Non-invasive transcranial ultrasound stimulation for neuromodulation.

Transcranial ultrasound stimulation (TUS) holds great potential as a tool to alter neural circuits non-invasively in both animals and humans. In contrast to established non-invasive brain stimulation methods, ultrasonic waves can be focused on both cortical and deep brain targets with the unprecedented spatial resolution as small as a few cubic millimeters. This focusing allows exclusive targeting of small subcortical structures, previously accessible only by invasive deep brain stimulation devices. The neuromodulatory effects of TUS are likely derived from the kinetic interaction of the ultrasound waves with neuronal membranes and their constitutive mechanosensitive ion channels, to produce short term and long-lasting changes in neuronal excitability and spontaneous firing rate. After decades of mechanistic and safety investigation, the technique has finally come of age, and an increasing number of human TUS studies are expected. Given its excellent compatibility with non-invasive brain mapping techniques, such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), as well as neuromodulatory techniques, such as transcranial magnetic stimulation (TMS), systemic TUS effects can readily be assessed in both basic and clinical research. In this review, we present the fundamentals of TUS for a broader audience. We provide up-to-date information on the physical and neurophysiological mechanisms of TUS, available readouts for its neural and behavioral effects, insights gained from animal models and human studies, potential clinical applications, and safety considerations. Moreover, we discuss the indirect effects of TUS on the nervous system through peripheral co-stimulation and how these confounding factors can be mitigated by proper control conditions.

Intra-Areal Visual Topography in Primate Brains Mapped with Probabilistic Tractography of Diffusion-Weighted Imaging.

Noninvasive diffusion-weighted magnetic resonance imaging (dMRI) can be used to map the neural connectivity between distinct areas in the intact brain, but the standard resolution achieved fundamentally limits the sensitivity of such maps. We investigated the sensitivity and specificity of high-resolution postmortem dMRI and probabilistic tractography in rhesus macaque brains to produce retinotopic maps of the lateral geniculate nucleus (LGN) and extrastriate cortical visual area V5/MT based on their topographic connections with the previously established functional retinotopic map of primary visual cortex (V1). We also replicated the differential connectivity of magnocellular and parvocellular LGN compartments with V1 across visual field positions. Predicted topographic maps based on dMRI data largely matched the established retinotopy of both LGN and V5/MT. Furthermore, tractography based on in vivo dMRI data from the same macaque brains acquired at standard field strength (3T) yielded comparable topographic maps in many cases. We conclude that tractography based on dMRI is sensitive enough to reveal the intrinsic organization of ordered connections between topographically organized neural structures and their resultant functional organization.

The structural and functional brain networks that support human social networks.

Social skills rely on a specific set of cognitive processes, raising the possibility that individual differences in social networks are related to differences in specific brain structural and functional networks. Here, we tested this hypothesis with multimodality neuroimaging. With diffusion MRI (DMRI), we showed that differences in structural integrity of particular white matter (WM) tracts, including cingulum bundle, extreme capsule and arcuate fasciculus were associated with an individual's social network size (SNS). A voxel-based morphology analysis demonstrated correlations between gray matter (GM) volume and SNS in limbic and temporal lobe regions. These structural changes co-occured with functional network differences. As a function of SNS, dorsomedial and dorsolateral prefrontal cortex showed altered resting-state functional connectivity with the default mode network (DMN). Finally, we integrated these three complementary methods, interrogating the relationship between social GM clusters and specific WM and resting-state networks (RSNs). Probabilistic tractography seeded in these GM nodes utilized the SNS-related WM pathways. Further, the spatial and functional overlap between the social GM clusters and the DMN was significantly closer than other control RSNs. These integrative analyses provide convergent evidence of the role of specific circuits in SNS, likely supporting the adaptive behavior necessary for success in extensive social environments.

Individual Differences in the Alignment of Structural and Functional Markers of the V5/MT Complex in Primates.

Extrastriate visual area V5/MT in primates is defined both structurally by myeloarchitecture and functionally by distinct responses to visual motion. Myelination is directly identifiable from postmortem histology but also indirectly by image contrast with structural magnetic resonance imaging (sMRI). First, we compared the identification of V5/MT using both sMRI and histology in Rhesus macaques. A section-by-section comparison of histological slices with in vivo and postmortem sMRI for the same block of cortical tissue showed precise correspondence in localizing heavy myelination for V5/MT and neighboring MST. Thus, sMRI in macaques accurately locates histologically defined myelin within areas known to be motion selective. Second, we investigated the functionally homologous human motion complex (hMT+) using high-resolution in vivo imaging. Humans showed considerable intersubject variability in hMT+ location, when defined with myelin-weighted sMRI signals to reveal structure. When comparing sMRI markers to functional MRI in response to moving stimuli, a region of high myelin signal was generally located within the hMT+ complex. However, there were considerable differences in the alignment of structural and functional markers between individuals. Our results suggest that variation in area identification for hMT+ based on structural and functional markers reflects individual differences in human regional brain architecture.

A weighted and directed interareal connectivity matrix for macaque cerebral cortex.

