Modeling motor-evoked potentials from neural field simulations of transcranial magnetic stimulation

Objective To develop a population-based biophysical model of motor-evoked potentials (MEPs) following transcranial magnetic stimulation (TMS). Methods We combined an existing MEP model with population-based cortical modeling. Layer 2/3 excitatory and inhibitory neural populations, modeled with neural-field theory, are stimulated with TMS and feed layer 5 corticospinal neurons, which also couple directly but weakly to the TMS pulse. The layer 5 output controls mean motoneuron responses, which generate a series of single motor-unit action potentials that are summed to estimate a MEP. Results A MEP waveform was generated comparable to those observed experimentally. The model captured TMS phenomena including a sigmoidal input–output curve, common paired pulse effects (short interval intracortical inhibition, intracortical facilitation, long interval intracortical inhibition) including responses to pharmacological interventions, and a cortical silent period. Changes in MEP amplitude following theta burst paradigms were observed including variability in outcome direction. Conclusions The model reproduces effects seen in common TMS paradigms. Significance The model allows population-based modeling of changes in cortical dynamics due to TMS protocols to be assessed in terms of changes in MEPs, thus allowing a clear comparison between population-based modeling predictions and typical experimental outcome measures

The association of intra-therapeutic heterogeneity of somatostatin receptor expression with morphological treatment response in patients undergoing PRRT with [177Lu]-DOTATATE

AIM: Purpose of this study was to evaluate the association of the spatial heterogeneity (asphericity, ASP) in intra-therapeutic SPECT/ CT imaging of somatostatin receptor (SSR) positive metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) for morphological treatment response to peptide receptor radionuclide therapy (PRRT). Secondly, we correlated ASP derived form a pre-therapeutic OctreoScan (ASP[In]) and an intra-therapeutic [177Lu]-SPECT/CT (ASP[Lu]). MATERIALS AND METHODS: Data from first therapy cycle [177Lu-DOTA0-Tyr3]octreotate ([177Lu]-DOTATATE)-PRRT was retrospectively analyzed in 33 patients (m = 20; w = 13; median age, 72 [46-88] years). The evaluation of response to PRRT was performed according to RECIST 1.1 in responding lesions [RL (SD, PR, CR), n = 104] and non-responding lesions [NRL (PD), n = 27]. The association of SSR tumor heterogeneity with morphological response was evaluated by Kruskal-Wallis test and receiver operating characteristic curve (ROC). The optimal threshold for separation (RL vs. NRL) was calculated using the Youden-index. Relationship between pre- and intra-therapeutic ASP was determined with Spearman's rank correlation coefficient (ρ) and Bland-Altman plots. RESULTS: A total of 131 lesions (liver: n = 59, lymph nodes: n = 48, bone: n = 19, pancreas: n = 5) were analyzed. Lesions with higher ASP values showed a significantly poorer response to PRRT (PD, median: 11.3, IQR: 8.5-15.5; SD, median: 3.4, IQR: 2.1-4.5; PR, median 1.7, IQR: 0.9-2.8; CR, median: 0.5, IQR: 0.0-1.3); Kruskal-Wallis, p5.45% (sensitivity 96% and specificity 82%). The correlation coefficient of pre- and intra-therapeutic ASP revealed ρ = 0.72 (p <0.01). The mean absolute difference between ASP[In] and ASP[Lu] was -0.04 (95% Limits of Agreement, -6.1-6.0). CONCLUSION: Pre- and intra-therapeutic ASP shows a strong correlation and might be an useful tool for therapy monitoring

No evidence for changes in GABA concentration, functional connectivity, or working memory following continuous theta burst stimulation over dorsolateral prefrontal cortex

