The neuroethics of non-invasive brain stimulation

Transcranial direct current stimulation (TDCS) is a brain stimulation tool that is portable, painless, inexpensive, apparently safe, and with potential long-term efficacy. Recent results obtained from TDCS experiments offer exciting possibilities for the enhancement and treatment of normal or impaired abilities, respectively. We discuss new neuroethical problems that have emerged from the usage of TDCS, and also focus on one of the most likely future applications of TDCS: enhancing learning and cognition in children with typical and atypical development.     

Semantic associations between signs and numerical categories in the prefrontal cortex

The utilization of symbols such as words and numbers as mental tools endows humans with unrivalled cognitive flexibility. In the number domain, a fundamental first step for the acquisition of numerical symbols is the semantic association of signs with cardinalities. We explored the primitives of such a semantic mapping process by recording single-cell activity in the monkey prefrontal and parietal cortices, brain structures critically involved in numerical cognition. Monkeys were trained to associate visual shapes with varying numbers of items in a matching task. After this long-term learning process, we found that the responses of many prefrontal neurons to the visual shapes reflected the associated numerical value in a behaviorally relevant way. In contrast, such association neurons were rarely found in the parietal lobe. These findings suggest a cardinal role of the prefrontal cortex in establishing semantic associations between signs and abstract categories, a cognitive precursor that may ultimately give rise to symbolic thinking in linguistic humans.     

Virtual dyscalculia induced by parietal-lobe TMS impairs automatic magnitude processing

People suffering from developmental dyscalculia encounter difficulties in automatically accessing numerical magnitudes [1-3]. For example, when instructed to attend to the physical size of a number while ignoring its numerical value, dyscalculic subjects, unlike healthy participants, fail to process the irrelevant dimension automatically and subsequently show a smaller size-congruity effect (difference in reaction time between incongruent [e.g., a physically large 2 and a physically small 4] and congruent [e.g., a physically small 2 and a physically large 4] conditions), and no facilitation (neutral [e.g., a physically small 2 and a physically large 2] versus congruent) [3]. Previous imaging studies determined the intraparietal sulcus (IPS) as a central area for numerical processing [4-11]. A few studies tried to identify the brain dysfunction underlying developmental dyscalculia but yielded mixed results regarding the involvement of the left [12] or the right [13] IPS. Here we applied fMRI-guided TMS neuronavigation to disrupt left- or right-IPS activation clusters in order to induce dyscalculic-like behavioral deficits in healthy volunteers. Automatic magnitude processing was impaired only during disruption of right-IPS activity. When using the identical paradigm with dyscalculic participants, we reproduced a result pattern similar to that obtained with nondyscalculic volunteers during right-IPS disruption. These findings provide direct evidence for the functional role of right IPS in automatic magnitude processing.     

Light activation of an innate olfactory avoidance response in Drosophila

How specific sensory stimuli evoke specific behaviors is a fundamental problem in neurobiology. In Drosophila, most odorants elicit attraction or avoidance depending on their concentration, as well as their identity [1]. Such odorants, moreover, typically activate combinations of glomeruli in the antennal lobe of the brain [2-4], complicating the dissection of the circuits translating odor recognition into behavior. Carbon dioxide (CO2), in contrast, elicits avoidance over a wide range of concentrations [5, 6] and activates only a single glomerulus, V [5]. The V glomerulus receives projections from olfactory receptor neurons (ORNs) that coexpress two GPCRs, Gr21a and Gr63a, that together comprise a CO2 receptor [7-9]. These CO2-sensitive ORNs, located in the ab1 sensilla of the antenna, are called ab1c neurons [10]. Genetic silencing of ab1c neurons indicates that they are necessary for CO2-avoidance behavior [5]. Whether activation of these neurons alone is sufficient to elicit this behavior, or whether CO2 avoidance requires additional inputs (e.g., from the respiratory system), remains unclear. Here, we show that artificial stimulation of ab1c neurons with light (normally attractive to flies) elicits the avoidance behavior typical of CO2. Thus, avoidance behavior appears hardwired into the olfactory circuitry that detects CO2 in Drosophila.     

