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Clinical Research
Applications: Academic neurosurgery, clinical neurosciences, psychiatry.
Neural plasticity and beyond
As a company, we are excited by the prospect of collaborating with clinicians, hospitals, and academic institutions to foster research programs using Nexstim technology. Please feel free to inquire as to how we can develop an economically viable solution to exploring your hypotheses involving nTMS, or inquire as to our current research goals.
Plast
Plasticity
Adapted from Julkunen & Karhu, ch. 16: Brain Plasticity in Neurosurgery
"Rather than waiting for a tumour to induce functional reorganization, prehabilitation uses nrTMS to try and move functionally eloquent brain regions away from a planned surgical site"
To date, there are only three published case reports on this technique; nevertheless, these reports provide proof of concept and valuable data for the noninvasive induction of functional reorganization by nrTMS. In all three cases, using a protocol of 7–12 sessions of nrTMS therapy for 10–20 min each day, the investigators were able to modify the organization of language networks (Barwood et al. 2011; Andoh and Martinot 2008; Barcia et al. 2012)
For neurosurgery, the most important application of nTMS is to produce momentary cortical maps representative of certain neural functions. Sources of plasticity can be considered as lesion-induced, use-dependent or the result of maladaptive plasticity.
Overview
In 2008, Duffau and colleagues reported how they were not able to resect gliomas completely during the first surgery because intraoperative mapping showed eloquent motor or language function within the region of the tumour (Robles et al. 2008). They followed these patients postoperatively, waiting for functional reorganization to take place. On repeat surgery, they were able to resect the tumour residual, because DES showed no further function in the tumor area.
In one case report, a patient suffering from a LGG within the hand knob of the precentral gyrus was initially deemed to have a non-resectable lesion. Preoperative nTMS mapping revealed motor areas to be outside the anatomically presumed motor eloquent cortex (Takahashi et al. 2012)
Gliomas have been shown to cause relocation of the functional motor areas, as they tend to shift motor areas in their close vicinity. Similar observations have been made in language-related areas as a potential hemispheric shift, and the SMA appears to play a major role in motor cortex plasticity in higher-grade tumour patients
Cortical maps of LGG patients have revealed various patterns of reorganization with brain functions remaining within the tumour, reorganizing around the tumor, spreading in the ipsilateral hemisphere, or even moving to the contralateral hemisphere
nrTMS language mapping allows for the longitudinal reexamination of patients with known tumours in high-risk regions. By following patients at regular intervals, nrTMS-based language mapping alerts the clinician when a previously unresectable tumour has become resectable due to the relocation of critical language sites (Krieg et al. 2014)
Consc
Consciousness
Previous studies have separately reported impaired functional, structural, and effective connectivity in patients with disorders of consciousness (DOC). The perturbational complexity index (PCI) is a transcranial magnetic stimulation (TMS) derived marker of effective connectivity.
Overview
With 23 patients and 14 healthy subjects, the researchers demonstrated that structural integrity, approached with global FA, could explain 74% of the effective connectivity variability, represented by the perturbational complexity index (PCI).
Results
Their findings demonstrated that the majority of effective connectivity variance is explained by structure, as approached by PCI and FA, respectively.
Bodart et al. (2018) assessed 23 patients with severe brain injury more than 4 weeks post-onset, leading toDOC or locked-in syndrome, and 14 healthy subjects. We calculated PCI using repeated single pulse TMS coupled with high-density electroencephalography, and used it as a surrogate of effective connectivity (fractional anisotropy; FA, used as a marker of structural integrity).
"This result underlines that both structural and effective connections need to be relatively preserved for consciousness to emerge."
TMS-EEG assess the effects of cortical stimulation on distant areas and thus provides a measure of effective neural connectivity.
Bodart et al. (2018).
TMS-EEG data indicating 'almost flat' in the patient with unresponsive wakefulness syndrome.
Calc
Calculation
"Overall, the high importance of the parietal lobe, especially the angular gyrus, and adjacent frontal areas for arithmetic processing were confirmed with this technique.
Maurer et al (2016) evaluated the feasibility of rTMS for locating cortical calculation function in healthy volunteers, and to establish this technique for future scientific applications as well as preoperative mapping in brain tumor patients
Overview
A meta-analysis of fMRI studies showed that regions such as the middle and superior frontal gyri were activated during calculation tasks. The detected cortical localizations in this study involving the left parietal lobe and adjacent frontal areas are confirmed by current literature using other modalities/lesion studies.
Results
The highest error rate (80 %) for all errors of all subjects was observed in the right ventral precentral gyrus. division task, a 45 % error rate was achieved in the left middle frontal gyrus. The subtraction task showed its highest error rate (40 %) in the right angular gyrus (anG). In the addition task a 35 % error rate was observed in the left anterior superior temporal gyrus. Lastly, the multiplication task induced a maximum error rate of 30 % in the left anG.
