Deep brain stimulation of the subgenual cingulum and uncinate fasciculus for the treatment of posttraumatic stress disorder.

Deep brain stimulation (DBS) has been investigated for neuropsychiatric disorders. In this phase 1 trial, we treated four posttraumatic stress disorder (PTSD) patients with DBS delivered to the subgenual cingulum and the uncinate fasciculus. In addition to validated clinical scales, patients underwent neuroimaging studies and psychophysiological assessments of fear conditioning, extinction, and recall. We show that the procedure is safe and potentially effective (55% reduction in Clinical Administered PTSD Scale scores). Posttreatment imaging data revealed metabolic activity changes in PTSD neurocircuits. During psychophysiological assessments, patients with PTSD had higher skin conductance responses when tested for recall compared to healthy controls. After DBS, this objectively measured variable was significantly reduced. Last, we found that a ratio between recall of extinguished and nonextinguished conditioned responses had a strong correlation with clinical outcome. As this variable was recorded at baseline, it may comprise a potential biomarker of treatment response.

Differential Generation of Saccade, Fixation, and Image-Onset Event-Related Potentials in the Human Mesial Temporal Lobe.

Event-related potentials (ERPs) are a commonly used electrophysiological signature for studying mesial temporal lobe (MTL) function during visual memory tasks. The ERPs associated with the onset of visual stimuli (image-onset) and eye movements (saccades and fixations) provide insights into the mechanisms of their generation. We hypothesized that since eye movements and image-onset provide MTL structures with salient visual information, perhaps they both engage similar neural mechanisms. To explore this question, we used intracranial electroencephalographic data from the MTLs of 11 patients with medically refractory epilepsy who participated in a visual search task. We characterized the electrophysiological responses of MTL structures to saccades, fixations, and image-onset. We demonstrated that the image-onset response is an evoked/additive response with a low-frequency power increase. In contrast, ERPs following eye movements appeared to arise from phase resetting of higher frequencies than the image-onset ERP. Intriguingly, this reset was associated with saccade onset and not termination (fixation), suggesting it is likely the MTL response to a corollary discharge, rather than a response to visual stimulation. We discuss the distinct mechanistic underpinnings of these responses which shed light on the underlying neural circuitry involved in visual memory processing.

Reconstruction of reaching movement trajectories using electrocorticographic signals in humans.

In this study, we used electrocorticographic (ECoG) signals to extract the onset of arm movement as well as the velocity of the hand as a function of time. ECoG recordings were obtained from three individuals while they performed reaching tasks in the left, right and forward directions. The ECoG electrodes were placed over the motor cortex contralateral to the moving arm. Movement onset was detected from gamma activity with near perfect accuracy (> 98%), and a multiple linear regression model was used to predict the trajectory of the reaching task in three-dimensional space with an accuracy exceeding 85%. An adaptive selection of frequency bands was used for movement classification and prediction. This demonstrates the efficacy of developing a real-time brain-machine interface for arm movements with as few as eight ECoG electrodes.

Lateral hypothalamic activity indicates hunger and satiety states in humans.

Lateral hypothalamic area (LHA) local field potentials (LFPs) were recorded in a Prader-Willi patient undergoing deep brain stimulation (DBS) for obesity. During hunger, exposure to food-related cues induced an increase in beta/low-gamma activity. In contrast, recordings during satiety were marked by prominent alpha rhythms. Based on these findings, we have delivered alpha-frequency DBS prior to and during food intake. Despite reporting an early sensation of fullness, the patient continued to crave food. This suggests that the pattern of activity in LHA may indicate hunger/satiety states in humans but attest to the complexity of conducting neuromodulation studies in obesity.

Time-course of coherence in the human basal ganglia during voluntary movements.