Nonsomatotopic Organization of the Higher Motor Centers in Octopus

Hyperredundant limbs with a virtually unlimited number of degrees of freedom (DOFs) pose a challenge for both biological and computational systems of motor control. In the flexible arms of the octopus, simplification strategies have evolved to reduce the number of controlled DOFs [1], [2] and [3]. Motor control in the octopus nervous system is hierarchically organized [4] and [5]. A relatively small central brain integrates a huge amount of visual and tactile information from the large optic lobes and the peripheral nervous system of the arms [6], [7], [8] and [9] and issues commands to lower motor centers controlling the elaborated neuromuscular system of the arms. This unique organization raises new questions on the organization of the octopus brain and whether and how it represents the rich movement repertoire. We developed a method of brain microstimulation in freely behaving animals and stimulated the higher motor centers—the basal lobes—thus inducing discrete and complex sets of movements. As stimulation strength increased, complex movements were recruited from basic components shared by different types of movement. We found no stimulation site where movements of a single arm or body part could be elicited. Discrete and complex components have no central topographical organization but are distributed over wide regions.     

Anterior prefrontal cortex inhibition impairs control over social emotional actions

When dealing with emotional situations, we often need to rapidly override automatic stimulus-response mappings and select an alternative course of action [1], for instance, when trying to manage, rather than avoid, another's aggressive behavior. The anterior prefrontal cortex (aPFC) has been linked to the control of these social emotional behaviors [2, 3]. We studied how this control is implemented by inhibiting the left aPFC with continuous theta burst stimulation (cTBS; [4]). The behavioral and cerebral consequences of this intervention were assessed with a task quantifying the control of social emotional actions and with concurrent measurements of brain perfusion. Inhibition of the aPFC led participants to commit more errors when they needed to select rule-driven responses overriding automatic action tendencies evoked by emotional faces. Concurrently, task-related perfusion decreased in bilateral aPFC and posterior parietal cortex and increased in amygdala and left fusiform face area. We infer that the aPFC controls social emotional behavior by upregulating regions involved in rule selection [5] and downregulating regions supporting the automatic evaluation of emotions [6]. These findings illustrate how exerting emotional control during social interactions requires the aPFC to coordinate rapid action selection processes, the detection of emotional conflicts, and the inhibition of emotionally-driven responses.     

Sensorimotor learning configures the human mirror system

Cells in the "mirror system" fire not only when an individual performs an action but also when one observes the same action performed by another agent [1-4]. The mirror system, found in premotor and parietal cortices of human and monkey brains, is thought to provide the foundation for social understanding and to enable the development of theory of mind and language [5-9]. However, it is unclear how mirror neurons acquire their mirror properties -- how they derive the information necessary to match observed with executed actions [10]. We address this by showing that it is possible to manipulate the selectivity of the human mirror system, and thereby make it operate as a countermirror system, by giving participants training to perform one action while observing another. Before this training, participants showed event-related muscle-specific responses to transcranial magnetic stimulation over motor cortex during observation of little- and index-finger movements [11-13]. After training, this normal mirror effect was reversed. These results indicate that the mirror properties of the mirror system are neither wholly innate [14] nor fixed once acquired; instead they develop through sensorimotor learning [15, 16]. Our findings indicate that the human mirror system is, to some extent, both a product and a process of social interaction.     

