Search

The mammalian cerebral cortex is anatomically organized into a six-layer motif. It is currently unknown whether a corresponding laminar motif of neuronal activity patterns exists across the cortex. Here we report such a motif in the power of local field potentials (LFPs). Using laminar probes, we recorded LFPs from 14 cortical areas across the cortical hierarchy in five macaque monkeys. The laminar locations of recordings were histologically identified by electrolytic lesions. Across all areas, we found a ubiquitous spectrolaminar pattern characterized by an increasing deep-to-superficial layer gradient of high-frequency power peaking in layers 2/3 and an increasing superficial-to-deep gradient of alpha-beta power peaking in layers 5/6. Laminar recordings from additional species showed that the spectrolaminar pattern is highly preserved among primates—macaque, marmoset and human—but more dissimilar in mouse. Our results suggest the existence of a canonical layer-based and frequency-based mechanism for cortical computation.

To describe the epidemiology and complications of platelet transfusions among hospitalized pediatric patients during 2010 to 2019.We performed a retrospective cohort study of hospitalized children within the Pediatric Health Information System database. Pediatric encounters receiving at least one platelet transfusion during hospitalization from 2010 to 2019 were identified. Data regarding demographics, diagnoses, procedures required during hospitalization, complications, and outcomes were extracted for eligible encounters.Within the Pediatric Health Information System database, 6 284 264 hospitalizations occurred from 2010 to 2019. A total of 244 464 hospitalizations required at least one platelet transfusion, yielding a prevalence of 3.89% (95% confidence interval [CI], 3.87%–3.91%). Transfusion prevalence did not change significantly across the decade (P value = .152). Two-thirds of children receiving platelet transfusions were in their first 6 years of life, and the majority identified as male (55%). Recipients most commonly had diseases of the circulatory system (21%, 52 008 of 244 979), perinatal disorders (16%, 38 054 of 244 979), or diseases of the hematologic/immune systems (15%, 37 466 of 244 979). When adjusted for age, support by extracorporeal membrane oxygenation, mechanical ventilation, surgical intervention, and diagnostic category, the odds of thrombosis, infection, and mortality increased by 2% (odds ratio [OR], 1.02; 95% CI, 1.016–1.020), 3% (OR, 1.03; 95% CI, 1.028–1.033), and 7% (OR, 1.07; 95% CI, 1.067–1.071), respectively, with each additional transfusion.The prevalence of platelet transfusions among pediatric inpatients remained consistent across the decade. Our finding that increasing numbers of transfusions may be associated with elevated morbidity and mortality is consistent with other observation and experimental studies, highlighting the need to be thoughtful in weighing risks and benefits when prescribing repeated platelet transfusions to hospitalized children.

The authors tested the spatial generalization of shape and color discriminations in 2 monkeys, in which 3 visual field quadrants were affected, respectively, by lesions in area V4, TEO, or both areas combined. The fourth quadrant served as a normal control. The monkeys were trained to discriminate stimuli presented in a standard location in each quadrant, followed by tests of discrimination performance in new locations in the same quadrant. In the quadrant affected by the V4 + TEO lesion, the authors found temporary but striking deficits in spatial generalization of shape and color discriminations over small distances, suggesting a contribution of areas V4 and TEO to short-range spatial generalization of visual skills.

Mutation or disruption of the SH3 and ankyrin repeat domains 3 (SHANK3) gene represents a highly penetrant, monogenic risk factor for autism spectrum disorder, and is a cause of Phelan–McDermid syndrome. Recent advances in gene editing have enabled the creation of genetically engineered non-human-primate models, which might better approximate the behavioural and neural phenotypes of autism spectrum disorder than do rodent models, and may lead to more effective treatments. Here we report CRISPR–Cas9-mediated generation of germline-transmissible mutations of SHANK3in cynomolgus macaques (Macaca fascicularis) and their F1 offspring. Genotyping of somatic cells as well as brain biopsies confirmed mutations in the SHANK3gene and reduced levels of SHANK3 protein in these macaques. Analysis of data from functional magnetic resonance imaging revealed altered local and global connectivity patterns that were indicative of circuit abnormalities. The founder mutants exhibited sleep disturbances, motor deficits and increased repetitive behaviours, as well as social and learning impairments. Together, these results parallel some aspects of the dysfunctions in the SHANK3gene and circuits, as well as the behavioural phenotypes, that characterize autism spectrum disorder and Phelan–McDermid syndrome. The CRISPR–Cas9-mediated generation of germline-transmissible mutations of SHANK3in cynomolgus macaques (Macaca fascicularis) forms the basis of a non-human-primate model of autism spectrum disorder and Phelan–McDermid syndrome.

