Developing a novel dual-injection FDG-PET imaging methodology to study the functional neuroanatomy of gait.

Gait is an excellent indicator of physical, emotional, and mental health. Previous studies have shown that gait impairments in ageing are common, but the neural basis of these impairments are unclear. Existing methodologies are suboptimal and novel paradigms capable of capturing neural activation related to real walking are needed. In this study, we used a hybrid PET/MR system and measured glucose metabolism related to both walking and standing with a dual-injection paradigm in a single study session. For this study, 15 healthy older adults (10 females, age range: 60.5-70.7 years) with normal cognition were recruited from the community. Each participant received an intravenous injection of [18F]-2-fluoro-2-deoxyglucose (FDG) before engaging in two distinct tasks, a static postural control task (standing) and a walking task. After each task, participants were imaged. To discern independent neural functions related to walking compared to standing, we applied a bespoke dose correction to remove the residual 18F signal of the first scan (PETSTAND) from the second scan (PETWALK) and proportional scaling to the global mean, cerebellum, or white matter (WM). Whole-brain differences in walking-elicited neural activity measured with FDG-PET were assessed using a one-sample t-test. In this study, we show that a dual-injection paradigm in healthy older adults is feasible with biologically valid findings. Our results with a dose correction and scaling to the global mean showed that walking, compared to standing, increased glucose consumption in the cuneus (Z = 7.03), the temporal gyrus (Z = 6.91) and the orbital frontal cortex (Z = 6.71). Subcortically, we observed increased glucose metabolism in the supraspinal locomotor network including the thalamus (Z = 6.55), cerebellar vermis and the brainstem (pedunculopontine/mesencephalic locomotor region). Exploratory analyses using proportional scaling to the cerebellum and WM returned similar findings. Here, we have established the feasibility and tolerability of a novel method capable of capturing neural activations related to actual walking and extended previous knowledge including the recruitment of brain regions involved in sensory processing. Our paradigm could be used to explore pathological alterations in various gait disorders.

Safety and tolerability of adjunct non-invasive vagus nerve stimulation in people with parkinson's: a study protocol.

BACKGROUND: Parkinson's disease (PD) is the fastest growing neurological condition worldwide. Recent theories suggest that symptoms of PD may arise due to spread of Lewy-body pathology where the process begins in the gut and propagate transynaptically via the vagus nerve to the central nervous system. In PD, gait impairments are common motor manifestations that are progressive and can appear early in the disease course. As therapies to mitigate gait impairments are limited, novel interventions targeting these and their consequences, i.e., reducing the risk of falls, are urgently needed. Non-invasive vagus nerve stimulation (nVNS) is a neuromodulation technique targeting the vagus nerve. We recently showed in a small pilot trial that a single dose of nVNS improved (decreased) discrete gait variability characteristics in those receiving active stimulation relative to those receiving sham stimulation. Further multi-dose, multi-session studies are needed to assess the safety and tolerability of the stimulation and if improvement in gait is sustained over time. DESIGN: This will be an investigator-initiated, single-site, proof-of-concept, double-blind sham-controlled randomised pilot trial in 40 people with PD. Participants will be randomly assigned on a 1:1 ratio to receive either active or sham transcutaneous cervical VNS. All participants will undergo comprehensive cognitive, autonomic and gait assessments during three sessions over 24 weeks, in addition to remote monitoring of ambulatory activity and falls, and exploratory analyses of cholinergic peripheral plasma markers. The primary outcome measure is the safety and tolerability of multi-dose nVNS in PD. Secondary outcomes include improvements in gait, cognition and autonomic function that will be summarised using descriptive statistics. DISCUSSION: This study will report on the proportion of eligible and enrolled patients, rates of eligibility and reasons for ineligibility. Adverse events will be recorded informing on the safety and device tolerability in PD. This study will additionally provide us with information for sample size calculations for future studies and evidence whether improvement in gait control is enhanced when nVNS is delivered repeatedly and sustained over time. TRIAL REGISTRATION: This trial is prospectively registered at www.isrctn.com/ISRCTN19394828 . Registered August 23, 2021.

