003csup\u003e40,45\u003c/sup\u003e. Similar observations were reported in subjects of SSD, suggestive that higher GABA is an SSD trait rather than associated with PD.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eImpulse control disorders\u003c/strong\u003e \u003cp\u003ePatients with PD\u0026thinsp;+\u0026thinsp;ICD were had lower thalamic GABA and equal MC GABA in comparison to PD-ICD\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. Difference between OFF and ON DA thalamic GABA (∆GABA) significantly correlated with impulsivity scores as measured by Questionnaire for Impulsive-Compulsive Disorders in Parkinson\u0026rsquo;s Disease-Rating Scale.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eVisual hallucinations\u003c/strong\u003e \u003cp\u003eFirbank et al, reported lower occipital cortex GABA in PD with visual hallucinations (VH)\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. No correlations were observed between GABA and neuropsychiatric inventory hallucination score but positive correlations were reported between GABA and visual acuity.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCognition\u003c/strong\u003e \u003cp\u003ePiras et al, reported positive correlations between mean cerebellar GABA and Stroop Word-Color Test short form error interference effect (SWCT- IE-E) and Stroop Word-Color Test short form time interference effect (SWCT- IE-T)\u003csup\u003e38\u003c/sup\u003e. Hemispheric differences were reported with the left hemisphere positively correlating with the SWCT-IE-E, and right hemisphere negatively correlating with SWCT-IE-T.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eNMS severity score\u003c/strong\u003e \u003cp\u003eSong et al, reported no correlations between brainstem GABA and total NMS severity questionnaire scores, or individual domains\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003e3.4.4. GABA in relation to medication/ surgical intervention (DBS)\u003c/h2\u003e \u003cp\u003eThree studies reported a direct comparison of OFF and ON state GABA levels\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e. Liu et al reported no difference between mPFC OFF and ON GABA\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e, and Song et al reported higher ON state brainstem GABA\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. Van Nuland et al, reported no differences between thalamic, MC and occipital cortex OFF and ON state GABA levels\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. No correlations were reported by Gong et al, between levodopa responsiveness and ∆GABA\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. Seger et al, reported inverse correlations between ON state putaminal GABA with response to dopaminergic treatment.\u003c/p\u003e \u003cp\u003eO\u0026rsquo;Gormon Tuura et al attempted to evaluate if pre-DBS basal ganglia and striatal GABA could predict response to DBS\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. GABA was considered to be a significant predictor of outcome however; this correlation was lost after removing an outlier.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e3.5. Quality assessment\u003c/h2\u003e \u003cp\u003eQuality assessment was based on MRS-Q\u003csup\u003e28\u003c/sup\u003e (Figure-4). High quality studies were based on Domain 2 and 3, i.e., sequence and scan parameters. Only Firbank et al, and Tian et al met required parameters\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e. A high-quality sequence was used in 86.3%(n\u0026thinsp;=\u0026thinsp;19), 63.6%(n\u0026thinsp;=\u0026thinsp;14) had the required number of averages, and only 22.7%(n\u0026thinsp;=\u0026thinsp;5) had adequate a voxel size. 77.27%(n\u0026thinsp;=\u0026thinsp;17) had an appropriate TE, however, 4 studies that did not comply used a different sequence. These criteria were recently established and several of the included studies are almost up to 2 decades old. Moreover, lack of reporting does not imply poor quality.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe current systematic review examined the role of GABA in PD as measured by single-voxel GABA spectroscopy. Across 22 included studies, a range of patterns of GABAergic alterations were noted in PD which suggest a multifaceted, region specific dysregulation of GABA related neurotransmission that extends the concepts of PD pathogenesis beyond the traditionally implicated canonical dopaminergic framework. Alterations in levels of GABA (or GABA+) were reported across numerous cortical and subcortical regions, with either increase, decrease of no change in comparison to controls. This heterogeneity reflects the complex neurochemical landscape in PD. Although methodological inconsistencies limit the possibility of carrying out a meta-analysis, patterns do emerge. Collectively, the observations provide evidence of GABAergic dysfunction in PD that is intricately associated with motor and non-motor symptoms. The need for standardisation from clinical and technical aspects of spectroscopy acquisition was also revealed.