Several series of near-infrared (NIR) fluorescent proteins (FPs) were recently engineered from bacterial phytochromes but were not systematically compared in neurons. To fluoresce, NIR FPs utilize an enzymatic derivative of heme, the linear tetrapyrrole biliverdin, as a chromophore whose level in neurons is poorly studied. Here, we evaluated NIR FPs of the iRFP protein family, which were reported to be the brightest in non-neuronal mammalian cells, in primary neuronal culture, in brain slices of mouse and monkey, and in mouse brain in vivo. We applied several fluorescence imaging modes, such as wide-field and confocal one-photon and two-photon microscopy, to compare photochemical and biophysical properties of various iRFPs. The iRFP682 and iRFP670 proteins exhibited the highest brightness and photostability under one-photon and two-photon excitation modes, respectively. All studied iRFPs exhibited efficient binding of the endogenous biliverdin chromophore in cultured neurons and in the mammalian brain and can be readily applied to neuroimaging.

Molecular genetic tools have had a profound impact on neuroscience, but until recently their application has largely been confined to a few model species, most notably mouse, zebrafish, Drosophila melanogaster and Caenorhabditis elegans. With the development of new genome engineering technologies such as CRISPR, it is becoming increasingly feasible to apply these molecular tools in a wider range of species, including nonhuman primates. This will lead to many opportunities for brain research, but it will also pose challenges. Here we identify some of these opportunities and challenges in light of recent and foreseeable technological advances and offer some suggestions. Our main focus is on the creation of new primate disease models for understanding the pathological mechanisms of brain disorders and for developing new approaches to effective treatment. However, we also emphasize that primate genetic models have great potential to address many fundamental questions about brain function, providing an essential foundation for future progress in disease research.

While lesions of visual areas V4 and TEO only modestly affect discrimination of isolated objects, they significantly impair the ability to selectively attend to an object surrounded by distracters. To test whether such deficits result from a loss of inputs to higher order areas, we recorded from area TE neurons after removing portions of V4 and TEO in a monkey. Responses to isolated targets in a lesion-affected visual quadrant were substantially preserved, indicating that TE still receives information even after removing a major source of input. Distracters increased or decreased the response to targets more in the lesion-affected than in the normal quadrant, supporting the idea that V4 andor TEO are sites where top-down attentional inputs filter out distracting stimuli.

Neurophysiological studies in monkeys show that when multiple visual stimuli appear simultaneously in the visual field, they are not processed independently, but rather interact in a mutually suppressive way. This suggests that multiple stimuli compete for neural representation. Consistent with this notion, we have previously found in humans that functional magnetic resonance imaging (fMRI) signals in V1 and ventral extrastriate areas V2, V4, and TEO are smaller for simultaneously presented (i.e., competing) stimuli than for the same stimuli presented sequentially (i.e., not competing). Here we report that suppressive interactions between stimuli are also present in dorsal extrastriate areas V3A and MT, and we compare these interactions to those in areas V1 through TEO. To exclude the possibility that the differences in responses to simultaneously and sequentially presented stimuli were due to differences in the number of transient onsets, we tested for suppressive interactions in area V4, in an experiment that held constant the number of transient onsets. We found that the fMRI response to a stimulus in the upper visual field was suppressed by the presence of nearby stimuli in the lower visual field. Further, we excluded the possibility that the greater fMRI responses to sequential compared with simultaneous presentations were due to exogeneous attentional cueing by having our subjects count T's or L's at fixation, an attentionally demanding task. Behavioral testing demonstrated that neither condition interfered with performance of the T/L task. Our previous findings suggested that suppressive interactions among nearby stimuli in areas V1 through TEO were scaled to the receptive field (RF) sizes of neurons in those areas. Here we tested this idea by parametrically varying the spatial separation among stimuli in the display. Display sizes ranged from 2 × 2° to 7 × 7° and were centered at 5.5° eccentricity. Based on the effects of display size on the magnitude of suppressive interactions, we estimated that RF sizes at an eccentricity of 5.5° were <2° in V1, 2–4° in V2, 4–6° in V4, larger than 7° (but still confined to a quadrant) in TEO, and larger than 6° (confined to a quadrant) in V3A. These estimates of RF sizes in human visual cortex are strikingly similar to those measured in physiological mapping studies in the homologous visual areas in monkeys.

