Publications

2006
Bermpohl F, Pascual-Leone A, Amedi A, Merabet LB, Fregni F, Gaab N, Alsop D, Schlaug G, Northoff G. Attentional modulation of emotional stimulus processing: an fMRI study using emotional expectancy. Hum Brain Mapp. 2006;27 (8) :662-77.Abstract
We used emotional expectancy to study attentional modulation in the processing of emotional stimuli. During functional magnetic resonance imaging (fMRI), volunteers saw emotional and neutral expectancy cues signaling the subsequent presentation of corresponding emotional or neutral pictorial stimuli. As a control, emotional and neutral pictures were presented without preceding expectancy cue, resulting in a 2 x 2 factorial design with the factors "expectancy" and "emotion." Statistical analysis revealed a significant positive interaction effect between these factors in the medial prefrontal cortex (MPFC, Brodmann area [BA] 9/10), amygdala, and dorsal midbrain. In all these regions, expectancy augmented the neural response to emotional but not to neutral pictures. Time course analysis of raw data suggests that this augmented activation was not preceded by baseline increases in MPFC and amygdala during the period of emotional expectancy. In a post-scanning session, the paradigm was presented for a second time to allow emotional intensity rating. Again, a significant interaction between expectancy and emotion was observed, with intensity ratings specifically enhanced in emotional photographs preceded by expectancy. There was a positive correlation between intensity ratings and blood oxygenation level-dependent (BOLD) signals in the left amygdala. We conclude that specific components of the emotion network show enhanced activation in response to emotional stimuli when these are preceded by expectancy. This enhancement effect is not present in neutral pictures and might parallel accentuated subjective feeling states.
Alfaro A, Concepción L, Merabet L, Fernández E. An atypical presentation of visual hallucinatory experiences following prolonged blindness. Neurocase. 2006;12 (4) :212-5.Abstract
We report a patient with long-standing blindness experiencing both simple and complex visual hallucinations secondary to a cortical arteriovenous malformation (AVM). The hallucinations were located in the right visual field corresponding to the contra-lateral site of cortical damage. This case contributes to our understanding of neurophysiological mechanisms underlying visual hallucinations and ongoing research investigating the phenomenology of hallucinations with respect to the cause and localization of neural damage.
Bermpohl F, Pascual-Leone A, Amedi A, Merabet LB, Fregni F, Gaab N, Alsop D, Schlaug G, Northoff G. Dissociable networks for the expectancy and perception of emotional stimuli in the human brain. Neuroimage. 2006;30 (2) :588-600.Abstract
William James posited that comparable brain regions were implicated in the anticipation and perception of a stimulus; however, dissociable networks (at least in part) may also underlie these processes. Recent functional neuroimaging studies have addressed this issue by comparing brain systems associated with the expectancy and perception of visual, tactile, nociceptive, and reward stimuli. In the present fMRI study, we addressed this issue in the domain of pictorial emotional stimuli (IAPS). Our paradigm involved the experimental conditions emotional expectancy, neutral expectancy, emotional picture perception, and neutral picture perception. Specifically, the emotional expectancy cue was uncertain in that it did not provide additional information regarding the positive or negative valence of the subsequent picture. Neutral expectancy and neutral picture perception served as control conditions, allowing the identification of expectancy and perception effects specific for emotion processing. To avoid contamination of the perception conditions by the preceding expectancy periods, 50% of the pictorial stimuli were presented without preceding expectancy cues. We found that the emotional expectancy cue specifically produced activation in the supracallosal anterior cingulate, cingulate motor area, and parieto-occipital sulcus. These regions were not significantly activated by emotional picture perception which recruited a different neuronal network, including the amygdala, insula, medial and lateral prefrontal cortex, cerebellum, and occipitotemporal areas. This dissociation may reflect a distinction between anticipatory and perceptive components of emotional stimulus processing.
Alsop D, Schlaug G, Northoff G, Gaab N, Fregni F, Pascual-Leone A, Amedi A, Merabet LB, Bermpohl F. Dissociable networks for the expectancy and perception of emotional stimuli in the human brain. NeuroImage. 2006;30 :588-600. Publisher's VersionAbstract

William James posited that comparable brain regions were implicated in the anticipation and perception of a stimulus; however, dissociable networks (at least in part) may also underlie these processes. Recent functional neuroimaging studies have addressed this issue by comparing brain systems associated with the expectancy and perception of visual, tactile, nociceptive, and reward stimuli. In the present fMRI study, we addressed this issue in the domain of pictorial emotional stimuli (IAPS). Our paradigm involved the experimental conditions emotional expectancy, neutral expectancy, emotional picture perception, and neutral picture perception. Specifically, the emotional expectancy cue was uncertain in that it did not provide additional information regarding the positive or negative valence of the subsequent picture. Neutral expectancy and neutral picture perception served as control conditions, allowing the identification of expectancy and perception effects specific for emotion processing. To avoid contamination of the perception conditions by the preceding expectancy periods, 50% of the pictorial stimuli were presented without preceding expectancy cues. We found that the emotional expectancy cue specifically produced activation in the supracallosal anterior cingulate, cingulate motor area, and parieto-occipital sulcus. These regions were not significantly activated by emotional picture perception which recruited a different neuronal network, including the amygdala, insula, medial and lateral prefrontal cortex, cerebellum, and occipitotemporal areas. This dissociation may reflect a distinction between anticipatory and perceptive components of emotional stimulus processing.