Continuous theta burst stimulation (cTBS) is thought to reduce cortical excitability and modulate functional connectivity, possibly by altering cortical inhibition at the site of stimulation. However, most evidence comes from the motor cortex and it remains unclear whether similar effects occur following stimulation over other brain regions. We assessed whether cTBS over left dorsolateral prefrontal cortex altered gamma aminobutyric acid (GABA) concentration, functional connectivity and brain dynamics at rest, and brain activation and memory performance during a working memory task. Seventeen healthy individuals participated in a randomised, sham-controlled, cross-over experiment. Before and after either real or sham cTBS, magnetic resonance spectroscopy was obtained at rest to measure GABA concentrations. Functional magnetic resonance imaging (fMRI) was also recorded at rest and during an n-back working memory task to measure functional connectivity, regional brain activity (low-frequency fluctuations), and task-related patterns of brain activity. We could not find evidence for changes in GABA concentration (P = 0.66, Bayes factor [BF10] = 0.07), resting-state functional connectivity (P(FWE) > 0.05), resting-state low-frequency fluctuations (P = 0.88, BF10 = 0.04), blood-oxygen level dependent activity during the n-back task (P(FWE) > 0.05), or working memory performance (P = 0.13, BF10 = 0.05) following real or sham cTBS. Our findings add to a growing body of literature suggesting the effects of cTBS are highly variable between individuals and question the notion that cTBS is a universal ‘inhibitory’ paradigm

PET measured hypoxia and MRI parameters in re-irradiated head and neck squamous cell carcinomas: findings of a prospective pilot study [version 2; peer review: 2 approved]

Background: Tumor hypoxia measured by dedicated tracers like [ 18F]fluoromisonidazole (FMISO) is a well-established prognostic factor in head and neck squamous cell carcinomas (HNSCC) treated with definitive chemoradiation (CRT). However, prevalence and characteristics of positron emission tomography (PET) measured hypoxia in patients with relapse after previous irradiation is missing. Here we report imaging findings of a prospective pilot study in HNSCC patients treated with re-irradiation. Methods: In 8 patients with recurrent HNSCC, diagnosed at a median of 18 months after initial radiotherapy/CRT, [ 18F]fluorodeoxyglucose (FDG)-PET/CT (n=8) and FMISO-PET/MRI (n=7) or FMISO-PET/CT (n=1) were performed. Static FMISO-PET was performed after 180 min. MRI sequences in PET/MRI included diffusion-weighted imaging with apparent diffusion coefficient (ADC) values and contrast enhanced T1w imaging (StarVIBE). Lesions (primary tumor recurrence, 4; cervical lymph node, 1; both, 3) were delineated on FDG-PET and FMISO-PET data using a background-adapted threshold-based method. SUV max and SUV mean in FDG- and FMISO-PET were derived, as well as maximum tumor-to-muscle ratio (TMR max) and hypoxic volume with 1.6-fold muscle SUV mean (HV 1.6) in FMISO-PET. Intensity of lesional contrast enhancement was rated relative to contralateral normal tissue. Average ADC values were derived from a 2D region of interest in the tumor. Results: In FMISO-PET, median TMR max was 1.7 (range: 1.1-1.8). Median HV 1.6 was 0.05 ml (range: 0-7.3 ml). Only in 2/8 patients, HV 1.6 was ≥1.0 ml. In FDG-PET, median SUV max was 9.3 (range: 5.0-20.1). On contrast enhanced imaging four lesions showed decreased and four lesions increased contrast enhancement compared to non-pathologic reference tissue. Median average ADC was 1,060 ×10 6 mm 2/s (range: 840-1,400 ×10 6 mm 2/s). Conclusions: This pilot study implies that hypoxia detectable by FMISO-PET may not be as prevalent as expected among loco-regional recurrent, HPV negative HNSCC. ADC values were only mildly reduced, and contrast enhancement was variable. The results require confirmation in larger sample sizes

Biophysical modeling of neural plasticity induced by transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) is a widely used noninvasive brain stimulation method capable of inducing plastic reorganisation of cortical circuits in humans. Changes in neural activity following TMS are often attributed to synaptic plasticity via process of long-term potentiation and depression (LTP/LTD). However, the precise way in which synaptic processes such as LTP/LTD modulate the activity of large populations of neurons, as stimulated en masse by TMS, are unclear. The recent development of biophysical models, which incorporate the physiological properties of TMS-induced plasticity mathematically, provide an excellent framework for reconciling synaptic and macroscopic plasticity. This article overviews the TMS paradigms used to induce plasticity, and their limitations. It then describes the development of biophysically-based numerical models of the mechanisms underlying LTP/LTD on population-level neuronal activity, and the application of these models to TMS plasticity paradigms, including theta burst and paired associative stimulation. Finally, it outlines how modeling can complement experimental work to improve mechanistic understandings and optimize outcomes of TMS-induced plasticity

The effects of NMDA receptor blockade on TMS-evoked EEG potentials from prefrontal and parietal cortex