We are interested in characterizing how brain networks interact and communicate with each other during voluntary movements. We recorded electrical activities from the globus pallidus pars interna (GPi), subthalamic nucleus (STN) and the motor cortex during voluntary wrist movements. Seven patients with dystonia and six patients with Parkinson's disease underwent bilateral deep brain stimulation (DBS) electrode placement. Local field potentials from the DBS electrodes and scalp EEG from the electrodes placed over the motor cortices were recorded while the patients performed externally triggered and self-initiated movements. The coherence calculated between the motor cortex and STN or GPi was found to be coupled to its power in both the beta and the gamma bands. The association of coherence with power suggests that a coupling in neural activity between the basal ganglia and the motor cortex is required for the execution of voluntary movements. Finally, we propose a mathematical model involving coupled neural oscillators which provides a possible explanation for how inter-regional coupling takes place.

Closed-Loop Interruption of Hippocampal Ripples through Fornix Stimulation in the Non-Human Primate.

BACKGROUND: Hippocampal sharp-wave ripples (SWRs) arising from synchronous bursting in CA3 pyramidal cells and propagating to CA1 are thought to facilitate memory consolidation. Stimulation of the CA3 axon collaterals comprising the hippocampal commissure in rats interrupts sharp-wave ripples and leads to memory impairment. In primates, however, these commissural collaterals are limited. Other hippocampal fiber pathways, like the fornix, may be potential targets for modulating ongoing hippocampal activity, with the short latencies necessary to interrupt ripples. OBJECTIVE: The aim of this study is to determine the efficacy of closed-loop stimulation adjacent to the fornix for interrupting hippocampal ripples. METHOD: Stimulating electrodes were implanted bilaterally alongside the fornix in the macaque, together with microelectrodes targeting the hippocampus for recording SWRs. We first verified that fornix stimulation reliably and selectively evoked a response in the hippocampus. We then implemented online detection and stimulation as hippocampal ripples occurred. RESULTS: The closed-loop interruption method was effective in interrupting ripples as well as the associated hippocampal multi-unit activity, demonstrating the feasibility of ripple interruption using fornix stimulation in primates. CONCLUSION: Analogous to murine research, such an approach will likely be useful in understanding the role of SWRs in memory formation in macaques and other primates sharing these pathways, such as humans. More generally, closed-loop stimulation of the fornix may prove effective in interrogating hippocampal-dependent memory processes. Finally, this rapid, contingent-DBS approach may be a means for modifying pathological high-frequency events within the hippocampus, and potentially throughout the extended hippocampal circuit.

Temporal alignment of electrocorticographic recordings for upper limb movement.

The detection of movement-related components of the brain activity is useful in the design of brain-machine interfaces. A common approach is to classify the brain activity into a number of templates or states. To find these templates, the neural responses are averaged over each movement task. For averaging to be effective, one must assume that the neural components occur at identical times over repeated trials. However, complex arm movements such as reaching and grasping are prone to cross-trial variability due to the way movements are performed. Typically initiation time, duration of movement and movement speed are variable even as a subject tries to reproduce the same task identically across trials. Therefore, movement-related neural activity will tend to occur at different times across the trials. Due to this mismatch, the averaging of neural activity will not bring into salience movement-related components. To address this problem, we present a method of alignment that accounts for the variabilities in the way the movements are conducted. In this study, arm speed was used to align neural activity. Four subjects had electrocorticographic (ECoG) electrodes implanted over their primary motor cortex and were asked to perform reaching and retrieving tasks using the upper limb contralateral to the site of electrode implantation. The arm speeds were aligned using a non-linear transformation of the temporal axes resulting in average spectrograms with superior visualization of movement-related neural activity when compared to averaging without alignment.

Course and variation of the intercostal artery by CT scan.