Alsop D, Schlaug G, Northoff G, Gaab N, Fregni F, Pascual-Leone A, Amedi A, Merabet LB, Bermpohl F. Attentional modulation of emotional stimulus processing: an fMRI study using emotional expectancy. Human brain mapping. 2006;27 :662-77. Publisher's VersionAbstract

We used emotional expectancy to study attentional modulation in the processing of emotional stimuli. During functional magnetic resonance imaging (fMRI), volunteers saw emotional and neutral expectancy cues signaling the subsequent presentation of corresponding emotional or neutral pictorial stimuli. As a control, emotional and neutral pictures were presented without preceding expectancy cue, resulting in a 2 x 2 factorial design with the factors "expectancy" and "emotion." Statistical analysis revealed a significant positive interaction effect between these factors in the medial prefrontal cortex (MPFC, Brodmann area [BA] 9/10), amygdala, and dorsal midbrain. In all these regions, expectancy augmented the neural response to emotional but not to neutral pictures. Time course analysis of raw data suggests that this augmented activation was not preceded by baseline increases in MPFC and amygdala during the period of emotional expectancy. In a post-scanning session, the paradigm was presented for a second time to allow emotional intensity rating. Again, a significant interaction between expectancy and emotion was observed, with intensity ratings specifically enhanced in emotional photographs preceded by expectancy. There was a positive correlation between intensity ratings and blood oxygenation level-dependent (BOLD) signals in the left amygdala. We conclude that specific components of the emotion network show enhanced activation in response to emotional stimuli when these are preceded by expectancy. This enhancement effect is not present in neutral pictures and might parallel accentuated subjective feeling states.

Fernandez E, Merabet L, Concepcion L, Alfaro A. An atypical presentation of visual hallucinatory experiences following prolonged blindness. Neurocase. 2006;12 :212-5. Publisher's VersionAbstract

We report a patient with long-standing blindness experiencing both simple and complex visual hallucinations secondary to a cortical arteriovenous malformation (AVM). The hallucinations were located in the right visual field corresponding to the contra-lateral site of cortical damage. This case contributes to our understanding of neurophysiological mechanisms underlying visual hallucinations and ongoing research investigating the phenomenology of hallucinations with respect to the cause and localization of neural damage.

Fernandez E, Merabet L, Concepcion L, Alfaro A. An atypical presentation of visual hallucinatory experiences following prolonged blindness. Neurocase. 2006;12 :212-5. Publisher's VersionAbstract

We report a patient with long-standing blindness experiencing both simple and complex visual hallucinations secondary to a cortical arteriovenous malformation (AVM). The hallucinations were located in the right visual field corresponding to the contra-lateral site of cortical damage. This case contributes to our understanding of neurophysiological mechanisms underlying visual hallucinations and ongoing research investigating the phenomenology of hallucinations with respect to the cause and localization of neural damage.

2005
Fernández E, Pelayo F, Romero S, Bongard M, Marin C, Alfaro A, Merabet L. Development of a cortical visual neuroprosthesis for the blind: the relevance of neuroplasticity. J Neural Eng. 2005;2 (4) :R1-12.Abstract
Clinical applications such as artificial vision require extraordinary, diverse, lengthy and intimate collaborations among basic scientists, engineers and clinicians. In this review, we present the state of research on a visual neuroprosthesis designed to interface with the occipital visual cortex as a means through which a limited, but useful, visual sense could be restored in profoundly blind individuals. We review the most important physiological principles regarding this neuroprosthetic approach and emphasize the role of neural plasticity in order to achieve desired behavioral outcomes. While full restoration of fine detailed vision with current technology is unlikely in the immediate near future, the discrimination of shapes and the localization of objects should be possible allowing blind subjects to navigate in a unfamiliar environment and perhaps even to read enlarged text. Continued research and development in neuroprosthesis technology will likely result in a substantial improvement in the quality of life of blind and visually impaired individuals.
Pascual-Leone A, Amedi A, Fregni F, Merabet LB. The plastic human brain cortex. Annu Rev Neurosci. 2005;28 :377-401.Abstract
Plasticity is an intrinsic property of the human brain and represents evolution's invention to enable the nervous system to escape the restrictions of its own genome and thus adapt to environmental pressures, physiologic changes, and experiences. Dynamic shifts in the strength of preexisting connections across distributed neural networks, changes in task-related cortico-cortical and cortico-subcortical coherence and modifications of the mapping between behavior and neural activity take place in response to changes in afferent input or efferent demand. Such rapid, ongoing changes may be followed by the establishment of new connections through dendritic growth and arborization. However, they harbor the danger that the evolving pattern of neural activation may in itself lead to abnormal behavior. Plasticity is the mechanism for development and learning, as much as a cause of pathology. The challenge we face is to learn enough about the mechanisms of plasticity to modulate them to achieve the best behavioral outcome for a given subject.
Merabet LB, Rizzo JF, Amedi A, Somers DC, Pascual-Leone A. What blindness can tell us about seeing again: merging neuroplasticity and neuroprostheses. Nat Rev Neurosci. 2005;6 (1) :71-7.Abstract
Significant progress has been made in the development of visual neuroprostheses to restore vision in blind individuals. Appropriate delivery of electrical stimulation to intact visual structures can evoke patterned sensations of light in those who have been blind for many years. However, success in developing functional visual prostheses requires an understanding of how to communicate effectively with the visually deprived brain in order to merge what is perceived visually with what is generated electrically.
Merabet LB, Fregni F, Amedi A, Pascual-Leone A. The plastic human brain cortex. Annual review of neuroscience. 2005;28 :377-401. Publisher's VersionAbstract