\u003c/p\u003e \u003cp\u003eDirect and indirect pathways, are the primary networks related to motor functioning which are tightly linked to PD pathogenesis and highly reliant on GABA as the key modulatory neurotransmitter(Figure-5). Dopamine is responsible for modulation of these pathways via excitatory D1 receptors - direct(facilitatory) pathway, and inhibitory D2 receptors -indirect(inhibitory) pathway\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Degeneration of dopaminergic neurons and subsequent dopaminergic deficit leads to an imbalance, producing excessive inhibition of the ventral lateral thalamic nucleus and in turn reduced facilitation of the MC. This model explains rigidity and bradykinesia; however, it does not necessarily explain tremor\u003csup\u003e\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e. Rest tremor is suggested to arise from a tremor network comprised of the basal ganglia-thalamocortical, and cerebello-thalamocortical circuit\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e. The \u0026lsquo;dimmer-switch\u0026rsquo; hypothesis suggests the GPi triggers tremor activity, and the cerebello-thalamocortical circuit modulates tremor amplitude\u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e. Thalamocortical communication is modulated by dopamine-dependent thalamic self-inhibition of the ventral intermediate nucleus (VIM) by the thalamic reticulate nucleus via D4 receptors\u003csup\u003e\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e. Dyskinesia is also associated with GABA wherein, loss of dopaminergic neurons leads to a reduction in postsynaptic activation of GABA receptors resulting in hyperexcitability of striatal neurons and subsequent dyskinesia\u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBeyond modulation, GABA also has a neuroprotective role. The GABA collapse hypothesis suggests that neurons are protected from calcium-based neurotoxicity by GABAergic inputs\u003csup\u003e\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e. Dopaminergic neurons are particularly affected owing to their high energy requirements and dependence on slow calcium-based pacemaker activity\u003csup\u003e\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e. A reduction in GABA is known to dysregulate calcium voltage gated channels leading to calcium related excitotoxicity and oxidative stress which can lead to ɑ-synuclein aggregation and further injury to dopaminergic neurons\u003csup\u003e\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e. Alterations in GABA metabolism, i.e., synthesis, reuptake, or changes in GABA receptor expression can also contribute to dysfunction. For instance, glutamic acid decarboxylase (GAD) is the main enzyme in GABA synthesis for conversion of glutamate to GABA, and a reduction of GAD expression in the PFC has been reported\u003csup\u003e\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e. It is imperative to understand that GABA is not restricted to only the above-described networks, rather GABAergic neurons are widespread including other critical cortical and subcortical networks. Alterations of GABA in these areas may significantly contribute toward the development of NMS in PD\u003csup\u003e17\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIt is evident that GABA plays a crucial physiological role and alterations may contribute to PD symptomatology. However, previous studies evaluating GABA in PD present a very heterogenous image of alterations, with gross variations in results across studies, regions of interest and clinical phenotypes (Figure-2, Figure-3). Hence it is challenging to provide a definite response regarding GABA alterations in PD and if MRS consistently replicates concepts put forth by classical models of PD pathogenesis. For instance, based on the reviewed studies, significant inter-regional and intra-regional variability was observed for GABA in PD-OFF state. With the exception of mPFC\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e, brainstem\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e and SN\u003csup\u003e29,30\u003c/sup\u003e, where no difference was observed, no other voxel with multiple studies reported consistent results. Within the basal ganglia which is the primary area of interest to PD, significant heterogeneity exists \u0026ndash; with equal observations of high\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e, equal\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e and low levels\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e of GABA in PD.