Abstract BACKGROUND There has been increasing interest in exploring ketogenic diet therapies (KDT) in patients with glioma given the poor prognosis. The purpose of this single-arm, open label phase 2 study was to rigorously examine the feasibility, safety, systemic biological activity, and cerebral activity of a KDT in patients with glioma. METHODS 25 patients with biopsy-confirmed WHO Grade 2–4 astrocytoma with stable disease following adjuvant chemotherapy were enrolled in an 8-week GLioma Atkins-based Diet (GLAD). GLAD consisted of 2 fasting days (calories<20% calculated estimated needs) interleaved between 5 modified Atkins diet days (net carbohydrates≤20 gm/day) each week. The primary outcome was dietary adherence by food records. Markers of systemic and cerebral activity included weekly urine ketones, serum insulin, glucose, hemoglobin A1c, IGF-1, and MR spectroscopy at baseline and week 8. RESULTS 21 patients completed the study. 80% of patients reached ≥40 mg/dL urine acetoacetate during the study. 48% of patients were adherent by food record. The diet was well-tolerated with two grade 3 adverse events (neutropenia, seizure). Measures of systemic activity including hemoglobin A1c, insulin, and fat body mass decreased significantly, while lean body mass increased. MR spectroscopy demonstrated increased ketone concentrations (β-hydroxybutyrate (bHB) and acetone (Ace)) in both lesional and contralateral brain, compared to baseline. Higher total choline (tCho) and glutamine (Gln) levels were observed in lesional as compared to contralateral brain at baseline, and both decreased following intervention. Average ketonuria correlated with cerebral ketones in lesional (tumor) and contralateral brain (bHB Rs0.52, p=0.05). There were no differences in cerebral metabolites in IDH-mutant glioma after controlling for ketonuria. CONCLUSIONS The GLAD dietary intervention, while demanding, produced meaningful ketonuria, and significant systemic and cerebral metabolic changes in participants. Participant ketonuria correlated with cerebral ketone concentration and appears to be a better indicator of systemic activity than patient-reported food records.
Functional MRS (fMRS) is a powerful technique to measure metabolite responses over time. However, noise and spectral contamination limit the ability to study individual metabolite time-courses. In this work, we propose to model fMRS spectra as a superposition of low-rank (L) and sparse components (S). L+S decomposition resulted in separation of temporally-correlated signal from noise in simulation. In vivo, L+S spectra had higher SNR compared to original data (P=0.007) and the mean glutamate time-course, using L+S spectra, was more strongly correlated to stimulus. L+S decomposition is a promising data-driven method to enhance sensitivity to dynamic changes in fMRS.
Learning a novel motor skill is dependent both on regional changes within the primary motor cortex (M1) contralateral to the active hand and also on modulation between and within anatomically distant but functionally connected brain regions. Interregional changes are particularly important in functional recovery after stroke, when critical plastic changes underpinning behavioral improvements are observed in both ipsilesional and contralesional M1s. It is increasingly understood that reduction in GABA in the contralateral M1 is necessary to allow learning of a motor task. However, the physiological mechanisms underpinning plasticity within other brain regions, most importantly the ipsilateral M1, are not well understood. Here, we used concurrent two-voxel magnetic resonance spectroscopy to simultaneously quantify changes in neurochemicals within left and right M1s in healthy humans of both sexes in response to transcranial direct current stimulation (tDCS) applied to left M1. We demonstrated a decrease in GABA in both the stimulated (left) and nonstimulated (right) M1 after anodal tDCS, whereas a decrease in GABA was only observed in nonstimulated M1 after cathodal stimulation. This GABA decrease in the nonstimulated M1 during cathodal tDCS was negatively correlated with microstructure of M1:M1 callosal fibers, as quantified by diffusion MRI, suggesting that structural features of these fibers may mediate GABA decrease in the unstimulated region. We found no significant changes in glutamate. Together, these findings shed light on the interactions between the two major network nodes underpinning motor plasticity, offering a potential framework from which to optimize future interventions to improve motor function after stroke. SIGNIFICANCE STATEMENT Learning of new motor skills depends on modulation both within and between brain regions. Here, we use a novel two-voxel magnetic resonance spectroscopy approach to quantify GABA and glutamate changes concurrently within the left and right primary motor cortex (M1) during three commonly used transcranial direct current stimulation montages: anodal, cathodal, and bilateral. We also examined how the neurochemical changes in the unstimulated hemisphere were related to white matter microstructure between the two M1s. Our results provide insights into the neurochemical changes underlying motor plasticity and may therefore assist in the development of further adjunct therapies.