With experience, an object can become behaviorally relevant and thereby quickly attract our interest when presented in a visual scene. A likely site of these learning effects is anterior inferior temporal (aIT) cortex, where neurons are thought to participate in the filtering of irrelevant information out of complex visual displays. We trained monkeys to saccade consistently to one of two pictures in an array, in return for a reward. The array was constructed by pairing two stimuli, one of which elicited a good response from the cell when presented alone (“good” stimulus) and the other of which elicited a poor response (“poor” stimulus). The activity of aIT cells was recorded while monkeys learned to saccade to either the good or poor stimulus in the array. We found that neuronal responses to the array were greater (before the saccade occurred) when training reinforced a saccade to the good stimulus than when training reinforced a saccade to the poor stimulus. This difference was not present on incorrect trials, i.e., when saccades to the incorrect stimulus were made. Thus the difference in activity was correlated with performance. The response difference grew over the course of the recording session, in parallel with the improvement in performance. The response difference was not preceded by a difference in the baseline activity of the cells, unlike what was found in studies of cued visual search and working memory in aIT cortex. Furthermore, we found similar effects in a version of the task in which any of 10 possible pairs of stimuli, prelearned before the recording session, could appear on a given trial, thereby precluding a working memory strategy. The results suggest that increasing the behavioral significance of a stimulus through training alters the neural representation of that stimulus in aIT cortex. As a result, neurons responding to features of the relevant stimulus may suppress neurons responding to features of irrelevant stimuli.

The functional status of the globus pallidus internal segment (GPi) plays a key role in mediating the effects of antiparkinsonian drugs. During long‐term levodopa therapy, patients develop abnormal movements, dyskinesias, the pathophysiological basis of which is poorly understood. We recorded single cells in the GPi of parkinsonian monkeys continuously through the “off” and “on” states, and 10 to 15 minutes later during “on with or without dyskinesias,” depending on two doses of levodopa. The transition from the “off” to the “on” state was characterized by a decrease (most cells), no change, or an increase in firing rate of individual cells. During dyskinesias, firing rates declined profoundly in almost all cells, with decrements as low as 97% in individual cells. These changes occurred only when dyskinesias were present. The difference in GPi activity between “on” and “on with dyskinesias” suggests that normal motor function in Parkinson's disease critically depends on fine tuning of the basal ganglia output. Dyskinesias result from an imbalanced low GPi discharge, a circumstance that may be susceptible to development of new therapeutic approaches.

Luck, Steven J., Leonardo Chelazzi, Steven A. Hillyard, and Robert Desimone.Neural mechanisms of spatial selective attention in areas V1, V2, and V4 of macaque visual cortex. J. Neurophysiol.77: 24–42, 1997. Many neurons in extrastriate visual cortex have large receptive fields, and this may lead to significant computational problems whenever multiple stimuli fall within a single field. Previous studies have suggested that when multiple stimuli fall within a cell's receptive field, they compete for the cell's response in a manner that can be biased in favor of attended stimuli. In the present study we examined this role of attention in areas V1, V2, and V4 of macaque monkeys with the use of a behavioral paradigm in which attention was directed to one of two stimulus locations. When two stimuli were presented simultaneously inside the cell's receptive field (which could be accomplished only in areas V2 and V4), we found that the cell's response was strongly influenced by which of the two stimuli was attended. The size of this attention effect was reduced when the attended and ignored stimuli were presented sequentially rather than simultaneously. In addition, the effects became very weak and inconsistent in these areas when only one of the two stimuli was located inside the receptive field. Attention thus modulated sensory responses primarily when two or more simultaneous stimuli competed for access to a neuron's receptive field. As in areas V2 and V4, attention did not modulate sensory responses in area V1 when only a single stimulus was inside the receptive field. In addition, the small receptive fields in this area precluded the simultaneous presentation of attended and ignored stimuli inside the receptive field, making it impossible to determine whether attention effects would be observed under the conditions that led to consistent attention effects in areas V2 and V4. Spontaneous firing rates in areas V2 and V4 were found to be 30–40% higher when attention was directed inside rather than outside the receptive field, even when no stimulus was present in the receptive field. Spontaneous firing rates also varied according to the particular location within the receptive field that was attended. These shifts in spontaneous activity may reflect a top-down signal that biases responses in favor of stimuli at the attended location.