Free-water imaging of the cholinergic basal forebrain and pedunculopontine nucleus in Parkinson's disease.

Free-water imaging can predict and monitor dopamine system degeneration in people with Parkinson's disease. It can also enhance the sensitivity of traditional diffusion tensor imaging (DTI) metrics for indexing neurodegeneration. However, these tools are yet to be applied to investigate cholinergic system degeneration in Parkinson's disease, which involves both the pedunculopontine nucleus and cholinergic basal forebrain. Free-water imaging, free-water-corrected DTI and volumetry were used to extract structural metrics from the cholinergic basal forebrain and pedunculopontine nucleus in 99 people with Parkinson's disease and 46 age-matched controls. Cognitive ability was tracked over 4.5 years. Pearson's partial correlations revealed that free-water-corrected DTI metrics in the pedunculopontine nucleus were associated with performance on cognitive tasks that required participants to make rapid choices (behavioural flexibility). Volumetric, free-water content and DTI metrics in the cholinergic basal forebrain were elevated in a sub-group of people with Parkinson's disease with evidence of cognitive impairment, and linear mixed modelling revealed that these metrics were differently associated with current and future changes to cognition. Free water and free-water-corrected DTI can index cholinergic degeneration that could enable stratification of patients in clinical trials of cholinergic interventions for cognitive decline. In addition, degeneration of the pedunculopontine nucleus impairs behavioural flexibility in Parkinson's disease, which may explain this region's role in increased risk of falls.

Gait-Related Metabolic Covariance Networks at Rest in Parkinson's Disease.

BACKGROUND: Gait impairments are characteristic motor manifestations and significant predictors of poor quality of life in Parkinson's disease (PD). Neuroimaging biomarkers for gait impairments in PD could facilitate effective interventions to improve these symptoms and are highly warranted. OBJECTIVE: The aim of this study was to identify neural networks of discrete gait impairments in PD. METHODS: Fifty-five participants with early-stage PD and 20 age-matched healthy volunteers underwent quantitative gait assessment deriving 12 discrete spatiotemporal gait characteristics and [18 F]-2-fluoro-2-deoxyglucose-positron emission tomography measuring resting cerebral glucose metabolism. A multivariate spatial covariance approach was used to identify metabolic brain networks that were related to discrete gait characteristics in PD. RESULTS: In PD, we identified two metabolic gait-related covariance networks. The first correlated with mean step velocity and mean step length (pace gait network), which involved relatively increased and decreased metabolism in frontal cortices, including the dorsolateral prefrontal and orbital frontal, insula, supplementary motor area, ventrolateral thalamus, cerebellum, and cuneus. The second correlated with swing time variability and step time variability (temporal variability gait network), which included relatively increased and decreased metabolism in sensorimotor, superior parietal cortex, basal ganglia, insula, hippocampus, red nucleus, and mediodorsal thalamus. Expression of both networks was significantly elevated in participants with PD relative to healthy volunteers and were not related to levodopa dosage or motor severity. CONCLUSIONS: We have identified two novel gait-related brain networks of altered glucose metabolism at rest. These gait networks could serve as a potential neuroimaging biomarker of gait impairments in PD and facilitate development of therapeutic strategies for these disabling symptoms. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Noninvasive vagus nerve stimulation in Parkinson's disease: current status and future prospects.

INTRODUCTION: Parkinson's disease (PD) is a common progressive neurodegenerative disorder with multifactorial etiology. While dopaminergic medication is the standard therapy in PD, it provides limited symptomatic treatment and non-pharmacological interventions are currently being trialed. AREAS COVERED: Recent pathophysiological theories of Parkinson's suggest that aggregated α-synuclein form in the gut and spread to nuclei in the brainstem via autonomic connections. In this paper, we review the novel hypothesis that noninvasive vagus nerve stimulation (nVNS), targeting efferent and afferent vagal projections, is a promising therapeutic tool to improve gait and cognitive control and ameliorate non-motor symptoms in people with Parkinson's. We conducted an unstructured search of the literature for any studies employing nVNS in PD as well as for studies examining the efficacy of nVNS on improving cognitive function and where nVNS has been applied to co-occurring conditions in PD. EXPERT OPINION: Evidence of nVNS as a novel therapeutic to improve gait in PD is preliminary, but early signs indicate the possibility that nVNS may be useful to target dopa-resistant gait characteristics in early PD. The evidence for nVNS as a therapeutic tool is, however, limited and further studies are needed in both brain health and disease.