A shift in sensory processing that enables the developing human brain to discriminate touch from pain

When and how infants begin to discriminate noxious from innocuous stimuli is a fundamental question in neuroscience [1]. However, little is known about the development of the necessary cortical somatosensory functional prerequisites in the intact human brain. Recent studies of developing brain networks have emphasized the importance of transient spontaneous and evoked neuronal bursting activity in the formation of functional circuits [2, 3]. These neuronal bursts are present during development and precede the onset of sensory functions [4, 5]. Their disappearance and the emergence of more adult-like activity are therefore thought to signal the maturation of functional brain circuitry [2, 4]. Here we show the changing patterns of neuronal activity that underlie the onset of nociception and touch discrimination in the preterm infant. We have conducted noninvasive electroencephalogram (EEG) recording of the brain neuronal activity in response to time-locked touches and clinically essential noxious lances of the heel in infants aged 28-45?weeks gestation. We show a transition in brain response following tactile and noxious stimulation from nonspecific, evenly dispersed neuronal bursts to modality-specific, localized, evoked potentials. The results suggest that specific neural circuits necessary for discrimination between touch and nociception emerge from 35-37?weeks gestation in the human brain.     

Frequency-Dependent Changes in the Regional Amplitude and Synchronization of Resting-State Functional MRI in Stroke

Resting-state functional magnetic resonance imaging (R-fMRI) has been intensively used to assess alterations of inter-regional functional connectivity in patients with stroke, but the regional properties of brain activity in stroke have not yet been fully investigated. Additionally, no study has examined a frequency effect on such regional properties in stroke patients, although this effect has been shown to play important roles in both normal brain functioning and functional abnormalities. Here we utilized R-fMRI to measure the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo), two major methods for characterizing the regional properties of R-fMRI, in three different frequency bands (slow-5: 0.01-0.027 Hz; slow-4: 0.027-0.73 Hz; and typical band: 0.01-0.1 Hz) in 19 stroke patients and 15 healthy controls. Both the ALFF and ReHo analyses revealed changes in brain activity in a number of brain regions, particularly the parietal cortex, in stroke patients compared with healthy controls. Remarkably, the regions with changed activity as detected by the slow-5 band data were more extensive, and this finding was true for both the ALFF and ReHo analyses. These results not only confirm previous studies showing abnormality in the parietal cortex in patients with stroke, but also suggest that R-fMRI studies of stroke should take frequency effects into account when measuring intrinsic brain activity.     

Boosting Cortical Activity at Beta-Band Frequencies Slows Movement in Humans

Neurons have a striking tendency to engage in oscillatory activities. One important type of oscillatory activity prevalent in the motor system occurs in the beta frequency band, at about 20 Hz. It is manifest during the maintenance of tonic contractions and is suppressed prior to and during voluntary movement [1], [2], [3], [4], [5], [6] and [7]. This and other correlative evidence suggests that beta activity might promote tonic contraction, while impairing motor processing related to new movements [3], [8] and [9]. Hence, bursts of beta activity in the cortex are associated with a strengthening of the motor effects of sensory feedback during tonic contraction and with reductions in the velocity of voluntary movements [9], [10] and [11]. Moreover, beta activity is increased when movement has to be resisted or voluntarily suppressed [7], [12] and [13]. Here we use imperceptible transcranial alternating-current stimulation to entrain cortical activity at 20 Hz in healthy subjects and show that this slows voluntary movement. The present findings are the first direct evidence of causality between any physiological oscillatory brain activity and concurrent motor behavior in the healthy human and help explain how the exaggerated beta activity found in Parkinson's disease can lead to motor slowing in this illness [14].     

