Safety Study of Transcranial Static Magnetic Field Stimulation (tSMS) of the Human Cortex.

BACKGROUND: Transcranial static magnetic field stimulation (tSMS) in humans reduces cortical excitability. OBJECTIVE: The objective of this study was to determine if prolonged tSMS (2 h) could be delivered safely in humans. Safety limits for this technique have not been described. METHODS: tSMS was applied for 2 h with a cylindric magnet on the occiput of 17 healthy subjects. We assessed tSMS-related safety aspects at tissue level by measuring levels of neuron-specific enolase (NSE, a marker of neuronal damage) and S100 (a marker of glial reactivity and damage). We also included an evaluation of cognitive side effects by using a battery of visuomotor and cognitive tests. RESULTS: tSMS did not induce any significant increase in NSE or S100. No cognitive alteration was detected. CONCLUSIONS: Our data indicate that the application of tSMS is safe in healthy human subjects, at least within these parameters.

Dopamine receptor 4 promoter polymorphism modulates memory and neuronal responses to salience.

Animal models and human functional imaging data implicate the dopamine system in mediating enhanced encoding of novel stimuli into human memory. A separate line of investigation suggests an association between a functional polymorphism in the promoter region for the human dopamine 4 receptor gene (DRD4) and sensitivity to novelty. We demonstrate, in two independent samples, that the -521C>T DRD4 promoter polymorphism determines the magnitude of human memory enhancement for contextually novel, perceptual oddball stimuli in an allele dose-dependent manner. The genotype-dependent memory enhancement conferred by the C allele is associated with increased neuronal responses during successful encoding of perceptual oddballs in the ventral striatum, an effect which is again allele dose-dependent. Furthermore, with repeated presentations of oddball stimuli, this memory advantage decreases, an effect mirrored by adaptation of activation in the hippocampus and substantia nigra/ventral tegmental area in C carriers only. Thus, a dynamic modulation of human memory enhancement for perceptually salient stimuli is associated with activation of a dopaminergic-hippocampal system, which is critically dependent on a functional polymorphism in the DRD4 promoter region.

Dynamic gamma frequency feedback coupling between higher and lower order visual cortices underlies perceptual completion in humans.

To perceive a coherent environment, incomplete or overlapping visual forms must be integrated into meaningful coherent percepts, a process referred to as "Gestalt" formation or perceptual completion. Increasing evidence suggests that this process engages oscillatory neuronal activity in a distributed neuronal assembly. A separate line of evidence suggests that Gestalt formation requires top-down feedback from higher order brain regions to early visual cortex. Here we combine magnetoencephalography (MEG) and effective connectivity analysis in the frequency domain to specifically address the effective coupling between sources of oscillatory brain activity during Gestalt formation. We demonstrate that perceptual completion of two-tone "Mooney" faces induces increased gamma frequency band power (55-71Hz) in human early visual, fusiform and parietal cortices. Within this distributed neuronal assembly fusiform and parietal gamma oscillators are coupled by forward and backward connectivity during Mooney face perception, indicating reciprocal influences of gamma activity between these higher order visual brain regions. Critically, gamma band oscillations in early visual cortex are modulated by top-down feedback connectivity from both fusiform and parietal cortices. Thus, we provide a mechanistic account of Gestalt perception in which gamma oscillations in feature sensitive and spatial attention-relevant brain regions reciprocally drive one another and convey global stimulus aspects to local processing units at low levels of the sensory hierarchy by top-down feedback. Our data therefore support the notion of inverse hierarchical processing within the visual system underlying awareness of coherent percepts.

Beta-adrenergic modulation of emotional memory-evoked human amygdala and hippocampal responses.

