New Hope for Those with Stroke and other Brain Lesions

Stroke is the leading cause of long-term preventable disability. Developing new technologies to help recover from a stroke and other brain lesions/damaged areas has attracted the best neuroscientists in this field1.

In this regard, there is much research showing beneficial effects of repetitive transcranial magnetic stimulation (rTMS) on the left dorsolateral prefrontal cortex (DLPFC) for treating various neuropsychiatric or neuropsychological disorders1-3.

Standard Transcranial Stimulation (TMS)

Decreased connectivity within the ventral visual stream in a patient with focal stroke

We have a great understanding of how standard transcranial magnetic stimulation (TMS) causes neurophysiological changes to reverse the damages that stroke causes in the brain. As a result of a concerted effort between our clinicians, scientists and neuropsychologists, we have developed novel strategies to enhance motor recovery.

Because standard TMS is a non-invasive tool it can be used repeatedly to help brain plasticity to reverse damages resulting from stroke. We have used TMS as a therapeutic modality to safely improve motor function in patients who had sustained damages to their body as a result of car accidents and genetically or behavior-induced damage to the brain.

We have experience in using standard TMS to treat different motor areas, such as the ipsilesional hemisphere, secondary motor areas, and contralesional hemisphere to achieve motor recovery. We also have used standard TMS to enhance upper extremity function.

Normal connectivity within the ventral visual stream in healthy volunteers matching age/sex

On the other hand, one of the most exciting developments in magnetic resonance imaging (MRI) has been the visualization of brain networks by resting-state functional connectivity or rsFC MRI. In a series of studies, fMRI has proven to be a powerful tool for revealing the effect of stroke on the functional connectivity of the brain.

For example, recently it has been reported4 that the default mode network (DMN), cognitive control network (CCN) and affective network (AN) found a depression-related increase in functional connectivity (FC) in the same dorsal region (i.e., dorsal medial prefrontal), called the dorsal nexus5.

This result suggests that depressive symptoms are not associated with a specific network but rather the dysfunction of several brain networks. Furthermore, PSD has been shown to cause changes in FC in DMN and AN.

These findings reinforced the hypothesis that these networks are deeply involved in the pathogenesis of PSD.

Since PSD has similar clinical symptoms with depression, it means that the fMRI must be used in the assessment of pathology and treatment of stroke.

Based on the above results, we have dedicated many resources to further enhance TMS potency by developing resting-state functional connectivity (rsFC) magnetic resonance imaging (MRI), or fMRI, systems to guide TMS treatment.

This technique brings state of art imaging techniques to detect the exact affected areas in the brain, not only through traditional visible signatures of stroke on anatomical MRI images, but also by developing functional biomarkers through the use of fMRI, which takes full advantage of the stimulation parameters and patient characteristics to produce an optimal response to our treatment. This is the future of non-invasive treatment for post-stroke recovery.

Learn about fMRI in Stroke and other Brain Lesions

Studies on the Effects of fMRI

In a recent study on rodents6 using fMRI to assess the effect of low-intensity (LI) TMS at 1 Hz, 10 Hz, and continuous theta-burst stimulation (cTBS) or biomimetic high-frequency stimulation (BHFS), LI-rTMS-induced changes in the resting-state networks (RSN) has been proven.

These RSN’s effects were observed:

(a) in the somatosensory cortex (following 10 HZ the synchrony of resting activity decreased ipsilaterally, and bilaterally following 1 Hz stimulation and BHFS, and increased ipsilaterally following cTBS);

(b) in the motor cortex (following 1 Hz TMS and 10 Hz observed bilateral changes, following BHFS a contralateral decrease in synchrony, and following cTBS an ipsilateral increase); and

(c) in the hippocampal region (following 10 Hz synchrony decreased ipsilaterally, and following 1 Hz TMS and BHFS bilaterally).