Infant neural sensitivity to dynamic eye gaze is associated with later emerging autism

Autism spectrum disorders (henceforth autism) are diagnosed in around 1% of the population [1]. Familial liability confers risk for a broad spectrum of difficulties including the broader autism phenotype (BAP) [2, 3]. There are currently no reliable predictors of autism in infancy, but characteristic behaviors emerge during the second year, enabling diagnosis after this age [4, 5]. Because indicators of brain functioning may be sensitive predictors, and atypical eye contact is characteristic of the syndrome [6-9] and the BAP [10, 11], we examined whether neural sensitivity to eye gaze during infancy is associated with later autism outcomes [12, 13]. We undertook a prospective longitudinal study of infants with and without familial risk for autism. At 6-10 months, we recorded infants' event-related potentials (ERPs) in response to viewing faces with eye gaze directed toward versus away from the infant [14]. Longitudinal analyses showed that characteristics of ERP components evoked in response to dynamic eye gaze shifts during infancy were associated with autism diagnosed at 36 months. ERP responses to eye gaze may help characterize developmental processes that lead to later emerging autism. Findings also elucidate the mechanisms driving the development of the social brain in infancy.     

抑郁症患者的脑CT灌注成像特征与认知功能的相关性

摘要 目的：探讨抑郁症患者的脑CT灌注成像特征与认知功能的相关性。方法：选取我院2020年1月到2023年1月收治的90例抑郁症患者作为研究对象,将其分为观察组,另选取同期来我院体检的90名健康志愿者作为对照组。收集所有受检者脑CT灌注成像检查数据,分析抑郁症患者的脑CT灌注成像特征,并建立受试者工作特征（ROC）曲线分析脑CT灌注成像对抑郁症的诊断效能。随后对观察组和对照组受检者均进行认知功能评估,其中包括连线检测（TMT）、视觉再生测验（VRT）、言语流畅性测验（VF）、数字广度测验（DST）以及数字符号测验（SDMT）,并分析脑CT灌注成像与抑郁症认知功能的相关性。结果：观察组与对照组受检者rCBV、rCBF、MTT、TIP、右枕叶、左枕叶、右颞叶、左颞叶、右顶叶、左顶叶CT值对比无明显差异（P＞0.05）,观察组与对照组受检者右额叶、左额叶CT值对比差异显著,观察组明显低于对照组（P＜0.05）;90例抑郁症患者经过汉密尔顿抑郁量表（HAMD）评估后分数均＞20分,确定存在抑郁症状,脑CT灌注成像与HAMD评分诊断抑郁症的准确性、灵敏度、特异性、阳性预测值和阴性预测值对比无明显差异（P＞0.05）,脑CT灌注成像的曲线下面积为83.89,最佳诊断着色界限值为82.53%,HAMD评分的曲线下面积为84.26,最佳诊断着色界限值为87.57%;观察组与对照组受检者连线提笔数、连线错误数、视觉再生检测结果对比无明显差异（P＞0.05）,观察组与对照组受检者连线、言语流畅性、数字广度、数字符号检测结果对比差异显著（P＜0.05）;Spearman相关分析结果表明：连线提笔数、连线错误数、视觉再生与脑CT灌注参数均无明显相关性（P＞0.05）,连线、言语流畅性、数字广度、数字符号与rCBV、rCBF、MTT、TIP、右枕叶、左枕叶、右颞叶、左颞叶、右顶叶、左顶叶CT值无明显相关性（P＞0.05）,连线与右额叶、左额叶CT值呈负相关（P＜0.05）,言语流畅性、数字广度、数字符号与右额叶、左额叶CT值呈正相关（P＜0.05）。结论：抑郁症患者的脑CT灌注成像与健康群体呈现差异,其中右额叶、左额叶差异情况最为显著,提示抑郁症患者可能存在大脑额叶功能改变,另外,抑郁症患者的大脑额叶功能与认知功能变化具有明显相关性。     

Coding of abstract quantity by ‘number neurons’ of the primate brain

Humans share with nonhuman animals a quantification system for representing the number of items as nonverbal mental magnitudes. Over the past decade, the anatomical substrates and neuronal mechanisms of this quantification system have been unraveled down to the level of single neurons. Work with behaviorally trained nonhuman primates identified a parieto-frontal cortical network with individual neurons selectively tuned to the number of items. Such ‘number neurons’ can track items across space, time, and modality to encode numerosity in a most abstract, supramodal way. The physiological properties of these neurons can explain fundamental psychophysical phenomena during numerosity judgments. Functionally overlapping groups of parietal neurons represent not only numerable-discrete quantity (numerosity), but also innumerable-continuous quantity (extent) and relations between quantities (proportions), supporting the idea of a generalized magnitude system in the brain. These studies establish putative homologies between the monkey and human brain and demonstrate the suitability of nonhuman primates as model system to explore the neurobiological roots of the brain’s nonverbal quantification system, which may constitute the evolutionary foundation of all further, more elaborate numerical skills in humans.     

