Drug addiction represents a significant public health concern that has high rates of relapse despite optimal medical therapy and rehabilitation support. New therapies are needed, and deep brain stimulation (DBS) may be an effective treatment. The past 15 years have seen numerous animal DBS studies for addiction to various drugs of abuse, with most reporting decreases in drug-seeking behavior with stimulation. The most common target for stimulation has been the nucleus accumbens, a key structure in the mesolimbic reward pathway. In addiction, the mesolimbic reward pathway undergoes a series of neuroplastic changes. Chief among them is a relative hypofunctioning of the prefrontal cortex, which is thought to lead to the diminished impulse control that is characteristic of drug addiction. The prefrontal cortex, as well as other targets involved in drug addiction such as the lateral habenula, hypothalamus, insula, and subthalamic nucleus have also been stimulated in animals, with encouraging results. Although animal studies have largely shown promising results, current DBS studies for drug addiction primarily use stimulation during active drug use. More data are needed on the effect of DBS during withdrawal in preventing future relapse. The published human experience for DBS for drug addiction is currently limited to several promising case series or case reports that are not controlled. Further animal and human work is needed to determine what role DBS can play in the treatment of drug addiction.
Tony R. Wang, Shayan Moosa, Robert F. Dallapiazza, W. Jeffrey Elias and Wendy J. Lynch
Nir Lipsman, W. Jeffrey Elias, Ryder P. Gwinn and Julie G. Pilitsis
Aaron E. Bond and W. Jeffrey Elias
The goal of this study was to improve the predictability of lesion size during focused ultrasound (FUS) thalamotomy procedures.
Treatment profiles and T2-weighted MRI (T2 MRI) studies obtained in 63 patients who participated in 3 clinical trials of FUS thalamotomy from February 2011 to March 2015 were reviewed retrospectively. Four damage estimate models were compared with lesion sizes measured on postprocedural T2 MRI. Models were based on 54°C × 3 seconds, 240 cumulative equivalent minutes at 43°C, and simple thermal threshold analysis, which recorded the maximum diameter that reached a temperature of at least 51°C and 54°C. Energy requirements per °C thermal rise above 37°C were also recorded.
Lesion diameters from T2 MRI correlated poorly from the day of the procedure to day 1 postprocedure (mean increase 78% [SD 79%]). There was more predictability of lesion size from day 1 to day 30, with a mean reduction in lesion diameter of 11% (SD 24%). Of the 4 models tested, the most correlative model to day 1 findings on T2 MRI was a 51°C threshold. The authors observed an increase in the energy requirement for each subsequent treatment sonication, with the largest percentage increase from treatment sonication 1 to treatment sonication 2 (mean increase 20% in energy required per °C increase in temperature above 37°C).
At the margins, 51°C temperature threshold diameters correlated best to lesion diameters measured at day 1 with T2 MRI. The lesion size from T2 MRI decreases from day 1 to day 30 in a predictable manner, much more so than from the day of the procedure to day 1 postprocedure. Energy requirements per °C rise above 37°C continuously increase with each successive sonication.
Tony R. Wang, Aaron E. Bond, Robert F. Dallapiazza, Aaron Blanke, David Tilden, Thomas E. Huerta, Shayan Moosa, Francesco U. Prada and W. Jeffrey Elias
Although the use of focused ultrasound (FUS) in neurosurgery dates to the 1950s, its clinical utility was limited by the need for a craniotomy to create an acoustic window. Recent technological advances have enabled efficient transcranial delivery of US. Moreover, US is now coupled with MRI to ensure precise energy delivery and monitoring. Thus, MRI-guided transcranial FUS lesioning is now being investigated for myriad neurological and psychiatric disorders. Among the first transcranial FUS treatments is thalamotomy for the treatment of various tremors. The authors provide a technical overview of FUS thalamotomy for tremor as well as important lessons learned during their experience with this emerging technology.