Measuring the brain's response to transcranial magnetic stimulation (TMS) with electroencephalography (EEG) offers unique insights into the cortical circuits activated following stimulation, particularly in non-motor regions where less is known about TMS physiology. However, the mechanisms underlying TMS-evoked EEG potentials (TEPs) remain largely unknown. We assessed TEP sensitivity to changes in excitatory neurotransmission mediated by n-methyl-d-aspartate (NMDA) receptors following stimulation of non-motor regions. In fourteen male volunteers, resting EEG and TEPs from prefrontal (PFC) and parietal (PAR) cortex were measured before and after administration of either dextromethorphan (NMDA receptor antagonist) or placebo across two sessions in a double-blinded pseudo-randomised crossover design. At baseline, there were amplitude differences between PFC and PAR TEPs across a wide time range (15-250 ms), however the signals were correlated after ~80 ms, suggesting early peaks reflect site-specific activity, whereas late peaks reflect activity patterns less dependent on the stimulated sites. Early TEP peaks were not reliably altered following dextromethorphan compared to placebo, although findings were less clear for later peaks, and low frequency resting oscillations were reduced in power. Our findings suggest that early TEP peaks (<80 ms) from PFC and PAR reflect stimulation site specific activity that is largely insensitive to changes in NMDA receptor-mediated neurotransmission.Nigel C. Rogasch, Carl Zipser, Ghazaleh Darmani, Tuomas P. Mutanen, Mana Biabani, Christoph Zrenner, Debora Desideri, Paolo Belardinelli, Florian Müller-Dahlhaus, Ulf Zieman

Personalized brain stimulation of memory networks

Available online 13 September 2022Background: The finding that transcranial magnetic stimulation (TMS) can enhance memory performance via stimulation of parietal sites within the Cortical-Hippocampal Network counts as one of the most exciting findings in this field in the past decade. However, the first independent effort aiming to fully replicate this finding found no discernible influence of TMS on memory performance. Objective: We examined whether this might relate to interindividual spatial variation in brain connectivity architecture, and the capacity of personalisation methodologies to overcome the noise inherent across independent scanners and cohorts. Methods: We implemented recently detailed personalisation methodology to retrospectively compute individual-specific parietal targets and then examined relation to TMS outcomes. Results: Closer proximity between actual and novel fMRI-personalized targets associated with greater improvement in memory performance. Conclusion: These findings demonstrate the potential importance of aligning brain stimulation targets according to individual-specific differences in brain connectivity, and extend upon recent findings in prefrontal cortex.Robin F.H. Cash, Joshua Hendrikse, Kavisha B Fernando, Sarah Thompson, Chao Suo, Alex Fornito, Murat Yücel, Nigel C. Rogasch, Andrew Zalesky, James P. Coxo

Shortened Tracer Uptake Time in GA-68-DOTATOC-PET of Meningiomas Does Not Impair Diagnostic Accuracy and PET Volume Definition

Ga-68-DOTATOC-PET/MRI can affect the planning target volume (PTV) definition of meningiomas before radiosurgery. A shorter tracer uptake time before image acquisition could allow the examination of more patients. The aim of this study was to investigate if shortening uptake time is possible without compromising diagnostic accuracy and PET volume. Fifteen patients (f = 12; mean age 52 years (34-80 years)) with meningiomas were prospectively examined with dynamic [68Ga]Ga-68-labeled [DOTA0-Phe1-Tyr3] octreotide (Ga-68-DOTATOC)-PET/MRI over 70 min before radiosurgery planning. Meningiomas were delineated manually in the PET dataset. PET volumes at each time point were compared to the reference standard 60 min post tracer injection (p.i.) using the Friedman test followed by a Wilcoxon signed-rank test and Bonferroni correction. In all patients, the earliest time point with 100% lesion detection compared to 60 min p.i. was identified. PET volumes did not change significantly from 15 min p.i. (p = 1.0) compared to 60 min p.i. The earliest time point with 100% lesion detection in all patients was 10 min p.i. In patients with meningiomas undergoing Ga-68-DOTATOC-PET, the tracer uptake time can safely be reduced to 15 min p.i. with comparable PET volume and 100% lesion detection compared to 60 min p.i

Motor cortical excitability and pre-supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity

Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson\u27s disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50 – 70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN − and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10 – 12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson\u27s disease