According to conventional neurobiological accounts of visual attention, attention serves to enhance extrastriate neuronal responses to a stimulus at one spatial location in the visual field. However, recent results from recordings in extrastriate cortex of monkeys suggest that any enhancing effect of attention is best understood in the context of competitive interactions among neurons representing all of the stimuli present in the visual field. These interactions can be biased in favour of behaviourally relevant stimuli as a result of many different processes, both spatial and non–spatial, and both bottom–up and top–down. The resolution of this competition results in the suppression of the neuronal representations of behaviourally irrelevant stimuli in extrastriate cortex. A main source of top–down influence may derive from neuronal systems underlying working memory.

The notion of a neuron that responds selectively to the image of a particular complex object has been controversial ever since Gross and his colleagues reported neurons in the temporal cortex of monkeys that were selective for the sight of a monkey's hand (Gross, Rocha-Miranda, & Bender, 1972). Since that time, evidence has mounted for neurons in the temporal lobe that respond selectively to faces. The present paper presents a critical analysis of the evidence for face neurons and discusses the implications of these neurons for models of object recognition. The paper also presents some possible reasons for the evolution of face neurons and suggests some analogies with the development of language in humans.

Suzuki, Wendy A., Earl K. Miller, and Robert Desimone.Object and place memory in the macaque entorhinal cortex. J. Neurophysiol.78: 1062–1081, 1997. Lesions of the entorhinal cortex in humans, monkeys, and rats impair memory for a variety of kinds of information, including memory for objects and places. To begin to understand the contribution of entorhinal cells to different forms of memory, responses of entorhinal cells were recorded as monkeys performed either an object or place memory task. The object memory task was a variation of delayed matching to sample. A sample picture was presented at the start of the trial, followed by a variable sequence of zero to four test pictures, ending with a repetition of the sample (i.e., a match). The place memory task was a variation of delayed matching to place. In this task, a cue stimulus was presented at a variable sequence of one to four “places” on a computer screen, ending with a repetition of one of the previously shown places (i.e., a match). For both tasks, the animals were rewarded for releasing a bar to the match. To solve these tasks, the monkey must 1) discriminate the stimuli, 2) maintain a memory of the appropriate stimuli during the course of the trial, and 3) evaluate whether a test stimulus matches previously presented stimuli. The responses of entorhinal cortex neurons were consistent with a role in all three of these processes in both tasks. We found that 47% and 55% of the visually responsive entorhinal cells responded selectively to the different objects or places presented during the object or place task, respectively. Similar to previous findings in prefrontal but not perirhinal cortex on the object task, some entorhinal cells had sample-specific delay activity that was maintained throughout all of the delay intervals in the sequence. For the place task, some cells had location-specific maintained activity in the delay immediately following a specific cue location. In addition, 59% and 22% of the visually responsive cells recorded during the object and place task, respectively, responded differently to the test stimuli according to whether they were matching or nonmatching to the stimuli held in memory. Responses of some cells were enhanced to matching stimuli, whereas others were suppressed. This suppression or enhancement typically occurred well before the animals' behavioral response, suggesting that this information could be used to perform the task. These results indicate that entorhinal cells receive sensory information about both objects and spatial locations and that their activity carries information about objects and locations held in short-term memory.

Chelazzi, Leonardo, John Duncan, Earl K. Miller, and Robert Desimone.Responses of neurons in inferior temporal cortex during memory-guided visual search. J. Neurophysiol.80: 2918–2940, 1998. A typical scene will contain many different objects, few of which are relevant to behavior at any given moment. Thus attentional mechanisms are needed to select relevant objects for visual processing and control over behavior. We examined this role of attention in the inferior temporal cortex of macaque monkeys, using a visual search paradigm. While the monkey maintained fixation, a cue stimulus was presented at the center of gaze, followed by a blank delay period. After the delay, an array of two to five choice stimuli was presented extrafoveally, and the monkey was rewarded for detecting a target stimulus matching the cue. The behavioral response was a saccadic eye movement to the target in one version of the task and a lever release in another. The array was composed of one “good” stimulus (effective in driving the cell when presented alone) and one or more “poor” stimuli (ineffective in driving the cell when presented alone). Most cells showed higher delay activity after a good stimulus used as the cue than after a poor stimulus. The baseline activity of cells was also higher preceding a good cue, if the animal expected it to occur. This activity may depend on a top-down bias in favor of cells coding the relevant stimulus. When the choice array was presented, most cells showed suppressive interactions between the stimuli as well as strong attention effects. When the choice array was presented in the contralateral visual field, most cells initially responded the same, regardless of which stimulus was the target. However, within 150–200 ms of array onset, responses were determined by the target stimulus. If the target was the good stimulus, the response to the array became equal to the response to the good stimulus presented alone. If the target was a poor stimulus, the response approached the response to that stimulus presented alone. Thus the influence of the nontarget stimulus was eliminated. These effects occurred well in advance of the behavioral response. When the array was positioned with stimuli on opposite sides of the vertical meridian, the contralateral stimulus appeared to dominate the response, and this dominant effect could not be overcome by attention. Overall, the results support a “biased competition” model of attention, according to which 1) objects in the visual field compete for representation in the cortex, and 2) this competition is biased in favor of the behaviorally relevant object by virtue of “top-down” feedback from structures involved in working memory.