BACKGROUND: It is conventionally taught that the intercostal artery is shielded in the intercostal groove of the superior rib. The continuous course and variability of the intercostal artery, and factors that may influence them, have not been described in a large number of arteries in vivo. METHODS: Maximal intensity projection reformats in the coronal plane were produced from CT scan pulmonary angiograms to identify the posterolateral course of the intercostal artery (seventh to 11th rib spaces). A novel semiautomated computer segmentation algorithm was used to measure distances between the lower border of the superior rib, the upper border of the inferior rib, and the position of the intercostal artery when exposed in the intercostal space. The position and variability of the artery were analyzed for association with clinical factors. RESULTS: Two hundred ninety-eight arteries from 47 patients were analyzed. The mean lateral distance from the spine over which the artery was exposed within the intercostal space was 39 mm, with wide variability (SD, 10 mm; 10th-90th centile, 28-51 mm). At 3 cm lateral distance from the spine, 17% of arteries were shielded by the superior rib, compared with 97% at 6 cm. Exposed artery length was not associated with age, sex, rib space, or side. The variability of arterial position was significantly associated with age (coefficient, 0.91; P < .001) and rib space number (coefficient, - 2.60; P < .001). CONCLUSIONS: The intercostal artery is exposed within the intercostal space in the first 6 cm lateral to the spine. The variability of its vertical position is greater in older patients and in more cephalad rib spaces.

Use of dynamic CT in acute respiratory distress syndrome (ARDS) with comparison of positive and negative pressure ventilation.

Negative pressure ventilation via an external device ('iron lung') has the potential to provide better oxygenation with reduced barotrauma in patients with ARDS. This study was designed to see if oxygenation differences between positive and negative ventilation could be explained by CT. Six anaesthetized rabbits had ARDS induced by repeated saline lavage. Rabbits were ventilated with positive pressure ventilation (PPV) and negative pressure ventilation (NPV) in turn. Dynamic CT images were acquired over the respiratory cycle. A computer-aided method was used to segment the lung and calculate the range of CT densities within each slice. Volumes of ventilated lung and atelectatic lung were measured over the respiratory cycle. NPV was associated with an increased percentage of ventilated lung and decreased percentage of atelectatic lung. The most significant differences in ventilation and atelectasis were seen at mid-inspiration and mid-expiration (ventilated lung NPV = 61%, ventilated lung PPV = 47%, p < 0.001; atelectatic lung NPV = 10%, atelectatic lung PPV 19%, p < 0.001). Aeration differences were not significant at end-inspiration. Dynamic CT can show differences in lung aeration between positive and negative ventilation in ARDS. These differences would not be appreciated if only static breath-hold CT was used.

Negative-pressure ventilation: better oxygenation and less lung injury.

RATIONALE: Conventional positive-pressure ventilation delivers pressure to the airways; in contrast, negative pressure is delivered globally to the chest and abdomen. OBJECTIVES: To test the hypothesis that ventilation with negative pressure results in better oxygenation and less injury than with positive pressure. METHODS: Anesthetized, surfactant-depleted rabbits were ventilated for 2.5 hours in pairs (positive or negative). Tidal volume was 12 ml . kg(-1), normocapnia was maintained by adjusting respiratory rate, and Fi(O(2)) was 1.0. MEASUREMENTS AND MAIN RESULTS: Lung injury was assessed with histologic scoring, perfusion using thermodilution (global perfusion), and injected intravascular microspheres (regional perfusion); and dynamic computed tomography was used to determine inflation patterns. Negative pressure was associated with a higher Pa(O(2)), a lower Pa-Pet(CO(2)) gradient (despite identical minute ventilation), and less lung injury. Lung perfusion (global and regional) was similar with positive and negative pressure. Positive end-expiratory pressure applied to the airway was more efficiently transmitted to the pleural space than comparable levels of negative end-expiratory pressure applied to the chest wall; however, the oxygenation associated with any level of end-expiratory lung volume was greater when achieved by negative versus positive pressure. Dynamic computed tomography suggested that lung distension achieved with negative pressure is characterized by greater proportions of normally aerated lung (with less atelectasis) during inspiration and at end-expiration. CONCLUSIONS: Negative-pressure ventilation results in superior oxygenation that is unrelated to lung perfusion and may be explained by more effective inflation of lung volume during both inspiration and expiration.