Human emotional experience is typically associated with enhanced episodic memory. We have used functional magnetic resonance imaging to demonstrate that successful encoding of emotional, compared to neutral, verbal stimuli evokes increased human amygdala responses. Items that evoke amygdala activation at encoding evoke greater hippocampal responses at retrieval compared to neutral items. Administration of the beta-adrenergic antagonist propranolol at encoding abolishes the enhanced amygdala encoding and hippocampal retrieval effects, despite propranolol being no longer present at retrieval. Thus, memory-related amygdala responses at encoding and hippocampal responses at recognition for emotional items depend on beta-adrenergic engagement at encoding. Our results suggest that human emotional memory is associated with a beta-adrenergic-dependent modulation of amygdala-hippocampal interactions.

An emotion-induced retrograde amnesia in humans is amygdala- and beta-adrenergic-dependent.

The influence of emotion on human memory is associated with two contradictory effects in the form of either emotion-induced enhancements or decrements in memory. In a series of experiments involving single word presentation, we show that enhanced memory for emotional words is strongly coupled to decrements in memory for items preceding the emotional stimulus, an effect that is more pronounced in women. These memory effects would appear to depend on a common neurobiological substrate, in that enhancements and decrements are reversed by propranolol, a beta-adrenergic antagonist, and abolished by selective bilateral amygdala damage. Thus, our findings suggest that amygdala-dependent beta-adrenergic modulation of episodic encoding has costs as well as benefits.

Automatic and intentional brain responses during evaluation of trustworthiness of faces.

Successful social interaction partly depends on appraisal of others from their facial appearance. A critical aspect of this appraisal relates to whether we consider others to be trustworthy. We determined the neural basis for such trustworthiness judgments using event-related functional magnetic resonance imaging. Subjects viewed faces and assessed either trustworthiness or age. In a parametric factorial design, trustworthiness ratings were correlated with BOLD signal change to reveal task-independent increased activity in bilateral amygdala and right insula in response to faces judged untrustworthy. Right superior temporal sulcus (STS) showed enhanced signal change during explicit trustworthiness judgments alone. The findings extend a proposed model of social cognition by highlighting a functional dissociation between automatic engagement of amygdala versus intentional engagement of STS in social judgment.

Dissociable human perirhinal, hippocampal, and parahippocampal roles during verbal encoding.

The precise contribution of perirhinal cortex to human episodic memory is uncertain. Human intracranial recordings highlight a role in successful episodic memory encoding, but encoding-related perirhinal activation has not been observed with functional imaging. By adapting functional magnetic resonance imaging scanning parameters to maximize sensitivity to medial temporal lobe activity, we demonstrate that left perirhinal and hippocampal responses during word list encoding are greater for subsequently recalled than forgotten words. Although perirhinal responses predict memory for all words, successful encoding of initial words in a list, demonstrating a primacy effect, is associated with parahippocampal and anterior hippocampal activation. We conclude that perirhinal cortex and hippocampus participate in successful memory encoding. Encoding-related parahippocampal and anterior hippocampal responses for initial, remembered words most likely reflects enhanced attentional orienting to these positionally distinctive items.

Anterior prefrontal cortex mediates rule learning in humans.

Despite a need for rule learning in everyday life, the brain regions involved in explicit rule induction remain undetermined. Here we use event-related functional magnetic resonance imaging to measure learning-dependent neuronal responses during an explicit categorization task. Subjects made category decisions, with feedback, to exemplar letter strings for which the rule governing category membership was periodically changed. Bilateral fronto-polar prefrontal cortices were selectively engaged following rule change. This activation pattern declined with improving task performance reflecting rule acquisition. The vocabulary of letters comprising the exemplars was also periodically changed, independently of rule changes. This exemplar change modulated activation in left anterior hippocampus. Our finding that fronto-polar cortex mediates rule learning supports a functional contribution of this region to generic reasoning and problem-solving behaviours.

Adaptive anterior hippocampal responses to oddball stimuli.