\u003c/p\u003e \u003cp\u003eIn this context, MRS sensitivity to GABA varies between compartments, and has reduced sensitivity in subcortical structures. MRS is particularly sensitive to extracellular, unbound GABA which is involved in tonic inhibition\u003csup\u003e\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e,\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e. Extracellular GABA depends on accumulation of GABA spill over from synaptic transmission along with a small percentage of GABA that is released by local glia cells\u003csup\u003e\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e,\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u003c/sup\u003e. Intracellular GABA is present in limited quantities as it is converted from glutamate on demand at the axon terminal, hence contributes minimally to the spectroscopy signal \u003csup\u003e\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e,\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u003c/sup\u003e. Furthermore, it is imperative to understand that the thalamus is not a single function, single connection structure. Rather a hub of afferent and efferent connections with varied functionality of each nuclei. This is relevant in context of evaluating motor symptoms in PD, wherein the ventral oralis anterior, i.e., ventral lateral nucleus is linked with the BGTC, whereas the VIM is linked with the CTC. It is plausible that results obtained from thalamic voxels may not be specific, and different influences and functions may nullify specific results. In the same vein, it is also pertinent to state that a larger voxel size is a methodological limitation of GABA editing spectroscopy owing to which specificity may be lost in attempting to evaluate brain regions, and significant overlaps exist, for e.g., the basal ganglia voxel is very large, and covers the putamen, globus pallidus externa and GPi, and each region probably has specific changes which cannot be evaluated.\u003c/p\u003e \u003cp\u003eIn contrast, almost all studies comparing patients in the ON state to HC consistently reported equal levels of GABA irrespective of region of interest. Only a single study reported higher putaminal ON state GABA compared to HC\u003csup\u003e44\u003c/sup\u003e. This is a crucial observation as it highlights levodopa induced normalisation of neurotransmitters in PD. The elevated putaminal GABA may be due to striatal GABAergic neurons, rather than GABAergic afferents, as primary striatal afferents are dopaminergic and glutamatergic, whereas medium sized GABAergic spiny neurons are the predominant cells in the striatum. Animal models suggest that nigrostriatal pathway lesions lead to elevated striatal GABA, and this may be observed in PD\u003csup\u003e66\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eVery few studies evaluated medication induced variations, and majority reported no differences. While intriguing, it is plausible and implores further evaluation of directionality of change, i.e., toward or away from normal. van Nuland et al\u003csup\u003e39\u003c/sup\u003e, evaluated this in the thalamus, motor and occipital cortex, however, they reported no influence of disease subtype or medication state. In contrast, Song et al\u003csup\u003e42\u003c/sup\u003e, reported lower brain stem GABA in PD-OFF state compared to HC and PD-ON state, suggesting levodopa induced normalisation of GABA. Numerous factors can affect observations of the impact of levodopa between and within studies. These can include dose of levodopa, time point in the ON state when data was acquired, individual variations in pharmacodynamics and pharmacokinetics of levodopa, stage of disease, dopamine reserve, etc.\u003c/p\u003e \u003cp\u003eThe exploration of GABAergic influences is inadequately and inconsistently explored. However, there are relevant observations within the limited studies. For instance, Gong et al, compared TDPD and PIGD PD\u003csup\u003e34\u003c/sup\u003e. Their observation of higher basal ganglia GABA in PIGD supports the classical model of PD pathogenesis, as it indicates the possibility of higher basal ganglia inhibition producing reduced excitation of the MC and subsequent reduction in movement. Axial symptoms of PD are often poorly responsive to dopaminergic treatment, and indicates the possibility of non-dopaminergic influences. The basal ganglia is a crucial hub for sensorimotor integration and descending projections toward the midbrain play a role in postural control and gait\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. O\u0026rsquo;Gormon Tuura et al reported a positive association between basal ganglia GABA and gait disturbance scores in akinetic-rigid PD, and PFC GABA and postural stability\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. However, they did not directly compare akinetic-rigid PD and TDPD. Only van Nuland et al\u003csup\u003e39\u003c/sup\u003e, focused on PD tremor and implications of dopaminergic medication. They reported an inverse relationship between MC GABA and tremor, suggesting that a reduction in cortical GABA produces higher tremor severity which is in line with current concepts and role of the CTC in tremor modulation. An attempt was also made to evaluate if basal ganglia GABA could predict response to subthalamic nucleus DBS. The study had limitations in sample size and moreover, the observed results of GABA being a good predictor were nullified after removal of a significant outlier\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. However, this is an interesting concept and deserves to be evaluated by future studies.