Purpose Sufficient control of the RF transmit field (B 1 + ) in small regions-of-interest (ROIs) is critical for single voxel MR spectroscopy at ultra-high field. Static RF shimming, using parallel transmit (pTx), can improve B 1 + , but must be calibrated for each participant and ROI, which limits its applicability. Additionally, specific-absorption-rate (SAR) becomes hard to predict. This work aimed to find RF shims, which can be applied to any participant, to produce the desired |B 1 + | within pre-defined target ROIs. Methods RF shims were found offline by joint-optimisation on a database, comprising B 1 + maps from 11 subjects, considering ROIs in occipital cortex, hippocampus and posterior-cingulate, as well as the whole brain. The B 1 + magnitude achieved using calibration-free RF shims was compared to a tailored shimming approach, and MR spectra were acquired using tailored and calibration-free RF shimming in 4 participants. Global and local 10g SAR deposition were modelled. Results Calibration-free RF shims resulted in similar |B 1 + | in small ROIs compared to tailored shimming, in addition to producing spectra of excellent quality and equivalent SNR. Only a small database size was required. SAR deposition was reduced compared to operating in quadrature mode for all ROIs. Conclusion This work demonstrates that static RF shims, optimised offline for small regions in single voxel MRS, avoid the need for lengthy B 1 + mapping and pTx optimisation for each ROI and participant. Furthermore, power settings may be increased when using calibration-free shims to better take advantage of the flexibility provided by RF shimming for regional acquisition at ultra-high field.
Abstract INTRODUCTION Exploiting metabolic vulnerabilities via ketosis is a promising approach for gliomas. The modified Atkins diet is a ketogenic diet therapy efficacious in adults with refractory epilepsy. We evaluated the feasibility, pharmacokinetics/pharmacodynamics(PK/PD), and cerebral activity of this dietary intervention intended to induce ketosis. METHODS 25 patients with biopsy-confirmed WHO Grade 2–4 astrocytoma with stable disease after adjuvant chemotherapy were enrolled in an 8-week GLioma Atkins-based Diet (GLAD). GLAD consisted of 2 ‘intermittent fasting’ days(IF; calories < 20% of recommended daily allowance) interleaved between 5 modified-Atkins diet days(MAD; carbohydrates < 20 gm/day) each week. The primary outcome was dietary compliance. Secondary outcomes were PK assessed by urine ketones post-FAST and post-MAD, PD assessed by serum insulin and IGF-1, and cerebral activity measured by MR spectroscopy at baseline and week 8. RESULTS Grade 2(n=2;8%), Grade 3(n=11;44%) and GBMs(n=12;48%) were enrolled. While only 48% of participants satisfied pre-defined compliance criteria, overall compliance with MAD(80%) was higher than IF(72%). Weight loss was observed (-4.8 + 2.2kg,p< 0.0001) consisting primarily of decreased fat mass (-2.5 + 3.1%,p< 0.0001), with increased lean body mass (2.4 + 3.2%,p< 0.0001), stable nutritional status (phase angle, -0.26 + 0.94%,p=0.22), and normalization of BMI. Urine acetoacetate significantly increased with 55% achieving moderate ketosis at week 8 (p=0.0005). Serum insulin and IGF-1 significantly decreased indicating systemic dietary response and were associated with higher ketones post-IF, but not post-MAD. MRS demonstrated cerebral activity with increased ketones in lesional (0.06±0.03- >0.27±0.06i.u,p=0.005) and contralateral brain at week 8 (0.041±0.01- >0.16±0.04i.u.,p=0.004). Higher cerebral acetone correlated with higher urine ketones (r >0.75,p< 0.02) and lower fasting glucose (r >-0.74,p< 0.05). CONCLUSIONS The GLAD diet was challenging to maintain but demonstrated quantifiable biologic effects systemically and intratumorally. MAD was more feasible than IF, but changes in PD markers correlated most strongly with IF. The role of ketogenic diet therapy for preventing glioma growth remains uncertain.
