Noninvasive hippocampal blood-brain barrier opening in Alzheimer's disease with focused ultrasound.

The blood-brain barrier (BBB) presents a significant challenge for treating brain disorders. The hippocampus is a key target for novel therapeutics, playing an important role in Alzheimer's disease (AD), epilepsy, and depression. Preclinical studies have shown that magnetic resonance (MR)-guided low-intensity focused ultrasound (FUS) can reversibly open the BBB and facilitate delivery of targeted brain therapeutics. We report initial clinical trial results evaluating the safety, feasibility, and reversibility of BBB opening with FUS treatment of the hippocampus and entorhinal cortex (EC) in patients with early AD. Six subjects tolerated a total of 17 FUS treatments with no adverse events and neither cognitive nor neurological worsening. Post-FUS contrast MRI revealed immediate and sizable hippocampal parenchymal enhancement indicating BBB opening, followed by BBB closure within 24 h. The average opening was 95% of the targeted FUS volume, which corresponds to 29% of the overall hippocampus volume. We demonstrate that FUS can safely, noninvasively, transiently, reproducibly, and focally mediate BBB opening in the hippocampus/EC in humans. This provides a unique translational opportunity to investigate therapeutic delivery in AD and other conditions.

Detailed analysis of allergic cutaneous reactions to spinal cord stimulator devices.

The use of spinal cord stimulation (SCS) devices to treat chronic, refractory neuropathic pain continues to expand in application. While device-related complications have been well described, inflammatory reactions to the components of these devices remain underreported. In contrast, hypersensitivity reactions associated with other implanted therapies, such as endovascular and cardiac rhythm devices, have been detailed. The purpose of this case series is to describe the clinical presentation and course of inflammatory reactions as well as the histology of these reactions. All patients required removal of the entire device after developing inflammatory reactions over a time course of 1-3 months. Two patients developed a foreign body reaction in the lead insertion wound as well as at the implantable pulse generator site, with histology positive for giant cells. One patient developed an inflammatory dermatitis on the flank and abdomen that resolved with topical hydrocortisone. "In vivo" testing with a lead extension fragment placed in the buttock resulted in a negative reaction followed by successful reimplantation of an SCS device. Inflammatory reactions to SCS devices can manifest as contact dermatitis, granuloma formation, or foreign body reactions with giant cell formation. Tissue diagnosis is essential, and is helpful to differentiate an inflammatory reaction from infection. The role of skin patch testing for 96 hours may not be suited to detect inflammatory giant cell reactions that manifest several weeks post implantation.

Transcranial brain stimulation: clinical applications and future directions.

Noninvasive brain stimulation is a valuable investigative tool and has potential therapeutic applications in cognitive neuroscience, neurophysiology, psychiatry, and neurology. Transcranial magnetic stimulation (TMS) is particularly useful to establish and map causal brain-behavior relations in motor and nonmotor cortical areas. Neuronavigated TMS is able to provide precise information related to the individual's functional anatomy that can be visualized and used during surgical interventions and critically aid in presurgical planning, reducing the need for riskier and more cumbersome intraoperative or invasive mapping procedures. This article reviews methodological aspects, clinical applications, and future directions of TMS-based mapping.

Low and therapeutic doses of antidepressants are associated with similar response in the context of multimodal treatment of pain.

BACKGROUND: Antidepressants are prescribed in a wide range of doses to treat both depression and chronic pain, with optimal psychopharmacology individualized for each patient. In the past decade more antidepressants from different chemical classes have become available and are being used for the treatment of both chronic pain and depression. OBJECTIVE: To review the utilization pattern changes and compare response rates of different classes and doses of antidepressants for various pain conditions in the context of multimodal therapies. DESIGN: Chart review. METHODS: We reviewed 5,916 records at an outpatient multidisciplinary pain center. Of these, 379 records were for patients diagnosed with cancer pain. Because the mechanisms and treatment approaches to cancer pain can differ greatly from non-cancer chronic pain, these records were excluded from the analysis. We assessed 1,506 medical records for patients with chronic non-caner pain who had used at least one antidepressant, with the main outcome measure being the Numeric Rating Pain Scale, 0-10. RESULTS: Of the 5,916 charts reviewed, 1,506 (25.4%) chronic non-cancer pain charts recorded the prescription of at least one antidepressant. Most patients received a combination of medications and procedures. Of the 450 patients receiving secondary amines, favorable responses were recorded for 340 (76%) patients, while 103 (23%) did not respond and 7 had unknown responses. Of the 492 patients receiving tertiary amines, favorable responses were recorded for 375 (76%) patients, while 113 (23%) did not respond, and 4 had unknown responses. Of the 533 patients receiving SSRI/SNRIs, favorable responses were recorded for 382 (72%) patients, while 147 (28%) did not respond, and 4 had unknown responses. Of the 369 patients receiving atypical antidepressants, favorable responses were recorded for 272 (74%) patients, while 94 (25%) did not respond, and 3 had unknown responses. LIMITATIONS: A retrospective study design and the use of antidepressants as a part of multimodal treatment of pain. CONCLUSION: The data suggest that in the context of multimodal treatment for chronic pain, antidepressant therapy at both low and therapeutic doses demonstrates similar response rates. Tricyclic antidepressants (TCAs), which include secondary and tertiary amines, as well as SSRI/SNRIs and atypicals, all appear to show similar favorable response rates.