Twenty healthy subjects underwent rTMS calculation mapping using 5 Hz/10 pulses. Fifty-two previously determined cortical spots of the whole hemispheres were stimulated on both sides. The subjects were instructed to perform the calculation task composed of 80 simple arithmetic operations while rTMS pulses were applied.
Duffau et al. (2002) showed the paramount importance of the left anG for arithmetic processing by using intraoperative electrostimulation in a patient with a left parietal lobe glioma.
Also explored by:
Montefinese et al. (2017), who demonstrated that two-digit mental addition and subtraction causally involve RH and LH cerebral areas of posterior parietal cortex to some degree.
Facial Recognition
Maurer et al. (2017) evaluated the the feasibility and spatial discrimination of repetitive nTMS (rTMS) mapping for detection of cortical face processing areas in a cohort of healthy volunteers (n=20).
Overview
Both hemispheres were investigated randomly with an interval of 2 weeks between mapping sessions. Fifty-two predetermined cortical spots of the whole hemispheres were mapped after baseline measurement, with 5hz/10 pulses.
Results
In 80% of all subjects rTMS elicited naming errors in the right middle middle frontal gyrus (mMFG). Concerning anomia errors, the highest error rate (35%) was achieved in the bilateral triangular inferior frontal gyrus (trIFG).
The data set consisted of 80 portraits/photos of popular persons in culture, entertainment, sports, and politics and was compiled in a way that volunteers between the age of 20–30 years were able to recognize and name them, with baseline test was performed by every volunteer prior to each session.
The exact localization of facial processing remains debatable since it involves a large variety of subfunctions and structures, including visual pathways like the OFA, memory-associated structures like the hippocampus, sensory components like the somatosensory cortex, or emotional aspects, such as those processed in the amygdala.
The observed localizations are well in accordance with the contemporary literature, and the mapping did not interfere with rTMS-induced language impairment.
"rTMS seems feasible for locating the cortical facial processing function and evoking prosopagnosia-like symptoms"
Face
Visuospatial function
"rnTMS-implemented HVOT is a feasible technique and can be successfully combined with DTI tractography of the SLF branches to achieve a 3D reconstruction of the most important cortico-subcortical components of the brain visuospatial network."
Raffa et al. (2021) paired rnTMS with the Hooper Visual Organization Test (HVOT), partnered with DTI tractoraphy to map the visuospatial network consisting of the three rbanches of the superior longitudinal fasciculus (SLF)
Overview
The reconstruction of the cortico-subcortical VS network was successfully used to plan and guide tumor resection. A gross total resection (GTR) was achieved in 85% of cases. After surgery no new VSAs deficits were observed and a slightly significant improvement of the HVOT score (p=0.02) was documented.
Results
The historical control group (Group B) included 20 patients matched for main clinical characteristics with patients in Group A, operated without the support of the nTMS-based planning. GTR was achieved in 90% of cases, but the postoperative HVOT score resulted to be worsened as compared to the preoperative period (p=0.03)
The comparison between groups showed a significantly improved postoperative HVOT score in Group A vs. Group B (p=0.03)
A repetitive stimulation was applied over both the hemispheres, with particular regard to the parietal lobe and the adjacent frontal, temporal and occipital gyri, during the execution of an nTMS-implemented version of the HVOT test.
Each participant underwent a baseline task without nTMS stimulation (train of 10 pulses with a 5hz frequency at 100% of the RMT intensity) three times, in order to eliminate unrecognized or misnamed drawings, to induce a learning-effect, and therefore to reduce as much as possible false-positive results.
Raffa et al. 2021
Also explored by:
Giglhuber et al. (2018), partnered with the greyscales task.
Salatino et al. (2019), partnered with the line length estimation task.
VSF
Neuro-rehabilitation
Ille et al. (2021) performed a randomized sham-controlled, double blinded trial on patients suffering from acute surgery-related paresis of upper extremities after glioma resection.
Overview
nrTMS can be used to up-regulate or down-regulate the ipsilateral motor cortex and enhance the cortical excitability of the contralateral hemisphere.
Results
nrTMS with physical therapy was associated with significantly greater upper extremity motor outcome than the sham stimulation combined with physical therapy.
The use of rTMS therapy with stroke patients is widely accepted. Various approaches to using rTMS therapy with stroke patients have been developed in the past, including down-regulating the contralesional hemisphere using low-frequency rTMS to reduce transcollosal inhibition (TCI).
Patients (n=39) were randomly assigned to receive either low frequency nrTMS (1Hz, 15min), or sham stimulation directly before physical therapy for seven days.
The trials results show for the first time that the down-regulation of the contralesional motor cortex and the suspected reduction of transcallosal inhibition significantly benefits motor recovery.
"Patients suffering from acute surgery-related paresis of the UE due to subcortical ischemia after glioma resection significantly benefit from low-frequency nrTMS stimulation therapy of the unaffected hemisphere"
The primary endpoint was the change in Fugl-Meyer Assessment at follow-up, compared to day 1 after surgery.
NEURO
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