Van Besien: Miltenyi Biotec: Research Funding.

Bussel: Prophylix: Consultancy, Research Funding; Momenta: Consultancy; Amgen Inc.: Consultancy, Research Funding; Uptodate: Honoraria; Novartis: Consultancy, Research Funding; Protalex: Consultancy; Rigel: Consultancy, Research Funding.

DITP is caused by drug-dependent antibodies that bind to platelets and cause their destruction only when drug is present. The chemotherapeutic agents oxaliplatin (OX) and irinotecan (IR) are recognized causes of DITP. OX is often given every other week together with 5-fluorouracil (5-FU) and leucovorin (LE) (FOLFOX) without or with irinotecan (FOLFOXIRI). To prevent chemotherapy-induced nausea and vomiting, patients treated with these regimens are usually conditioned with anti-emetics, including serotonin 5-HT3 receptor antagonist, corticosteroids and anti-histamines. We characterized two patients treated for metastatic colon cancer with these regimens who acutely developed profound thrombocytopenia (TP) and bleeding requiring platelet transfusions after 20 and 18 cycles of treatment, respectively. In each case, platelets returned to normal in about one week. On the suspicion that TP was caused by DDAbs, OX (Patient 1) and IR (Patient 2) were omitted from the next round of treatment, but bleeding and profound TP recurred in both cases. Patient 1 had a third episode of severe TP when both OX and LE were replaced by IR and Patient 2 had two further episodes when first OX then OX + LE were omitted.

Phillips: Kyowa Kirin: Research Funding; Celgene: Speakers Bureau; Takeda: Speakers Bureau.

No relevant conflicts of interest to declare.

A letter to the editor is presented in response to the article "The Age of the Red Pen" which appears in the August 22, 2015 issue and addresses the CRSPR-Cas9 gene-editing system, techniques for editing genomes, and the research work conducted by scientists such as Feng Zhang and George Church.

Neuromuscular respiratory failure is a rare complication of systemic immunoglobulin light chain amyloidosis. We describe a case of a 70-year-old Caucasian man with multiple myeloma who presented with worsening dyspnea. The patient was diagnosed with and treated for congestive heart failure but continued to suffer from hypercapnic respiratory insufficiency. He had restrictive physiology on pulmonary function tests and abnormal phrenic nerve conduction studies, consistent with neuromuscular respiratory failure. The diagnosis of systemic immunoglobulin light chain amyloidosis was made based on the clinical context and a cardiac biopsy. Despite treatment attempts, the patient passed away in the intensive care unit from hypercapnic respiratory failure. Autopsy revealed dense diaphragmatic amyloid deposits without phrenic nerve infiltration or demyelination or lung parenchymal involvement. Only 5 cases of neuromuscular respiratory failure due to amyloid infiltration of the diaphragm have been described. All cases, including this, were characterized by rapid progression and high mortality. Therefore, diaphragmatic amyloidosis should be on the differential for progressive neuromuscular respiratory failure in patients with multiple myeloma or any other monoclonal gammopathy. Given its poor prognosis, early recognition of this condition is essential in order to address goals of care and encourage pursuit of palliative measures.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

EFFECTS of scopolamine on performance of a delayed matching-to-sample task and on the properties of neurons in anterior-ventral inferior temporal (IT) cortex were examined in two monkeys. Both monkeys were impaired on the task after systemic administration of scopolamine, suggesting that scopolamine disrupts recency memory. Despite the behavioral deficit, neurons in IT cortex, a region having an important role in visual memory and neuronal properties consistent with that role, were largely unaffected by scopolamine. This dissociation between the behavioral and neuronal effects of scopolamine indicates that the drug either acts at a different site or disrupts unobserved mechanisms at the IT site.