Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS) are two types of non-invasive transcranial brain stimulation (TBS). They are useful tools for stroke research and may be potential adjunct therapies for functional recovery. However, stroke often causes large cerebral lesions, which are commonly accompanied by a secondary enlargement of the ventricles and atrophy. These structural alterations substantially change the conductivity distribution inside the head, which may have potentially important consequences for both brain stimulation methods. We therefore aimed to characterize the impact of these changes on the spatial distribution of the electric field generated by both TBS methods. In addition to confirming the safety of TBS in the presence of large stroke-related structural changes, our aim was to clarify whether targeted stimulation is still possible. Realistic head models containing large cortical and subcortical stroke lesions in the right parietal cortex were created using MR images of two patients. For TMS, the electric field of a double coil was simulated using the finite-element method. Systematic variations of the coil position relative to the lesion were tested. For TDCS, the finite-element method was used to simulate a standard approach with two electrode pads, and the position of one electrode was systematically varied. For both TMS and TDCS, the lesion caused electric field “hot spots” in the cortex. However, these maxima were not substantially stronger than those seen in a healthy control. The electric field pattern induced by TMS was not substantially changed by the lesions. However, the average field strength generated by TDCS was substantially decreased. This effect occurred for both head models and even when both electrodes were distant to the lesion, caused by increased current shunting through the lesion and enlarged ventricles. Judging from the similar peak field strengths compared to the healthy control, both TBS methods are safe in patients with large brain lesions (in practice, however, additional factors such as potentially lowered thresholds for seizure-induction have to be considered). Focused stimulation by TMS seems to be possible, but standard tDCS protocols appear to be less efficient than they are in healthy subjects, strongly suggesting that tDCS studies in this population might benefit from individualized treatment planning based on realistic field calculations.
Transcranial brain stimulation (TBS) methods are useful tools to induce and to quantify neural plasticity, and as such are increasingly being used in stroke research and as potential adjunct therapies in stroke rehabilitation. The cerebral lesions caused by stroke result in persisting physical or cognitive impairments in around 50% of all survivors (Di Carlo, 2008; Leys et al., 2005 ; Young and Forster, 2007), meaning that new therapies are urgently needed. Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS) are two TBS approaches which are being increasingly utilised in stroke research. Single-pulse TMS combined with electromyography (EMG) or electroencephalography (EEG) can be used to assess cortical excitability, for example to index the functional state of the perilesional tissue. The neuromodulatory effects of repetitive TMS protocols (rTMS) may, in association with neuro-rehabilitative treatments, enhance motor recovery (Liew et al., 2014). Similar results have been demonstrated for TDCS. For example, anodal TDCS of the hand area in the primary motor cortex has been shown to improve motor performance of the affected hand (Allman et al., 2016; Hummel et al., 2005 ; Stagg et al., 2012) and anodal TDCS applied over the left frontal cortex enhanced naming accuracy in patients with aphasia (Baker et al., 2010). However, not all studies report a clear-cut positive impact of TBS on the stroke symptoms. Rather, the observed effects are often weak and not consistent across patients, demonstrating the need for a better understanding of the underlying biophysical and physiological mechanisms.
Compared with healthy subjects, several factors might contribute to a change in the neuroplastic response to TBS protocols in stroke patients, including changes in the neural responsiveness to the applied electric fields, as well as differences in the underlying physiology and metabolism (Blicher et al., 2009; Blicher et al., 2015 ; O’Shea et al., 2014). When the lesions are large, they may also substantially alter the generated electric field pattern, meaning that the assumptions on spatial targeting as derived from biophysical modelling and physiological experiments in healthy subjects might no longer be valid. Stroke lesions are often accompanied by secondary macrostructural changes such as cortical atrophy and enlargement of the ventricles (e.g., Skriver et al., 1990), which may further contribute to changes in the field pattern. In addition, the safety of TBS in patients with large lesions needs to be further clarified, as it is possible that the lesions might cause stimulation “hot spots”. In chronic patients, the stroke cavity becomes filled with corticospinal fluid (CSF), which might cause shunting of current, funnelling the generated currents towards the surrounding brain tissue and potentially causing localized areas of dangerously high field strengths.
Here, using finite-element calculations and individual head models derived from structural MR images, we focused on the impact of a large cortical lesion in chronic stroke on the electric field pattern generated in the brain by TMS and TDCS, respectively. Firstly, we assessed the safety of the stimulation by comparing the achieved field strengths with those estimated for a healthy control. Secondly, we tested how reliably we can accurately target the perilesional tissue, often the desired target for TBS, as reorganisation here is thought to underpin functional recovery (Kwakkel et al., 2004). Finally, we were also interested to see whether any observed changes in the field pattern were specific to a patient with a cortical lesion (which is connected to the CSF layer underneath the skull), or whether similar effects might occur in case of large chronic subcortical lesion. We therefore additionally tested the field distribution in a head model of a patient with a subcortical lesion occurring at a similar position as the cortical lesion.
2. Materials and methods
2.1. Selection of patients
The aim of this study was to characterize the effect of a large chronic cortical stroke lesion on the electric field distribution generated by TBS, and to compare the effects of this lesion to that caused by a large chronic subcortical lesion. MR images of several patients were visually inspected to select two datasets, which had a cortical [P01] and subcortical lesion [P02], respectively, within the same gross anatomical regions.
Patient P01 was a 36 year old female with episodic migraine; she was admitted with left hemiparalysis, fascial palsy and a total NIHSS score of 16 due to a right ICI/MCI occlusion. She was treated with IV thrombolysis and thrombectomy and recanalization was achieved 5 h after symptom onset. One year post-stroke she still suffered from motor impairment (Wolf Motor Function Test [WMFT] score of 30) and was scanned as part of a clinical study investigating the effect of combining Constraint-Induced Movement Therapy and tDCS (Figlewski et al., 2017; Clinical trials NCT01983319, Regional Ethics approval: 1-10-72-268-13). The structural scans showed a cortical lesion in the right parietal lobe (Fig. 1A). The lesion volume, delineated manually with reference to T1- and T2-weighted imaging, was 26,415 mm3.
A) Coronal view of patient P01 with a cortical lesion in the right hemisphere. The top shows the T1-weighted MR image and the bottom the reconstructed head mesh. The view was chosen to include the lesion centre. The lesion is marked by red dashed circles. B) Corresponding view of patient P02 with a large subcortical lesion at a similar location in the right hemisphere. C) Corresponding view of the data set of the healthy control. D) The coil and electrode positions were systematically moved along two directions that were approximately perpendicular to each other. Five positions were manually placed every 2 cm in posterior – anterior direction symmetrically around the centre of the cortical lesion. The same was repeated along the lateral – medial direction. Both lines share the same centre position above the lesion, resulting in 9 positions in total. E) At each position, two coil orientations were tested which resulted in a current flow underneath the coil centre from anterior to posterior (top) and from lateral to medial, respectively (bottom). F) For each position of the yellow “stimulating” electrode, two positions of the blue return electrode were tested. First, the contralateral equivalent of the electrode position above the centre of the cortical lesion was used (top). In addition, a position on the contralateral forehead was tested (bottom).