\u003c/p\u003e \u003cp\u003eSeveral studies have focused on evaluating NMS in PD as these extend beyond the conventional understanding of PD pathogenesis. The motor network is one of many roles of the basal ganglia as it is well established that limbic and associative/cognitive loops also exist\u003csup\u003e\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e,\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u003c/sup\u003e. This implies that dopaminergic deficit or even excess can strongly influence the development of NMS. Almost all studies evaluating GABA and NMS have focused on neuropsychiatric domain of NMS\u0026ndash;depression, SSD, ICD, hallucinations, and cognition. Perhaps this is supported by the corpus of previous studies evaluating spectroscopic alterations in psychiatric disorders\u003csup\u003e\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e,\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e\u003c/sup\u003e. The presence of existing information helps form parallels between pure psychiatric disorders and the psychiatric NMS seen in PD, aiding in ascertaining the basis for NMS.\u003c/p\u003e \u003cp\u003eDepression occurs secondary to an imbalance in excitation and inhibition in the PFC secondary to altered inhibitory transmission to key glutamatergic regions\u003csup\u003e\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e\u003c/sup\u003e leading to suppressed excitatory neurotransmission. This observation was also made by Liu et al\u003csup\u003e48\u003c/sup\u003e who reported higher mPFC GABA in PD depression. The study designs by Delli Pizzi et al\u003csup\u003e40,45\u003c/sup\u003e to evaluate PD with SSD is ideal to dissect the exact changes. They included four groups \u0026ndash; PD with SSD, PD without SSD, pure SSD and HC. These comparisons revealed that higher mPFC GABA was seen in both PD with SSD and pure SSD, indicating that higher GABA was a SSD trait rather than associated with PD. Such a design would also be helpful to understand other crucial NMS like ICD and psychosis which often tend to be medication related. Trujillo et al\u003csup\u003e46\u003c/sup\u003e, reported a reduction in thalamic GABA in PD with ICD, further substantiating the complex regional interplay and impaired inhibitory mechanisms in thalamocortical circuits. Psychosis in PD is an important NMS, and Firbank et al suggested that low GABA levels may predispose development of hallucinations, however, the occurrence of visual hallucinations is controlled by other factors such as visual environment and attention\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. These observations open therapeutic avenues for attempting to use other groups of medication. Interestingly, cognitive alterations were evaluated in relation to cerebellar GABA levels by Piras et al\u003csup\u003e38\u003c/sup\u003e, and significant role of GABA in producing decreased efficiency in filtering task-irrelevant information. Although this is not the traditional choice for studying cognition, it significantly expands the scope of regions associated with cognition.\u003c/p\u003e \u003cp\u003eThere are several reasons to explain the heterogeneity of results across the observed studies. From a methodological perspective, there was variability in field strengths, pulse sequences, voxel location, voxel size, quantification reference, and methods of processing. Majority of the evaluated studies used MEGA-PRESS, however, this sequence although robust has limitations due to sensitivity to motion, frequency shifts and a large chemical shift displacement error (CSDE)\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. This may impede the specificity of data acquired from the voxel, particularly in crowded subcortical area of the basal ganglia and thalamus. Several studies have reported GABA/tCr ratios however there is lack of consensus about the stability of tCr concentrations and if it is truly unaltered in patients with PD for use as an internal reference. Altered tCr levels have been reported in the PD basal ganglia but not in other regions, and some studies report altered level following administration of levodopa\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e\u003c/sup\u003e. Hence, it may be inappropriate to use tCr as a reference especially for the basal ganglia. Perhaps, studies should consider reporting absolute values to permit better interpretation and uniformity. This is emphasised by the observation that within voxels similar observations of GABA alterations were often reported by the same group who probably followed relatively uniform methods. For e.g. both observations of high GABA in the basal ganglia were by the same group\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e, or even the mPFC\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e, brainstem\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e and SN\u003csup\u003e29,30\u003c/sup\u003e. Another confounder in interpretation is the interchangeable use of GABA\u0026thinsp;+\u0026thinsp;and GABA. Both measures have different implications and authors should be careful in stating whether the reported GABA concentration includes macromolecules and homocarnosine or if the used TE permitted the measurement of GABA rather than GABA+. Finally, lack of complete reporting of details further confounds the problem. Future studies should consider including details suggested in the MRSinMRS guidelines\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e, this would permit replication and interpretation of studies.