Preschoolers' precision of the approximate number system predicts later school mathematics performance

The Approximate Number System (ANS) is a primitive mental system of nonverbal representations that supports an intuitive sense of number in human adults, children, infants, and other animal species. The numerical approximations produced by the ANS are characteristically imprecise and, in humans, this precision gradually improves from infancy to adulthood. Throughout development, wide ranging individual differences in ANS precision are evident within age groups. These individual differences have been linked to formal mathematics outcomes, based on concurrent, retrospective, or short-term longitudinal correlations observed during the school age years. However, it remains unknown whether this approximate number sense actually serves as a foundation for these school mathematics abilities. Here we show that ANS precision measured at preschool, prior to formal instruction in mathematics, selectively predicts performance on school mathematics at 6 years of age. In contrast, ANS precision does not predict non-numerical cognitive abilities. To our knowledge, these results provide the first evidence for early ANS precision, measured before the onset of formal education, predicting later mathematical abilities.     

Rhesus monkeys attribute perceptions to others

Paramount among human cognitive abilities is the capacity to reason about what others think, want, and see--a capacity referred to as a theory of mind (ToM). Despite its importance in human cognition, the extent to which other primates share human ToM capacities has for decades remained a mystery. To date, primates [1, 2] have performed poorly in behavioral tasks that require ToM abilities, despite the fact that some macaques are known to encode social stimuli at the level of single neurons [3-5]. Here, we presented rhesus macaques with a more ecologically relevant ToM task in which subjects could "steal" a contested grape from one of two human competitors. In six experiments, monkeys selectively retrieved the grape from an experimenter who was incapable of seeing the grape rather than an experimenter who was visually aware. These results suggest that rhesus macaques possess an essential component of ToM: the ability to deduce what others perceive on the basis of where they are looking. These results converge with new findings illustrating the importance of competitive paradigms in apes [6]. Moreover, they raise the possibility that, in primates, cortical cells thought to encode where others are looking [7] may encode what those individuals see as well.     

Rapid memory reactivation revealed by oscillatory entrainment

Episodic memory refers to humans' unique ability to mentally reconstruct past events. Neurocomputational models predict that remembering entails the reinstatement of brain activity that was present when an event was initially experienced [1-5], a claim that has recently gained support from functional imaging work in humans [6-14]. The nature of this reactivation, however, is still unclear. Cognitive models claim that retrieval is set off by an early reactivation of stored memory representations ("ecphory") [15-17]. However, reinstatement as found in imaging studies might also reflect postretrieval processes that operate on the products of retrieval and are thus a consequence rather than a precondition of remembering. Here, we used frequency entrainment as a novel method of tagging memories in the human electroencephalogram (EEG). Participants studied words presented on flickering backgrounds, entraining a steady-state brain response at either 6 or 10?Hz. We found that these frequency signatures rapidly reemerged during a later memory test when participants successfully recognized?a word. An additional behavioral experiment suggested that this reactivation occurs in the absence of conscious memory for the frequencies entrained during study. The findings provide empirical evidence for the role of rapid, likely unconscious memory reactivation during retrieval.     