The role of the cingulate cortex in the generation of motor tics and the experience of the premonitory urge-to-tic in Tourette syndrome.

Tourette syndrome (TS) is a neurological disorder of childhood onset that is characterized by the occurrence of motor and vocal tics. TS is associated with cortical-striatal-thalamic-cortical circuit [CSTC] dysfunction and hyper-excitability of cortical limbic and motor regions that are thought to lead to the occurrence of tics. Individuals with TS often report that their tics are preceded by 'premonitory sensory/urge phenomena' (PU) that are described as uncomfortable bodily sensations that precede the execution of a tic and are experienced as a strong urge for motor discharge. While the precise role played by PU in the occurrence of tics is largely unknown, they are nonetheless of considerable theoretical and clinical importance as they form a core component of many behavioural therapies used in the treatment of tic disorders. Recent evidence indicates that the cingulate cortex may play an important role in the generation of PU in TS, and in 'urges-for-action' more generally. In the current study, we utilized voxel-based morphometry (VBM) techniques, together with 'seed-to-voxel' structural covariance network (SCN) mapping, to investigate the putative role played by the cingulate cortex in the generation of motor tics and the experience of PU in a relatively large group of young people with TS. Whole-brain VBM analysis revealed that TS was associated with clusters of significantly reduced grey matter volumes bilaterally within: the orbito-frontal cortex; the cerebellum; and the anterior and mid-cingulate cortex. Similarly, analysis of SCNs associated with bilateral mid- and anterior cingulate 'seed' regions demonstrated that TS is associated with increased structural covariance primarily with the bilateral motor cerebellum; the inferior frontal cortex; and the posterior cingulate cortex.

Entraining Movement-Related Brain Oscillations to Suppress Tics in Tourette Syndrome.

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by the occurrence of vocal and motor tics. Tics are involuntary, repetitive movements and vocalizations that occur in bouts, typically many times in a single day, and are often preceded by a strong urge-to-tic-referred to as a premonitory urge (PU). TS is associated with the following: dysfunction within cortical-striatal-thalamic-cortical (CSTC) brain circuits implicated in the selection of movements, impaired operation of GABA signaling within the striatum, and hyper-excitability of cortical sensorimotor regions that might contribute to the occurrence of tics. Non-invasive brain stimulation delivered to cortical motor areas can modulate cortical motor excitability, entrain brain oscillations, and reduce tics in TS. However, these techniques are not optimal for treatment outside of the clinic. We investigated whether rhythmic pulses of median nerve stimulation (MNS) could entrain brain oscillations linked to the suppression of movement and influence the initiation of tics in TS. We demonstrate that pulse trains of rhythmic MNS, delivered at 12 Hz, entrain sensorimotor mu-band oscillations, whereas pulse trains of arrhythmic MNS do not. Furthermore, we demonstrate that although rhythmic mu stimulation has statistically significant but small effects on the initiation of volitional movements and no discernable effect on performance of an attentionally demanding cognitive task, it nonetheless leads to a large reduction in tic frequency and tic intensity in individuals with TS. This approach has considerable potential, in our view, to be developed into a therapeutic device suitable for use outside of the clinic to suppress tics and PU in TS.

A feasibility study for somatomotor cortical mapping in Tourette syndrome using neuronavigated transcranial magnetic stimulation.

