Wael F. Asaad

Selective representation of relevant information by neurons in the primate prefrontal cortex

The severe limitation of the capacity of working memory, the ability to store temporarily and manipulate information, necessitates mechanisms that restrict access to it. Here we report tests to discover whether the activity of neurons in the prefrontal (PF)cortex, the putative neural correlate of working memory, might reflect these mechanisms and preferentially represent behaviourally relevant information. Monkeys performed a ‘delayed-matching-to-sample’ task with an array of three objects. Only one of the objects in the array was relevant for task performance and the monkeys needed to find that object (the target) and remember its location. For many PF neurons, activity to physically identical arrays varied with the target location; the location of the non-target objects had little or no influence on activity. Information about the target location was present in activity as early as 140 ms after array onset. Also, information about which object was the target was reflected in the sustained activity of many PF neurons. These results suggest that the prefrontal cortex is involved in selecting and maintaining behaviourally relevant information.

Concentric orientation summation in human form vision

Psychophysical data demonstrate that orientation information in concentric, random-dot Glass patterns is summed linearly to extract a global form percept. Surprisingly, no such global pooling was found for Glass patterns with parallel structure. A simple neural model explains these results and agrees with recent V4 single unit physiology. As V4 provides the major input to IT, global concentric units may play an important role in analyzing complex images such as faces. In support of this possibility, deficits in the perception of concentric Glass patterns have recently been linked to prosopagnosia.

Human dorsal anterior cingulate cortex neurons mediate ongoing behavioural adaptation

The ability to optimize behavioural performance when confronted with continuously evolving environmental demands is a key element of human cognition. The dorsal anterior cingulate cortex (dACC), which lies on the medial surface of the frontal lobes, is important in regulating cognitive control. Hypotheses about its function include guiding reward-based decision making, monitoring for conflict between competing responses and predicting task difficulty. Precise mechanisms of dACC function remain unknown, however, because of the limited number of human neurophysiological studies. Here we use functional imaging and human single-neuron recordings to show that the firing of individual dACC neurons encodes current and recent cognitive load. We demonstrate that the modulation of current dACC activity by previous activity produces a behavioural adaptation that accelerates reactions to cues of similar difficulty to previous ones, and retards reactions to cues of different difficulty. Furthermore, this conflict adaptation, or Gratton effect, is abolished after surgically targeted ablation of the dACC. Our results demonstrate that the dACC provides a continuously updated prediction of expected cognitive demand to optimize future behavioural responses. In situations with stable cognitive demands, this signal promotes efficiency by hastening responses, but in situations with changing demands it engenders accuracy by delaying responses.

ATTENUATION OF NMDA RECEPTOR ACTIVITY AND NEUROTOXICITY BY NITROXYL ANION,NO-

Recent evidence indicates that the NO-related species, nitroxyl anion (NO), is produced in physiological systems by several redox metal-containing proteins, including hemoglobin, nitric oxide synthase (NOS), superoxide dismutase, and S-nitrosothiols (SNOs), which have recently been identified in brain. However, the chemical biology of NO- remains largely unknown. Here, we show that NO- -unlike NO*, but reminiscent of NO+ transfer (or S-nitrosylation)- -reacts mainly with Cys-399 in the NR2A subunit of the N-methyl-D-aspartate (NMDA) receptor to curtail excessive Ca2+ influx and thus provide neuroprotection from excitotoxic insults. This effect of NO- closely resembles that of NOS, which also downregulates NMDA receptor activity under similar conditions in culture.

A Neural Circuit Model of Flexible Sensorimotor Mapping: Learning and Forgetting on Multiple Timescales

Volitional behavior relies on the brains ability to remap sensory flow to motor programs whenever demanded by a changed behavioral context. To investigate the circuit basis of such flexible behavior, we have developed a biophysically based decision-making network model of spiking neurons for arbitrary sensorimotor mapping. The model quantitatively reproduces behavioral and prefrontal single-cell data from an experiment in which monkeys learn visuomotor associations that are reversed unpredictably from time to time. We show that when synaptic modifications occur on multiple timescales, the model behavior becomes flexible only when needed: slow components of learning usually dominate the decision process. However, if behavioral contexts change frequently enough, fast components of plasticity take over, and the behavior exhibits a quick forget-and-learn pattern. This model prediction is confirmed by monkey data. Therefore, our work reveals a scenario for conditional associative learning that is distinct from instant switching between sets of well-established sensorimotor associations.

Risk factors for hemorrhage during microelectrode-guided deep brain stimulation and the introduction of an improved microelectrode design.