Retrograde tracer injections in 29 of the 91 areas of the macaque cerebral cortex revealed 1,615 interareal pathways, a third of which have not previously been reported. A weight index (extrinsic fraction of labeled neurons [FLNe]) was determined for each area-to-area pathway. Newly found projections were weaker on average compared with the known projections; nevertheless, the 2 sets of pathways had extensively overlapping weight distributions. Repeat injections across individuals revealed modest FLNe variability given the range of FLNe values (standard deviation <1 log unit, range 5 log units). The connectivity profile for each area conformed to a lognormal distribution, where a majority of projections are moderate or weak in strength. In the G29 × 29 interareal subgraph, two-thirds of the connections that can exist do exist. Analysis of the smallest set of areas that collects links from all 91 nodes of the G29 × 91 subgraph (dominating set analysis) confirms the dense (66%) structure of the cortical matrix. The G29 × 29 subgraph suggests an unexpectedly high incidence of unidirectional links. The directed and weighted G29 × 91 connectivity matrix for the macaque will be valuable for comparison with connectivity analyses in other species, including humans. It will also inform future modeling studies that explore the regularities of cortical networks.

Neuroscience: a more dynamic view of the social brain.

Information relevant for social interactions is thought to be processed in specific neural circuits. Recent studies shed new light on how that social information is encoded and processed by different brain areas.

Social network size affects neural circuits in macaques.

It has been suggested that variation in brain structure correlates with the sizes of individuals' social networks. Whether variation in social network size causes variation in brain structure, however, is unknown. To address this question, we neuroimaged 23 monkeys that had been living in social groups set to different sizes. Subject comparison revealed that living in larger groups caused increases in gray matter in mid-superior temporal sulcus and rostral prefrontal cortex and increased coupling of activity in frontal and temporal cortex. Social network size, therefore, contributes to changes both in brain structure and function. The changes have potential implications for an animal's success in a social context; gray matter differences in similar areas were also correlated with each animal's dominance within its social network.

Separate value comparison and learning mechanisms in macaque medial and lateral orbitofrontal cortex.

Uncertainty about the function of orbitofrontal cortex (OFC) in guiding decision-making may be a result of its medial (mOFC) and lateral (lOFC) divisions having distinct functions. Here we test the hypothesis that the mOFC is more concerned with reward-guided decision making, in contrast with the lOFC's role in reward-guided learning. Macaques performed three-armed bandit tasks and the effects of selective mOFC lesions were contrasted against lOFC lesions. First, we present analyses that make it possible to measure reward-credit assignment--a crucial component of reward-value learning--independently of the decisions animals make. The mOFC lesions do not lead to impairments in reward-credit assignment that are seen after lOFC lesions. Second, we examined how the reward values of choice options were compared. We present three analyses, one of which examines reward-guided decision making independently of reward-value learning. Lesions of the mOFC, but not the lOFC, disrupted reward-guided decision making. Impairments after mOFC lesions were a function of the multiple option contexts in which decisions were made. Contrary to axiomatic assumptions of decision theory, the mOFC-lesioned animals' value comparisons were no longer independent of irrelevant alternatives.

Does the medial orbitofrontal cortex have a role in social valuation?

It has been claimed that social behaviour changes after lesions of the ventromedial prefrontal cortex (vmPFC). However, lesions in humans are rarely restricted to a well defined cortical area. Although vmPFC lesions usually include medial orbitofrontal cortex (mOFC), they typically also affect subgenual and/or perigenual anterior cingulate cortex. The purpose of the current study is to investigate the role of mOFC in social valuation and decision-making. We tested four macaque monkeys prior to and after focal lesions of mOFC. Comparison of the animals' pre- and postoperative performance revealed that, unlike lesions of anterior cingulate gyrus (ACCg), lesions of mOFC did not induce alterations in social valuation. MOFC lesions did, however, induce mild impairments in a probabilistic two-choice decision task, which were not seen after ACCg lesions. In summary, the double dissociation between the patterns of impairment suggest that vmPFC involvement in both decision-making and social valuation may be mediated by distinct subregions centred on mOFC and ACCg respectively.

Experimental esophageal carcinogenesis: technical standardization and results.

The aim of this research was to determine the occurrence of epidermoid carcinoma of the esophagus induced by diethylnitrosamine (DEN) in Wistar rats. DEN was administered (250-300 g) in drinking water (10 mg/kg body weight) to four groups of rats for 72 h/week, for a duration of 90, 120, 150, or 200 days (groups T90, T120, T150, and T200). Ten animals whose drinking water did not contain DEN constituted the control group. All rats were sacrificed and their esophaguses studied macro- and microscopically. The control group did not exhibit either carcinomas or preneoplasic lesions. The T120 and T200 groups presented, respectively, 47 and 58 in situ carcinomas; 1 and 20 submucosal carcinomas (P < 0.05); 4 and 17 microinvasive carcinomas (P < 0.05); 4 and 11 advanced carcinomas (P < 0.05); and 1 and 1 cases of benign hyperplasia. Pulmonary and liver carcinomas were also found in the T200 group. The majority of advanced macroscopic lesions in the T200 group were polypoid, exophytic, and not microscopically invasive in the esophageal wall. This research confirms the effectiveness of the DEN in bringing about carcinogenesis in the Wistar rat esophagus and also shows that the lesions are dosage dependent.