These findings demonstrate that TMS modulates functional connectivity within the RSN with frequency-specific outcomes. These rodent results are similar to changes observed in humans following TMS treatment.

In another study7, patients with first acute ischemic stroke onset were analyzed for the performance of a fMRI and found that the functional connectivity (FC) of the motor network in acute ischemic stroke is independently associated with functional outcomes.

Aberrant connectivity in a patient with brain lesions due to poisoning

Specifically, the FC between ipsilesional primary motor cortex (M1) and contralesional dorsal premotor area (PMd), were independently associated with unfavorable outcomes, whereas the FC of the default mode network was not different between groups. These results showed that interhemispheric FC of the motor network is an independent predictor of functional outcomes in patients with acute ischemic stroke.

A randomized, double-blind, SHAM-controlled study, recently showed the effects of high-frequency left DLPFC rTMS on resting-state activity8. These investigators measured resting-state brain activity with the fractional amplitude of low-frequency fluctuation (fALFF) and functional connectivity (FC).

Normal connectivity in healthy volunteers matching age/sex

They reported increased fALFF in rostral anterior cingulate cortex (rACC) after 20 Hz rTMS, while no changes were found after SHAM stimulation. Xue et al8 used the suprathreshold rACC cluster as the seed and found increased FC in the left temporal cortex.

These results show that high-frequency rTMS on the left DLPFC enhances low-frequency resting-state brain activity in the target site and remote sites, as reflected by fALFF and FC. This way TMS can be used to reach remote sites affected by stroke.

Inversely, fMRI can be used to find the exact location of the cortical counterpart of the networks in which an inaccessible brain region has been affected by stroke. We have developed fMRI-guided TMS to specifically treat those suffering from a stroke.


References

1. Hoyer EH, Celnik PA. Understanding and enhancing motor recovery after stroke using transcranial magnetic stimulation. Restor Neurol Neurosci. 2011;29(6):395-409.

2. Málly J, Dinya E. Recovery of motor disability and spasticity in post-stroke after repetitive transcranial magnetic stimulation (rTMS). Brain Res Bull. 2008 Jul 1;76(4):388-95.

3. Takeuchi N, Chuma T, Matsuo Y, Watanabe I, Ikoma K. Repetitive transcranial magnetic stimulation of contralesional primary motor cortex improves hand function after stroke. Stroke. 2005 Dec;36(12):2681-6.

4. Zhang P, Wang J, Xu Q, Song Z, Dai J, Wang J. Altered functional connectivity in post-ischemic stroke depression: A resting-state functional magnetic resonance imaging study. Eur J Radiol. 2018 Mar;100:156-165.

5. Sheline YI, Price JL, Yan Z, Mintun MA. Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus. Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):11020-5.

6. Seewoo BJ, Feindel KW, Etherington SJ, Rodger J. Resting-state fMRI study of brain activation using low-intensity repetitive transcranial magnetic stimulation in rats. Sci Rep. 2018 Apr 30;8(1):6706.

7. Chi NF, Ku HL, Chen DY, Tseng YC, Chen CJ, Lin YC, Hsieh YC, Chan L, Chiou HY, Hsu CY, Hu CJ. Cerebral Motor Functional Connectivity at the Acute Stage: An Outcome Predictor of Ischemic Stroke. Sci Rep. 2018 Nov 14;8(1):16803.

8. Xue SW, Guo Y, Peng W, Zhang J, Chang D, Zang YF, Wang Z. Increased Low-Frequency Resting-State Brain Activity by High-Frequency Repetitive TMS on the Left Dorsolateral Prefrontal Cortex. Front Psychol. 2017 Dec 22;8:2266.

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Neurotherapeutix is the leading clinic for functional imaging guided transcranial magnetic stimulation (TMS), a safe, innovative, and non-invasive methodology for treating a wide range of acute and chronic mental disorders and brain injuries. Our advanced fMRI technology allows us to map the brain for the... Learn More »

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