Robert F. Dallapiazza, Kelsie F. Timbie, Stephen Holmberg, Jeremy Gatesman, M. Beatriz Lopes, Richard J. Price, G. Wilson Miller and W. Jeffrey Elias
Ultrasound can be precisely focused through the intact human skull to target deep regions of the brain for stereotactic ablations. Acoustic energy at much lower intensities is capable of both exciting and inhibiting neural tissues without causing tissue heating or damage. The objective of this study was to demonstrate the effects of low-intensity focused ultrasound (LIFU) for neuromodulation and selective mapping in the thalamus of a large-brain animal.
Ten Yorkshire swine (Sus scrofa domesticus) were used in this study. In the first neuromodulation experiment, the lemniscal sensory thalamus was stereotactically targeted with LIFU, and somatosensory evoked potentials (SSEPs) were monitored. In a second mapping experiment, the ventromedial and ventroposterolateral sensory thalamic nuclei were alternately targeted with LIFU, while both trigeminal and tibial evoked SSEPs were recorded. Temperature at the acoustic focus was assessed using MR thermography. At the end of the experiments, all tissues were assessed histologically for damage.
LIFU targeted to the ventroposterolateral thalamic nucleus suppressed SSEP amplitude to 71.6% ± 11.4% (mean ± SD) compared with baseline recordings. Second, we found a similar degree of inhibition with a high spatial resolution (∼ 2 mm) since adjacent thalamic nuclei could be selectively inhibited. The ventromedial thalamic nucleus could be inhibited without affecting the ventrolateral nucleus. During MR thermography imaging, there was no observed tissue heating during LIFU sonications and no histological evidence of tissue damage.
These results suggest that LIFU can be safely used to modulate neuronal circuits in the central nervous system and that noninvasive brain mapping with focused ultrasound may be feasible in humans.
Aaron E. Bond, Robert F. Dallapiazza, M. Beatriz Lopes and W. Jeffrey Elias
Stereotactic deep brain stimulation surgery is most commonly performed while patients are awake. This allows for intraoperative clinical assessment and electrophysiological target verification, thereby promoting favorable outcomes with few side effects. Intraoperative CT and MRI have challenged this concept of clinical treatment validation. Image-guided surgery is capable of delivering electrodes precisely to a planned, stereotactic target; however, these methods can be limited by low anatomical resolution even with sophisticated MRI modalities. The authors are developing a novel method using convection-enhanced delivery to safely manipulate the extracellular space surrounding common anatomical targets for surgery. By altering the extracellular content of deep subcortical structures and their associated white matter tracts, the MRI visualization of the basal ganglia can be improved to better define the anatomy. This technique could greatly improve the accuracy and success of stereotactic surgery, potentially eliminating the reliance on awake surgery.
Observations were made in the clinical setting where vasogenic and cytotoxic edema improved the MRI visualization of the basal ganglia. These findings were replicated in the experimental setting using an FDA-approved intracerebral catheter that was stereotactically inserted into the thalamus or basal ganglia of 7 swine. Five swine were infused with normal saline, and 2 were infused with autologous CSF. Flow rates varied between 1 μl/min to 6 μl/min to achieve convective distributions. Concurrent MRI was performed at 15-minute intervals to monitor the volume of infusion and observe the imaging changes of the deep subcortical structures. The animals were then clinically observed, and necropsy was performed within 48 hours, 1 week, or 1 month for histological analysis.
In all animals, the white matter tracts became hyperintense on T2-weighted imaging as compared with basal ganglia nuclei, enabling better definition of the deep brain anatomy. The volume of distribution and infusion (Vd/Vi ratio) ranged from 2.5 to 4.5. There were no observed clinical effects from the infusions. Histological analysis demonstrated mild neuronal effects from saline infusions but no effects from CSF infusions.
This work provides the initial foundation for a novel approach to improve the visualization of deep brain anatomy during MRI-guided, stereotactic procedures. Convective infusions of CSF alter the extracellular fluid content of the brain for improved MRI without evidence of clinical or toxic effects.