The treatment of portal hypertension by videolaparoscopy in situs inversus totalis.

A rare case of a 32-year-old male with situs inversus totalis viscerum admitted to hospital for hematemesis owing to portal hypertension of Laennec cirrhosis was treated for the first time by videolaparoscopic surgery. Situs inversus diagnosis was confirmed by thoracic radiography, electrocardiogram, echocardiogram, abdominal echography and computed tomography. Upper gastrointestinal endoscopy showed esophageal varices and large varices in the fundus of the stomach. A successful operation (azygo-portal disconnection, splenic artery ligation without splenectomy; transesophageal suturing of esophageal varices without opening the esophagus and cholecystectomy), was performed by videolaparoscopy. The uneventful postoperative evolution (4-day hospitalization) reinforces the viability of the videolaparoscopic approach and the possibility of the application of this procedure even to situs inversus totalis organorum.

Video laparoscopy for the treatment of bleeding esophageal varices.

Bleeding from esophageal varices is the major cause of death in patients with portal hypertension. The ideal surgical procedure should effectively control bleeding, with as little impairment of liver function as possible and with low rates of encephalopathy. Based on this objective, we propose the azygoportal disconnection (APD) with splenic artery ligation, and suturing of the gastric and esophageal varies without opening the esophagus, by video laparoscopy. With the patient placed in a semigynecologic position, we use five trocars, and the intervention begins by dissection of the diaphragmatic hiatus and isolation of the esophagus. Then devascularization of the gastric fundus is accomplished. After that, dissection and ligature between clips of the splenic artery are performed. The surgery proceeds with dissection and ligation of the vessels of the lesser curvature. After orally introducing a 12-mm Fouchet probe, we suture the varices of the distal esophagus transmurally, with interrupted sutures. The procedure is accomplished with a floppy Nissen valve. Between March 1994 and May 1995, four patients were treated with this method, two men and two women with a mean age of 54 years. All of them had hepatic cirrhosis. Three patients were classified Child B and the other Child C. Surgical indication in all subjects was persistent bleeding of the esophageal varices, after failure of such clinical attempts as endoscopic sclerosis and tamponade with the Sangstaken-Blakemore balloon. The operation mean time was 177 min. Neither bleeding nor hemodynamic changes occurred during the surgery. The patients were sent to the intensive care unit (ICU) postoperatively for a mean time of 3 days, and they were discharged from the hospital between days 8 and 10. The evolution demonstrated stabilization of the hepatic function and regression of the varices from grades III and IV to grade I. No bleeding recurred. Although this study had a small number of patients, we believe that this operation made by mini-invasive technique permits a quick recovery, reducing the global morbidity of this procedure.

Laparoscopic cholecystectomy in children and adolescents.

During the period between August 1991 and November 1995, seven patients under age 17 were submitted to videolaparoscopic cholecystectomy (LC). Two were males and five females with ages ranging from 12 to 16 years (mean 13.8 years). The diagnosis of chronic cholecystitis with gallstones was made by the clinical history and physical and ultrasonographic examinations. There was no evidence of an association with hemolytic diseases, familial hyperlipidemia or Glucose-6-phosphate dehydrogenase (G6PD) deficiency. The surgery was performed under general anesthesia and the abdomen approached by four ports: a 10 mm umbilical incision, a 5 mm cystic, a 5 mm one at the xiphoid appendix and a 10 mm one at the left lateral margin of the left rectus abdominal muscle between the umbilical scar and the xiphoid appendix. Operative time averaged 120 minutes (105-150 min). One case required conversion to laparotomic approach because of Mirizzi's Syndrome, which was diagnosed by intraoperative cholangiography performed in all cases. There were no deaths or major postoperative complications. Hospital stays ranged from 1-3 days in the six patients submitted to LC. Thus LC in children can be considered a good method, requiring only more care regarding the use of proper equipment, complete and careful dissection of the biliary hilus, and intraoperative cholangiography. The latter is indispensable, as these children can present a higher rate of anatomic anomalies. The advantages of this techniques include a less painful postoperative period with a faster recovery, and it is especially recommended in children, who are less tolerant to physical restriction and pain than adults.

Hemobilia as a complication of laparoscopic cholecystectomy.

Laparoscopic surgery, mainly laparoscopic cholecystectomy, is a recently developed surgical procedure that has rapidly gained acceptance. Its complications remain to be critically analyzed. In this initial series of 69 patients, the rate of complications was 4.3%, and the conversion to open rate was 8.7%. A late complication occurring 4 months after surgery is presented. Upper gastrointestinal bleeding from hemobilia resulted from a cystic artery aneurysm communication with the cystic duct. This study stresses the importance of careful management of biliary structures to avoid the possibility of late and severe complications that can result from using this new surgical procedure.