An efficient memory system requires the ability to detect and preferentially encode novel stimuli. Human electrophysiological recordings demonstrate differential hippocampal responses to novel vs. familiar stimuli, as well as to oddball stimuli. Although functional imaging experiments of novelty detection have demonstrated hippocampal activation, oddball-evoked hippocampal activation has not been demonstrated. Here we use event-related functional magnetic resonance imaging (fMRI) to measure hippocampal responses to three types of oddball words: perceptual, semantic, and emotional. We demonstrate left anterior hippocampal sensitivity to all three oddball types, with adaptation of responses across multiple oddball presentations. This adaptive hippocampal oddball response was not modulated by depth of processing, suggesting a high degree of automaticity in the underlying process. However, an interaction with depth of encoding for semantic oddballs was evident in a more lateral left anterior hippocampal region. We conclude that the hippocampal response to oddballs demonstrates a second-order novelty effect, being sensitive to the "novelty of novelty" of oddball stimuli. The data provide support for a more general theory that a function of the anterior hippocampus is to register mismatches between expectation and experience.

Brain mechanisms for detecting perceptual, semantic, and emotional deviance.

The observation that we note the exceptional over the mundane has been the subject of extensive psychological and electrophysiological analysis in "oddball" paradigms. Whether detection of a sensory oddball reflects the operation of a generic mechanism or, alternatively, mechanisms sensitive to specific attributes of stimulus deviance is unknown. To address this question we used event-related functional MRI (fMRI) to measure neural responses during presentation of nouns, of which a proportion were perceptually, semantically, or emotionally deviant. Oddballs, regardless of deviant attributes and depth of processing, activated right inferior prefrontal and bilateral posterior fusiform cortices. Attribute-specific responses, independent of depth of processing, were evident in bilateral fusiform cortices for perceptual oddballs and left amygdala for emotional oddballs. By contrast, an interaction with depth of processing was evident in left prefrontal cortex for semantic oddballs. We conclude that detection of oddballs reflects the operation of a generic "deviance detection system," involving right prefrontal and fusiform cortices in addition to specific brain regions sensitive to the stimulus attributes that determine the qualitative characteristics of deviance.

How does the brain sustain a visual percept?

Perception involves the processing of sensory stimuli and their translation into conscious experience. A novel percept can, once synthesized, be maintained or discarded from awareness. We used event-related functional magnetic resonance imaging to separate the neural responses associated with the maintenance of a percept, produced by single-image, random-dot stereograms, from the response evoked at the onset of the percept. The latter was associated with distributed bilateral activation in the posterior thalamus and regions in the occipito-temporal, parietal and frontal cortices. In contrast, sustained perception was associated with activation of the pre-frontal cortex and hippocampus. This observation suggests that sustaining a visual percept involves neuroanatomical systems which are implicated in memory function and which are distinct from those engaged during perceptual synthesis.

Segregating the functions of human hippocampus.

It is now accepted that hippocampal lesions impair episodic memory. However, the precise functional role of the hippocampus in episodic memory remains elusive. Recent functional imaging data implicate the hippocampus in processing novelty, a finding supported by human in vivo recordings and event-related potential studies. Here we measure hippocampal responses to novelty, using functional MRI (fMRI), during an item-learning paradigm generated from an artificial grammar system. During learning, two distinct types of novelty were periodically introduced: perceptual novelty, pertaining to the physical characteristics of stimuli (in this case visual characteristics), and exemplar novelty, reflecting semantic characteristics of stimuli (in this case grammatical status within a rule system). We demonstrate a left anterior hippocampal response to both types of novelty and adaptation of these responses with stimulus familiarity. By contrast to these novelty effects, we also show bilateral posterior hippocampal responses with increasing exemplar familiarity. These results suggest a functional dissociation within the hippocampus with respect to the relative familiarity of study items. Neural responses in anterior hippocampus index generic novelty, whereas posterior hippocampal responses index familiarity to stimuli that have behavioral relevance (i.e., only exemplar familiarity). These findings add to recent evidence for functional segregation within the human hippocampus during learning.