The return of the lesion for localization and therapy

Abstract

Historically, pathological brain lesions provided the foundation for localization of symptoms and therapeutic lesions were used as a treatment for brain diseases. New medications, functional neuroimaging and deep brain stimulation have led to a decline in lesions in the past few decades. However, recent advances have improved our ability to localize lesion-induced symptoms, including localization to brain circuits rather than individual brain regions. Improved localization can lead to more precise treatment targets, which may mitigate traditional advantages of deep brain stimulation over lesions such as reversibility and tunability. New tools for creating therapeutic brain lesions such as high intensity focused ultrasound allow for lesions to be placed without a skin incision and are already in clinical use for tremor. Although there are limitations, and caution is warranted, improvements in lesion-based localization are refining our therapeutic targets and improved technology is providing new ways to create therapeutic lesions, which together may facilitate the return of the lesion.

Keywords: MRgFUS; connectivity; lesion mapping; lesion network mapping; stroke.

Figure 1

Timeline of selected events illustrating the role of lesions in neuroscience and medicine. Top: Spontaneously occurring lesions played a defining role in mapping human brain function, including localization of neurological and psychiatric symptoms. The role of lesions declined with the advent of functional imaging techniques such as PET and functional MRI (fMRI) but is now on the rise due to modern lesion mapping techniques. Bottom: Brain lesions have been used to treat neurological and psychiatric symptoms for nearly one and a half centuries. The therapeutic role of lesions decreased with the development of effective medications and deep brain stimulation (DBS) but is now on the rise due to modern lesioning technologies such as magnetic resonance-guided focused ultrasound (MRgFUS). Note that this timeline is not intended to be comprehensive, but to illustrate the rise, fall and return of lesions. There are exceptions to these historical trends, including DBS treatments explored in 1950s,^, subthalamic nucleus lesions in 1990, and many lesion studies that occurred during the epoch of functional neuroimaging. DTI = diffusion tensor imaging; PD = Parkinson's disease.

Figure 2

Using brain circuit data to improve lesion-based localization and treatment. (A) Lesions resulting in essential tremor relief (left). Using normative connectome data, functional connectivity between each lesion location and the rest of the brain can be computed (middle). Brain regions connected to all lesion locations disrupting tremor can then be identified, identifying peaks in the ventral intermediate nucleus (VIM) of the thalamus (the current main therapeutic target for tremor; right). Modified with permission from Joutsa et al. (B) Examples of lesions that did or did not result in remission of smoking addiction (left) with their corresponding connectivity profiles (middle). Brain voxels best representing the connectivity difference between lesion locations disrupting addiction versus lesion locations in patients who continued smoking included the insula/opercular region and paracingulate cortex (right). Figure modified from Joutsa et al. Image distributed under a Attribution 4.0 International (CC BY 4.0) license.

Figure 3

Evolution of therapeutic lesions in functional neurosurgery. (A) Examples of lesions from different time points in history. Early ablative lesions such those resulting from prefrontal leucotomy (left) were large and spanned multiple brain regions. After introduction of stereotactic frames around 1947, lesions became more precise, such as those generated by stereotactic cingulotomy (middle). Current lesions generated by modern ablative surgery are small, precise, and even barely visible on MRI just 3 months after the procedure, such as lesions created by magnetic resonance-guided focused ultrasound (MRgFUS) (right). Frontal lobotomy: Image distributed under a CC-BY-3.0 license, courtesy to Frank Gaillard. Cingulotomy: Image distributed under a CC Attribution-Share Alike 4.0 license, courtesy of operativeneurosurgery.com. (B) The number of MRgFUS procedures for tremor have increased rapidly over the past few years. Data provided by InSightec for the commercial neuro-exablate system.

Figure 4

Schematic illustration of connectomic lesioning. (A) Current clinical lesions (blue sphere) may intersect white matter connections associated with clinical benefit (red fibres) but also detrimental connections associated with less benefit or side effects (blue fibres). In the future, optimized lesions (green sphere) can be guided by connectivity to intersect only beneficial tracts while avoiding the detrimental ones. Red and blue fibre tracts are taken from a recent study of beneficial and detrimental connections for improving obsessive-compulsive disorder (OCD) following deep brain stimulation (DBS) to the anterior limb of the internal capsule. (B) Schematic illustrating how the clinical value of lesions versus DBS could change as the precision of our therapeutic target increases. When the therapeutic target is unclear, DBS has a major advantage over lesions due to reversibility and tunability. As the target and lesioning technique become more precise, this advantage is diminished, and we may reach an inflection point where lesions become preferable over DBS (due to lower infection risk and higher convenience). It should be noted that this schematic does not account for other possible future developments, such as closed-loop DBS, which could increase the benefit of DBS. MRgFUS = magnetic resonance-guided focused ultrasound.