\u003c/p\u003e \u003cp\u003eConsidering the fact that motor subtypes, NMS and medication can contribute to specific changes in GABA levels, clinical phenotyping is critical to outcomes. Numerous studies reported no difference between PD and HC, however it is possible that the admixture of multiple phenotypes in a single PD group led to nullifying of specific alterations in comparison to HC. These may have become evident if patient selection and groups were more specific. The dosage of levodopa used to induce an ON state for scanning was also not clearly described in most studies. It is evident that levodopa may have a strong modulatory influence and variations in dosing across subjects even within the same study will lead to variations. In addition, use of the other medication, caffeine, other stimulants, was not consistently reported and this can often confound results. Perhaps similar to the MRSinMRS guidelines, clinical reporting guidelines are also required to ensure transparency and increase interpretability.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eGABA plays a significant role in balancing numerous processes. At a neuronal level it prevents calcium related neurotoxicity, and at a circuit-based level it has the significant role in preventing dysfunctional motor hyperactivity. GABA plays a definite role in the pathogenesis of PD, and complex, distinct regional alterations contribute to the development of motor and non-motor symptoms in PD.\u003c/p\u003e \u003cp\u003eThis area of research has immense potential and there is scope for significant improvement and exploration in future studies. Methodological uniformity and upgradation to more optimised sequences with low CSDE such as MEGA-semiLASER or scanning at higher field strengths may yield more precise information. Spectroscopy should be integrated with other methods of evaluating GABA metabolism such as \u003csup\u003e11\u003c/sup\u003eC-Flumazenil imaging, and a bimodal approach using TMS. Considering the possibility of synchronous alterations in excitation and inhibition, levels of excitatory neurotransmitters, i.e., glutamate, glutamate\u0026thinsp;+\u0026thinsp;glutamine (Glx), the corresponding alterations in GABA, and change in excitatory-inhibitory balance should also be evaluated. Of higher importance is the requirement for detailed clinical phenotyping, longitudinal studies and assessment of other domains of NMS such as sleep dysfunction. This is essential if any attempts need to made at exploring newer, non-dopaminergic therapeutic options. Finally, the evaluation of prodromal PD, and at-risk populations, mutation carriers may perhaps aid in developing imaging biomarkers for PD.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eSource of funding\u003c/h2\u003e\n\u003cp\u003eDBT/ Wellcome Trust India Alliance Early Career Fellowship (IA/CPHE/21/1/505953) \u0026ndash; awarded to SP.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial Disclosure/Conflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone of the authors have any financial disclosure to make or have any conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of generative AI in scientific writing\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo generative AI tool was used in the preparation of this manuscript\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003e(1) Research project: A. Conception, B. Organization, C. Execution; (2) Analysis: A. Design, B. Execution, C. Review and critique; (3) Manuscript: A. Writing of the first draft, B. Review and critique.SP: 1A, 1B, 1C, 2A, 2B, 3ADKD: 2C, 3BMK: 2C, 3BRY: 2C, 3BPKP: 2C, 3BJS: 2C, 3B\u003c/p\u003e\n\u003ch2\u003eAcknowledgements:\u003c/h2\u003e\n\u003cp\u003eAll figures were created by SP using BioRender\u003c/p\u003e\n\u003ch2\u003eData Availability Statement:\u003c/h2\u003e\n\u003cp\u003eData sharing not applicable to this article as no datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003ch3\u003eAuthor Roles\u003c/h3\u003e\n\u003cp\u003e(1) Research project: A. Conception, B. Organization, C. Execution;\u003c/p\u003e\n\u003cp\u003e(2) Analysis: A. Design, B. Execution, C. Review and critique;\u003c/p\u003e\n\u003cp\u003e(3) Manuscript: A. Writing of the first draft, B. Review and critique.