ABSTRACT Background Rhythmic median nerve stimulation (MNS) at 10 Hz has been shown to cause a substantial reduction in tic frequency in individuals with Tourette syndrome. The mechanism of action is currently unknown but is hypothesized to involve entrainment of oscillations within the sensorimotor cortex. Objective We used functional magnetic resonance spectroscopy (fMRS) to explore the dynamic effects of MNS on neurometabolite concentrations. Methods Here, we investigated the effects of rhythmic and arrhythmic 10 Hz MNS on glutamate (Glu) and GABA concentrations in the contralateral sensorimotor cortex in 15 healthy controls, using a blocked fMRS design. We used a Mescher–Garwood‐semi‐localized by adiabatic selective refocusing (MEGA‐sLASER) sequence at 7 T. Results Our results show no difference in the difference‐from‐baseline measures between the two stimulation conditions. Looking at the effect of MNS over both conditions there is a trend for an initial increase in Glu/tCr (total creatine) followed by a decrease over time, whereas GABA/tCr decreased during each stimulation block. Conclusions These results suggest that despite entrainment of oscillations during rhythmic MNS, there are no significant differences in the tonic neuromodulatory effects of rhythmic and arrhythmic stimulation. The reduction in Glu over the course of stimulation may reflect a decrease in the glutamatergic firing due to adaptation. This may make it less likely that an involuntary movement is generated during continuous stimulation.
Motivation: Functional magnetic resonance spectroscopy (fMRS) shows promise in studying task-related metabolite changes but has been largely confined to single-voxel. Goal(s): To evaluate two-voxel fMRS at 7 T to measure simultaneous bilateral metabolite changes during a unilateral motor task. Approach: A modified Hadamard-encoded MRS scheme with dynamic fMRS spectral-temporal fitting for analysis was employed. Results: Distinct patterns of BOLD activation in contra- and ipsilateral VOIs were detected with significant increases in Glutamate (Glu) in either VOI during a unilateral taskImpact: We demonstrate the feasibility of simultaneous two-voxel MRS to detect bilateral glutamate changes in response to a unilateral motor task. This approach holds promise to increase our understanding of the neurochemical underpinnings of fMRI signals across interconnected brain regions.
There is renewed interest in exploring treatment strategies which target metabolic pathways involved in gliomagenesis, including ketogenic diets. The purpose of this pilot study was to evaluate the feasibility of proton MR spectroscopy (MRS) to detect the cerebral metabolic activity of an 8-week GLioma Atkins-based Diet (GLAD) in patients with glioma. Patients with grade 3-4 astrocytoma were enrolled after completing adjuvant chemotherapy, before first recurrence. GLAD consisted of 20gm carbohydrate restriction (modified Atkins diet) along with 2 days per week of intermittent fasting (caloric restriction to 20% recommended daily allowance). MRS was performed in both the lesion and a mirror voxel in the contralateral hemisphere at baseline and week 8. Data were analyzed using the ‘LCModel’ program using a basis set of three ketone bodies (acetone (Ace), beta-hydroxybutyrate (BHB), acetoacetate (AcAc)), 2-hydroxyglutarate (2-HG), citrate (Cit), and some standard metabolites. Interim analysis is reported after 12 patients enrolled; mean age 49 ± 11 years; 8 male; 5 grade IV astrocytomas. Two patients did not complete the study; two were excluded for incomplete data. As expected, concentrations of tNAA (p<0.028) and Lac (p<0.023) were different between lesion and normal brain at baseline. Ketone body concentrations were nearly undetectable at baseline; however by week 8, Ace and BHB were reliably detected in both lesion ([Ace]=0.08->0.32 ± 0.19, p=0.005; [BHB]=0.07->0.6 ± 0.68, p=0.05) and contralateral brain ([Ace]=0.01->0.16 ± 0.14, p=0.015; [BHB]=0->0.23 ± 0.25, p=0.021). In the lesion, BHB rose by 1.0mM from baseline to Week 8 in IDH1 mutant as compared to a decrease by -0.13mM in wild-type astrocytomas (p<0.002). The increase in BHB but not Ace was also significantly greater in patients with higher dietary compliance as measured by urine ketones (p<0.03). These preliminary results demonstrate the ability of brain MRS to monitor the metabolic consequences of a ketogenic diet in patients with high-grade glioma.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