Impaired parietal magnitude processing in developmental dyscalculia

Developmental dyscalculia (DD) is a specific learning disability affecting the acquisition of school-level mathematical abilities in the context of otherwise normal academic achievement, with prevalence estimates in the order of 3-6%. Behavioural studies show deficits in elementary numerical processing among individuals with pure DD, indicating that deficits in higher-level mathematical skills may stem from impaired representation and processing of basic numerical magnitude. Adult neuropsychological and neuroimaging research points to the intraparietal sulcus as a key region for the representation and processing of numerical magnitude. This raises the possibility of a parietal dysfunction as a root cause of DD. We show that, in children with pure DD, the right intraparietal sulcus is not modulated in response to numerical processing demands to the same degree as in typically developing children. This finding provides the first direct evidence for a specific impairment of parietal magnitude systems in DD during non-symbolic numerosity processing.     

Neural substrates of intermanual transfer of a newly acquired motor skill

In healthy humans, the two cerebral hemispheres show functional specialization to a degree unmatched in other animals, and such strong hemispheric specialization contributes to unimanual skill acquisition [1, 2]. When most humans learn a new motor skill with one hand, this process results in performance improvements in the opposite hand as well [3-6]. Despite the obvious adaptive advantage of such intermanual transfer, there is no direct evidence identifying the neural substrates of this form of skill acquisition [7-9]. Here, we used functional magnetic resonance imaging (fMRI) to study brain regions activated during intermanual transfer of a learned sequence of finger movements. First, we found that the supplementary motor area (SMA) has more activity when a skill has transferred well than when it has transferred poorly. Second, we found that fMRI activity in the ventrolateral posterior thalamic nucleus correlated with successful future intermanual transfer, whereas activity in the ventrolateral anterior thalamic nucleus correlated with past intermanual transfer. Third, we found that repetitive transcranial magnetic stimulation applied over the SMA blocked intermanual transfer without affecting skill acquisition. These findings provide direct evidence for an SMA-based mechanism that supports intermanual transfer of motor-skill learning.     

Ectopic G-protein expression in dopamine and serotonin neurons blocks cocaine sensitization in Drosophila melanogaster

Sensitization to repeated doses of psychostimulants is thought to be an important component underlying the addictive process in humans [1] [2] [3] [4]. In all vertebrate animal models, including humans [5], and even in fruit flies, sensitization is observed after repeated exposure to volatilized crack cocaine [6]. In vertebrates, sensitization is thought to be initiated by processes occurring in brain regions that contain dopamine cell bodies [2] [7]. Here, we show that modulated cell signaling in the Drosophila dopamine and serotonin neurons plays an essential role in cocaine sensitization. Targeted expression of either a stimulatory (Galpha(s)) or inhibitory (Galpha(i)) Galpha subunit, or tetanus toxin light chain (TNT) in dopamine and serotonin neurons of living flies blocked behavioral sensitization to repeated cocaine exposures. These flies showed alterations in their initial cocaine responsiveness that correlated with compensatory adaptations of postsynaptic receptor sensitivity. Finally, repeated drug stimulation of a nerve cord preparation that is postsynaptic to the brain amine cells failed to induce sensitization, further showing the importance of presynaptic modulation in sensitization.     

Monkeys match the number of voices they hear to the number of faces they see

Convergent evidence demonstrates that adult humans possess numerical representations that are independent of language [1, 2, 3, 4, 5 and 6]. Human infants and nonhuman animals can also make purely numerical discriminations, implicating both developmental and evolutionary bases for adult humans' language-independent representations of number [7 and 8]. Recent evidence suggests that the nonverbal representations of number held by human adults are not constrained by the sensory modality in which they were perceived [9]. Previous studies, however, have yielded conflicting results concerning whether the number representations held by nonhuman animals and human infants are tied to the modality in which they were established [10, 11, 12, 13, 14 and 15]. Here, we report that untrained monkeys preferentially looked at a dynamic video display depicting the number of conspecifics that matched the number of vocalizations they heard. These findings suggest that number representations held by monkeys, like those held by adult humans, are unfettered by stimulus modality.