Transcranial ultrasound stimulation in humans is associated with an auditory confound that can be effectively masked.

BACKGROUND: Transcranial ultrasound stimulation (TUS) is emerging as a potentially powerful, non-invasive technique for focal brain stimulation. Recent animal work suggests, however, that TUS effects may be confounded by indirect stimulation of early auditory pathways. OBJECTIVE: We aimed to investigate in human participants whether TUS elicits audible sounds and if these can be masked by an audio signal. METHODS: In 18 healthy participants, T1-weighted magnetic resonance brain imaging was acquired for 3D ultrasound simulations to determine optimal transducer placements and source amplitudes. Thermal simulations ensured that temperature rises were <0.5 °C at the target and <3 °C in the skull. To test for non-specific auditory activation, TUS (500 kHz, 300 ms burst, modulated at 1 kHz with 50% duty cycle) was applied to primary visual cortex and participants were asked to distinguish stimulation from non-stimulation trials. EEG was recorded throughout the task. Furthermore, ex-vivo skull experiments tested for the presence of skull vibrations during TUS. RESULTS: We found that participants can hear sound during TUS and can distinguish between stimulation and non-stimulation trials. This was corroborated by EEG recordings indicating auditory activation associated with TUS. Delivering an audio waveform to participants through earphones while TUS was applied reduced detection rates to chance level and abolished the TUS-induced auditory EEG signal. Ex vivo skull experiments demonstrated that sound is conducted through the skull at the pulse repetition frequency of the ultrasound. CONCLUSION: Future studies using TUS in humans need to take this auditory confound into account and mask stimulation appropriately.

Network-wide abnormalities explain memory variability in hippocampal amnesia.

Patients with hippocampal amnesia play a central role in memory neuroscience but the neural underpinnings of amnesia are hotly debated. We hypothesized that focal hippocampal damage is associated with changes across the extended hippocampal system and that these, rather than hippocampal atrophy per se, would explain variability in memory between patients. We assessed this hypothesis in a uniquely large cohort of patients (n = 38) after autoimmune limbic encephalitis, a syndrome associated with focal structural hippocampal pathology. These patients showed impaired recall, recognition and maintenance of new information, and remote autobiographical amnesia. Besides hippocampal atrophy, we observed correlatively reduced thalamic and entorhinal cortical volume, resting-state inter-hippocampal connectivity and activity in posteromedial cortex. Associations of hippocampal volume with recall, recognition, and remote memory were fully mediated by wider network abnormalities, and were only direct in forgetting. Network abnormalities may explain the variability across studies of amnesia and speak to debates in memory neuroscience.

Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity.

LTA 4H is a ubiquitously distributed 69 kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA 4H stereospecifically catalyzes the transformation of the unstable epoxide LTA 4 to the diol LTB 4, a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, and T cells. Inhibiting the formation of LTB 4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease (IBD), asthma, and atherosclerosis. We developed a pharmacophore model using a known inhibitor manually docked into the active site of LTA 4H to identify a subset of compounds for screening. From this work we identified a series of benzoxazole, benzthiazole, and benzimidazole inhibitors. SAR studies resulted in the identification of several potent inhibitors with an appropriate cross-reactivity profile and excellent PK/PD properties. Our efforts focused on further profiling JNJ 27265732, which showed encouraging efficacy in a disease model relevant to IBD.

Vinylation of aromatic halides using inexpensive organosilicon reagents. Illustration of design of experiment protocols.

The preparation of styrenes by palladium-catalyzed cross-coupling of aromatic iodides and bromides with divinyltetramethyldisiloxane (DVDS) in the presence of inexpensive silanolate activators has been developed. To facilitate the discovery of optimal reaction conditions, Design of Experiment (DoE) protocols were used. By the guided selection of reagents, stoichiometries, temperatures, and solvents, the vinylation reaction was rapidly optimized with three stages consisting of ca. 175 experiments (of a possible 1440 combinations). A variety of aromatic iodides undergo cross-coupling at room temperature in the presence of potassium trimethylsilanoate using Pd(dba)2 in DMF in good yields. Triphenylphosphine oxide is needed to extend catalyst lifetime. Application of these conditions to aryl bromides was accomplished by the development of two complementary protocols. First, the direct implementation of the successful reaction conditions using aryl iodides at elevated temperature in THF provided the corresponding styrenes in good to excellent yields. Alternatively, the use of potassium triethylsilanolate and a bulky "Buchwald-type" ligand allows for the vinylation reactions to occur at or just above room temperature. A wide range of bromides underwent coupling in good yields for each of the protocols described.