\u003c/p\u003e\n\u003cp\u003eSP: 1A, 1B, 1C, 2A, 2B, 3A\u003c/p\u003e\n\u003cp\u003eDKD: 2C, 3B\u003c/p\u003e\n\u003cp\u003eMK: 2C, 3B\u003c/p\u003e\n\u003cp\u003eRY: 2C, 3B\u003c/p\u003e\n\u003cp\u003ePKP: 2C, 3B\u003c/p\u003e\n\u003cp\u003eJS: 2C, 3B\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55(3):181\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTitova N, Qamar MA, Chaudhuri KR. The nonmotor features of Parkinson's disease. International review of neurobiology. 2017;132:33\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVan Wamelen DJ, Sauerbier A, Leta V, Rodriguez-Blazquez C, Falup-Pecurariu C, Rodriguez-Violante M, et al. 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Radiology. 2016;278(2):505\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-parkinsons-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjparkd","sideBox":"Learn more about [npj Parkinson's Disease](http://www.nature.com/npjparkd/)","snPcode":"41531","submissionUrl":"https://submission.springernature.com/new-submission/41531/3","title":"npj Parkinson's Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"GABA, PD, Spectroscopy, Motor, Non-motor","lastPublishedDoi":"10.21203/rs.3.rs-8407027/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8407027/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe pathogenesis of Parkinson\u0026rsquo;s disease (PD) includes neurotransmitters beyond dopamine with suggestions of serotonergic, noradrenergic, cholinergic and GABAergic involvement. In this context advanced methods of magnetic resonance spectroscopy (MRS) permit the in-vivo quantification of GABA. This article aims to systematically review the existing literature on GABAergic alterations in PD as quantified by in-vivo proton MRS with a focus on ascertaining the influence of GABA on motor and non-motor symptoms, motor subtypes, effect of medication status and methodological variations across studies.\u003c/p\u003e \u003cp\u003eA systematic search of PubMed and Scopus was carried out in April 2025 with a relevant Boolean phrase. A total of 22 studies met the inclusion criteria. From a methodological perspective, there was variability in magnetic field strengths, pulse sequences, voxel location, voxel size, quantification reference, and methods of processing. Review of reported GABA levels revealed a very heterogenous set of alterations, with gross variations in GABA observed across studies, regions of interest and clinical phenotypes. These observations suggest a multifaceted dysregulation of GABA related neurotransmission that extends the concepts of PD pathogenesis beyond the traditionally implicated canonical dopaminergic framework.\u003c/p\u003e \u003cp\u003eGABA plays a definite modulatory role in the pathogenesis of PD, and complex, distinct regional alterations contribute to the development of motor and non-motor symptoms in PD. Standardisation of GABA spectroscopy methods and ideal patient selection is crucial to identify definite patterns of alterations.\u003c/p\u003e","manuscriptTitle":"GABAergic dysfunction in Parkinson’s disease: Insights from in vivo proton magnetic resonance spectroscopy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-30 10:02:17","doi":"10.21203/rs.3.rs-8407027/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-28T14:57:36+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-26T16:44:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"137276187390303372127209922257103821089","date":"2026-03-24T03:41:28+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-01T20:33:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"232352547284052525670592372726725248257","date":"2026-02-17T15:37:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"214698955527846586391395399684281619810","date":"2025-12-24T13:22:56+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-24T09:14:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-24T07:37:10+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-24T06:07:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Parkinson's Disease","date":"2025-12-19T16:09:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-parkinsons-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjparkd","sideBox":"Learn more about [npj Parkinson's Disease](http://www.nature.com/npjparkd/)","snPcode":"41531","submissionUrl":"https://submission.springernature.com/new-submission/41531/3","title":"npj Parkinson's Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c0a3bdcc-68bb-4b21-9488-0451341ecea4","owner":[],"postedDate":"December 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":60177982,"name":"Health sciences/Diseases"},{"id":60177983,"name":"Health sciences/Neurology"},{"id":60177984,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2026-05-16T12:08:56+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-30 10:02:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8407027","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8407027","identity":"rs-8407027","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}