Ultrasound and neuroinflammation: immune modulation via the heat shock response.

Current pharmacological therapeutic approaches targeting chronic inflammation exhibit transient efficacy, often with adverse effects, limiting their widespread use - especially in the context of neuroinflammation. Effective interventions require the consideration of homeostatic function, pathway dysregulation, and pleiotropic effects when evaluating therapeutic targets. Signalling molecules have multiple functions dependent on the immune context, and this complexity results in therapeutics targeting a single signalling molecule often failing in clinical translation. Additionally, the administration of non-physiologic levels of neurotrophic or anti-inflammatory factors can alter endogenous signalling, resulting in unanticipated effects. Exacerbating these challenges, the central nervous system (CNS) is isolated by the blood brain barrier (BBB), restricting the infiltration of many pharmaceutical compounds into the brain tissue. Consequently, there has been marked interest in therapeutic techniques capable of modulating the immune response in a pleiotropic manner; ultrasound remains on this frontier. While ultrasound has been used therapeutically in peripheral tissues - accelerating healing in wounds, bone fractures, and reducing inflammation - it is only recently that it has been applied to the CNS. The transcranial application of low intensity pulsed ultrasound (LIPUS) has successfully mitigated neuroinflammation in vivo, in models of neurodegenerative disease across a broad spectrum of ultrasound parameters. To date, the underlying biological effects and signalling pathways modulated by ultrasound are poorly understood, with a diverse array of reported molecules implicated. The distributed nature of the beneficial response to LIPUS implies the involvement of an, as yet, undetermined upstream signalling pathway, homologous to the protective effect of febrile range hyperthermia in chronic inflammation. As such, we review the heat shock response (HSR), a protective signalling pathway activated by thermal and mechanical stress, as the possible upstream regulator of the anti-inflammatory effects of ultrasound.

Predicting high-intensity focused ultrasound thalamotomy lesions using 2D magnetic resonance thermometry and 3D Gaussian modeling.

PURPOSE: To develop a method of using two-dimensional (2D) magnetic resonance thermometry, and three-dimensional (3D) Gaussian modeling to predict the volume, shape, and location of 1 day postoperative T1w high-intensity focused ultrasound lesions in medication refractory tremor patients; thereby facilitating a better comprehension of thermal damage thresholds, which can be utilized to reduce adverse events, and improve patient outcome. METHODS: Fifteen patients underwent magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy, which was performed at our center using an InSightec ExAblate 4000 system (Haifa, Israel), and guided by magnetic resonance imaging using a 3 T Discovery 750 (General Electric Healthcare, Waukesha, WI, USA). For treatment monitoring, 2D MR thermometry (temperature sensitivity: -0.00909 ppm/°C, bandwidth: 279 Hz/pixel) was performed in multiple orthogonal planes (sagittal, coronal, and axial) intraoperatively. These images were temporally filtered using a general linear model approach to reduce noise. Temporal volumes of filtered temperature maps with a peak temperature ≥ 47°C were aligned and fitted with a 3D Gaussian to create a canonical heating model. We then fitted the filtered 2D temperature maps with a 3D Gaussian, and used the relationships derived from the 3D heating model to estimate the 3D temperature distribution. These temperature distributions were converted into thermal dose distributions and accumulated across time to create an accumulated thermal dose (ATD) profile. Thresholded ATD profiles were then correlated with manually traced T1-weighted 1 day postoperative lesion volumes across patients, and linear regression slopes were plotted against varying ATD thresholds. Additionally, the Dice-Sørensen coefficient (DSC) was calculated to quantify the volumetric overlap between predicted, and actual lesions. RESULTS: On average, 18.1 (standard deviation (SD): ±4.6, range: 10-29) sonications were performed with an average peak temperature achieved of 62.4°C (SD: ±2.4, range: 58.2-67.7). An ATD threshold of 35.8 CEM43 was found to give a unity linear regression slope; this corresponded to an average DSC of 0.689 (SD: ±0.090, range: 0.476-0.815). CONCLUSIONS: Using multiplanar 2D MR thermometry and 3D Gaussian modeling, we were able to achieve very good (DSC = 0.689) predictions of T1w 1 day postoperative lesion volume, shape and location at an ATD threshold of approximately 36 CEM43. Furthermore, this method has the potential to be used in clinical evaluations to further elucidate the relationship between thermal damage and clinical outcome. Accurate 3D lesion prediction will facilitate improved clinical decision making in future MRgFUS thalamotomies.

Focused ultrasound resolves persistent radiosurgery related change in a patient with tremor.

We report on a patient who underwent magnetic resonance guided focused ultrasound (MRgFUS) thalamotomy to treat tremor 3 years after a stereotactic radiosurgery (SRS) thalamotomy. The SRS produced only limited and transient improvements and was associated with a persistent hyperintensity on T2-FLAIR MR images. The MRgFUS thalamotomy was successful, with tremor improvement at 3 months, no adverse effects, and radiological appearance of the MRgFUS lesion similar to other patients undergoing this therapy. We also observed that the SRS-related T2-FLAIR hyperintensity had increased signal intensity 1 day post-MRgFUS, but appeared completely resolved 3 months post-MRgFUS. In conclusion, the case demonstrates that MRgFUS thalamotomy may effectively control tremor in patients with a history of SRS thalamotomy. We also speculate on the potential mechanisms of the apparent resolution of radiation-related change, and discuss possible applications of MRgFUS to reduce persistent SRS-related inflammation.