Tourette syndrome (TS) is a hyperkinetic movement disorder characterised by the occurrence of chronic motor and vocal tics, and is associated with alterations in the balance of excitatory and inhibitory signalling within key brain networks; in particular the cortical-striatal-thalamic-cortical (CSTC) brain circuits that are implicated in movement selection and habit learning. Converging evidence indicates abnormal brain network function in TS may be largely due to the impaired operation of GABA signalling within the striatum and within cortical motor areas, leading to the occurrence of tics. TS has been linked to a heightened sensitivity to somatic stimulation and altered processing of somatosensory information, and there is evidence to indicate that alterations in GABAergic function is likely to contribute to altered somatomotor function. Based upon this evidence, we hypothesised that the specificity of somatomotor representations in primary motor cortex would likely be reduced in individuals with TS. To test this, we used a rapid acquisition method together with neuronavigated transcranial magnetic stimulation (nTMS) to measure the cortical representation of a several different muscles in a group of young adults with TS and a matched group of typically developing individuals.

The role of the insula in the generation of motor tics and the experience of the premonitory urge-to-tic in Tourette syndrome.

Tourette syndrome (TS) is a neurological disorder of childhood onset that is characterised by the occurrence of motor and vocal tics. TS is associated with cortical-striatal-thalamic-cortical circuit [CSTC] dysfunction and hyper-excitability of cortical limbic and motor regions that are thought to lead to the occurrence of tics. Importantly, individuals with TS often report that their tics are preceded by 'premonitory sensory/urge phenomena' (PU) that are described as uncomfortable bodily sensations that precede the execution of a tic and are experienced as a strong urge for motor discharge. While the precise role played by PU in the occurrence of tics is largely unknown, they are nonetheless of considerable theoretical and clinical importance, not least because they form the core component in many behavioural therapies used in the treatment of tic disorders. Several lines of evidence indicate that the insular cortex may play a particularly important role in the generation of PU in TS and 'urges-for-action' more generally. In the current study we utilised voxel-based morphometry techniques together with 'seed-to-voxel' structural covariance network (SCN) mapping to investigate the putative role played by the right insular cortex in the generation of motor tics and the experience of PU in a relatively large group of young people TS. We demonstrate that clinical measures of motor tic severity and PU are uncorrelated with one another, that motor tic severity and PU scores are associated with separate regions of the insular cortex, and that the insula is associated with different structural covariance networks in individuals with TS compared to a matched group of typically developing individuals.

Alterations in cerebellar grey matter structure and covariance networks in young people with Tourette syndrome.

Tourette syndrome (TS) is a childhood-onset neurological disorder characterised by the occurrence of motor and vocal tics and the presence of premonitory sensory/urge phenomena. Functional neuroimaging studies in humans, and experimental investigations in animals, have shown that the genesis of tics in TS involve a complex interaction between cortical-striatal-thalamic-cortical brain circuits and additionally appears to involve the cerebellum. Furthermore, structural brain imaging studies have demonstrated alterations in grey matter (GM) volume in TS across a wide range of brain areas, including alterations in GM volume within the cerebellum. Until now, no study to our knowledge has yet investigated how GM structural covariance networks linked to the cerebellum may be altered in individuals with TS. In this study we employed voxel-based morphometry, and a 'seed-to-voxel' structural covariance network (SCN) mapping approach, to investigate alterations in GM cerebellar volume in people with TS, and alterations in cerebellar SCNs associated with TS. Data from 64 young participants was entered in the final analysis, of which 28 had TS while 36 were age-and sex-matched healthy volunteers. Using the spatially unbiased atlas template of the cerebellum and brainstem (SUIT) atlas, we found reduced GM volume in cerebellar lobule involved in higher-order cognitive functions and sensorimotor processing, in patients. In addition, we found that several areas located in frontal and cingulate cortices and sensorimotor network in addition to subcortical areas show altered structural covariance with our cerebellar seed compared to age-matched controls. These results add to the increasing evidence that cortico-basal ganglia-cerebellar interactions play an important role in tic symptomology.

Alterations in the microstructure of white matter in children and adolescents with Tourette syndrome measured using tract-based spatial statistics and probabilistic tractography.