OBJECTIVEHemorrhage is an infrequent but potentially devastating complication of deep brain stimulation (DBS) surgery. We examined the factors associated with hemorrhage after DBS surgery and evaluated a modified microelectrode design that may improve the safety of this procedure. METHODSAll microelectrode-guided DBS procedures performed at our institution between January 2000 and March 2008 were included in this study. A new microelectrode design with decreased diameter was introduced in May 2004, and data from the 2 types of electrodes were compared. RESULTSWe examined 246 microelectrode-guided lead implantations in 130 patients. Postoperative imaging revealed 7 hemorrhages (2.8%). Five of the 7 (2.0%) resulted in focal neurological deficits, all of which resolved within 1 month with the exception of 1 patient lost to follow-up. The new microelectrode design significantly decreased the number of hemorrhages (P = 0.04). A surgical trajectory traversing the ventricle also contributed significantly to the overall hemorrhage rate (P = 0.02) and specifically to the intraventricular hemorrhage rate (P = 0.01). In addition, the new microelectrode design significantly decreased the rate of intraventricular hemorrhage, given a ventricular penetration (P = 0.01). The mean age of patients with hemorrhage was significantly higher than that of patients without hemorrhage (P = 0.02). Hypertension, sex, and number of microelectrodes passed did not significantly contribute to hemorrhage rates in our population. CONCLUSIONThe rate of complications after DBS surgery is not uniformly distributed across all cases. In particular, the rates of hemorrhage were increased in older patients. Importantly, transventricular electrode trajectories appeared to increase the risk of hemorrhage. A new microelectrode design minimizing the volume of brain parenchyma penetrated during microelectrode recording leads to decreased rates of hemorrhage, particularly if the ventricles are breached.

A flexible software tool for temporally-precise behavioral control in Matlab

Systems and cognitive neuroscience depend on carefully designed and precisely implemented behavioral tasks to elicit the neural phenomena of interest. To facilitate this process, we have developed a software system that allows for the straightforward coding and temporally-reliable execution of these tasks in Matlab. We find that, in most cases, millisecond accuracy is attainable, and those instances in which it is not are usually related to predictable, programmed events. In this report, we describe the design of our system, benchmark its performance in a real-world setting, and describe some key features.

Predictors of cranioplasty complications in stroke and trauma patients

OBJECT Decompressive craniectomy mandates subsequent cranioplasty. Complications of cranioplasty may be independent of the initial craniectomy, or they may be contingent upon the craniectomy. Authors of this study aimed to identify surgery- and patient-specific risk factors related to the development of surgical site infection and other complications following cranioplasty. METHODS A consecutive cohort of patients of all ages and both sexes who had undergone cranioplasty following craniectomy for stroke or trauma at a single institution in the period from May 2004 to May 2012 was retrospectively established. Patients who had undergone craniectomy for infectious lesions or neoplasia were excluded. A logistic regression analysis was performed to model and predict determinants related to infection following cranioplasty. RESULTS Two hundred thirty-nine patients met the study criteria. The overall rate of complication following cranioplasty was 23.85% (57 patients). Complications included, predominantly, surgical site infection, hydrocephalus, and new-onset seizures. Logistic regression analysis identified previous reoperation (OR 3.25, 95% CI 1.30-8.11, p = 0.01) and therapeutic indication for stroke (OR 2.45, 95% CI 1.11-5.39, p = 0.03) as significantly associated with the development of cranioplasty infection. Patient age, location of cranioplasty, presence of an intracranial device, bone flap preservation method, cranioplasty material, booking method, and time interval > 90 days between initial craniectomy and cranioplasty were not predictive of the development of cranioplasty infection. CONCLUSIONS Cranioplasty complications are common. Cranioplasty infection rates are predicted by reoperation following craniectomy and therapeutic indication (stroke). These variables may be associated with patient-centered risk factors that increase cranioplasty infection risk.

A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer's Disease

Background: Deep brain stimulation (DBS) is used to modulate the activity of dysfunctional brain circuits. The safety and efficacy of DBS in dementia is unknown. Objective: To assess DBS of memory circuits as a treatment for patients with mild Alzheimer’s disease (AD). Methods: We evaluated active “on” versus sham “off” bilateral DBS directed at the fornix-a major fiber bundle in the brain’s memory circuit-in a randomized, double-blind trial (ClinicalTrials.gov NCT01608061) in 42 patients with mild AD. We measured cognitive function and cerebral glucose metabolism up to 12 months post-implantation. Results: Surgery and electrical stimulation were safe and well tolerated. There were no significant differences in the primary cognitive outcomes (ADAS-Cog 13, CDR-SB) in the “on” versus “off” stimulation group at 12 months for the whole cohort. Patients receiving stimulation showed increased metabolism at 6 months but this was not significant at 12 months. On post-hoc analysis, there was a significant interaction between age and treatment outcome: in contrast to patients <65 years old (n = 12) whose results trended toward being worse with DBS ON versus OFF, in patients≥65 (n = 30) DBS-f ON treatment was associated with a trend toward both benefit on clinical outcomes and a greater increase in cerebral glucose metabolism. Conclusion: DBS for AD was safe and associated with increased cerebral glucose metabolism. There were no differences in cognitive outcomes for participants as a whole, but participants aged≥65 years may have derived benefit while there was possible worsening in patients below age 65 years with stimulation.

Achieving behavioral control with millisecond resolution in a high-level programming environment

The creation of psychophysical tasks for the behavioral neurosciences has generally relied upon low-level software running on a limited range of hardware. Despite the availability of software that allows the coding of behavioral tasks in high-level programming environments, many researchers are still reluctant to trust the temporal accuracy and resolution of programs running in such environments, especially when they run atop non-real-time operating systems. Thus, the creation of behavioral paradigms has been slowed by the intricacy of the coding required and their dissemination across labs has been hampered by the various types of hardware needed. However, we demonstrate here that, when proper measures are taken to handle the various sources of temporal error, accuracy can be achieved at the 1 ms time-scale that is relevant for the alignment of behavioral and neural events.