Tourette syndrome (TS) is a neurodevelopmental disorder characterised by repetitive and intermittent motor and vocal tics. TS is thought to reflect fronto-striatal dysfunction and the aetiology of the disorder has been linked to widespread alterations in the functional and structural integrity of the brain. The aim of this study was to assess white matter (WM) abnormalities in a large sample of young patients with TS in comparison to a sample of matched typically developing control individuals (CS) using diffusion MRI. The study included 35 patients with TS (3 females; mean age: 14.0 ± 3.3) and 35 CS (3 females; mean age: 13.9 ± 3.3). Diffusion MRI data was analysed using tract-based spatial statistics (TBSS) and probabilistic tractography. Patients with TS demonstrated both marked and widespread decreases in axial diffusivity (AD) together with altered WM connectivity. Moreover, we showed that tic severity and the frequency of premonitory urges (PU) were associated with increased connectivity between primary motor cortex (M1) and the caudate nuclei, and increased information transfer between M1 and the insula, respectively. This is to our knowledge the first study to employ both TBSS and probabilistic tractography in a sample of young patients with TS. Our results contribute to the limited existing literature demonstrating altered connectivity in TS and confirm previous results suggesting in particular, that altered insular function contributes to increased frequency of PU.

Activation induced changes in GABA: Functional MRS at 7T with MEGA-sLASER.

Functional magnetic resonance spectroscopy (fMRS) has been used to assess the dynamic metabolic responses of the brain to a physiological stimulus non-invasively. However, only limited information on the dynamic functional response of γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain, is available. We aimed to measure the activation-induced changes in GABA unambiguously using a spectral editing method, instead of the conventional direct detection techniques used in previous fMRS studies. The Mescher-Garwood-semi-localised by adiabatic selective refocusing (MEGA-sLASER) sequence was developed at 7T to obtain the time course of GABA concentration without macromolecular contamination. A significant decrease (-12±5%) in the GABA to total creatine ratio (GABA/tCr) was observed in the motor cortex during a period of 10min of hand-clenching, compared to an initial baseline level (GABA/tCr =0.11±0.02) at rest. An increase in the Glx (glutamate and glutamine) to tCr ratio was also found, which is in agreement with previous findings. In contrast, no significant changes in NAA/tCr and tCr were detected. With consistent and highly efficient editing performance for GABA detection and the advantage of visually identifying GABA resonances in the spectra, MEGA-sLASER is demonstrated to be an effective method for studying of dynamic changes in GABA at 7T.

Comparing GABA-dependent physiological measures of inhibition with proton magnetic resonance spectroscopy measurement of GABA using ultra-high-field MRI.

Imbalances in glutamatergic (excitatory) and GABA (inhibitory) signalling within key brain networks are thought to underlie many brain and mental health disorders, and for this reason there is considerable interest in investigating how individual variability in localised concentrations of these molecules relate to brain disorders. Magnetic resonance spectroscopy (MRS) provides a reliable means of measuring, in vivo, concentrations of neurometabolites such as GABA, glutamate and glutamine that can be correlated with brain function and dysfunction. However, an issue of much debate is whether the GABA observed and measured using MRS represents the entire pool of GABA available for measurement (i.e., metabolic, intracellular, and extracellular) or is instead limited to only some portion of it. GABA function can also be investigated indirectly in humans through the use of non-invasive transcranial magnetic stimulation (TMS) techniques that can be used to measure cortical excitability and GABA-mediated physiological inhibition. To investigate this issue further we collected in a single session both types of measurement, i.e., TMS measures of cortical excitability and physiological inhibition and ultra-high-field (7 T) MRS measures of GABA, glutamate and glutamine, from the left sensorimotor cortex of the same group of right-handed individuals. We found that TMS and MRS measures were largely uncorrelated with one another, save for the plateau of the TMS IO curve that was negatively correlated with MRS-Glutamate (Glu) and intra-cortical facilitation (10ms ISI) that was positively associated with MRS-Glutamate concentration. These findings are consistent with the view that the GABA concentrations measured using the MRS largely represent pools of GABA that are linked to tonic rather than phasic inhibition and thus contribute to the inhibitory tone of a brain area rather than GABAergic synaptic transmission.