Plasticity is an intrinsic property of the human brain and represents evolution's invention to enable the nervous system to escape the restrictions of its own genome and thus adapt to environmental pressures, physiologic changes, and experiences. Dynamic shifts in the strength of preexisting connections across distributed neural networks, changes in task-related cortico-cortical and cortico-subcortical coherence and modifications of the mapping between behavior and neural activity take place in response to changes in afferent input or efferent demand. Such rapid, ongoing changes may be followed by the establishment of new connections through dendritic growth and arborization. However, they harbor the danger that the evolving pattern of neural activation may in itself lead to abnormal behavior. Plasticity is the mechanism for development and learning, as much as a cause of pathology. The challenge we face is to learn enough about the mechanisms of plasticity to modulate them to achieve the best behavioral outcome for a given subject.

Pascual-Leone A, Somers DC, Amedi A, Rizzo JF, Merabet LB. What blindness can tell us about seeing again: merging neuroplasticity and neuroprostheses. Nature reviews. Neuroscience. 2005;6 :71-7. Publisher's VersionAbstract

Significant progress has been made in the development of visual neuroprostheses to restore vision in blind individuals. Appropriate delivery of electrical stimulation to intact visual structures can evoke patterned sensations of light in those who have been blind for many years. However, success in developing functional visual prostheses requires an understanding of how to communicate effectively with the visually deprived brain in order to merge what is perceived visually with what is generated electrically.

Alfaro A, Merabet L, Marin C, Bongard M, Pelayo F, Romero S, Fernandez E. Development of a cortical visual neuroprosthesis for the blind: the relevance of neuroplasticity. Journal of neural engineering. 2005;2 :R1-12. Publisher's VersionAbstract

Clinical applications such as artificial vision require extraordinary, diverse, lengthy and intimate collaborations among basic scientists, engineers and clinicians. In this review, we present the state of research on a visual neuroprosthesis designed to interface with the occipital visual cortex as a means through which a limited, but useful, visual sense could be restored in profoundly blind individuals. We review the most important physiological principles regarding this neuroprosthetic approach and emphasize the role of neural plasticity in order to achieve desired behavioral outcomes. While full restoration of fine detailed vision with current technology is unlikely in the immediate near future, the discrimination of shapes and the localization of objects should be possible allowing blind subjects to navigate in a unfamiliar environment and perhaps even to read enlarged text. Continued research and development in neuroprosthesis technology will likely result in a substantial improvement in the quality of life of blind and visually impaired individuals.

2004
Théoret H, Merabet L, Pascual-Leone A. Behavioral and neuroplastic changes in the blind: evidence for functionally relevant cross-modal interactions. J Physiol Paris. 2004;98 (1-3) :221-33.Abstract
The study of blind individuals provides insight into the brain re-organization and behavioral compensations that occur following sensory deprivation. While behavioral studies have yielded conflicting results in terms of performance levels within the remaining senses, deafferentation of visual cortical areas through peripheral blindness results in clear neuroplastic changes. Most striking is the activation of occipital cortex in response to auditory and tactile stimulation. Indeed, parts of the "unimodal" visual cortex are recruited by other sensory modalities to process sensory information in a functionally relevant manner. In addition, a larger area of the sensorimotor cortex is devoted to the representation of the reading finger in blind Braille readers. The "visual" function of the deafferented occipital cortex is also altered, where transcranial magnetic stimulation-induced phosphenes can be elicited in only 20% of blind subjects. The neural mechanisms underlying these changes remain elusive but recent data showing rapid cross-modal plasticity in blindfolded, sighted subjects argue against the establishment of new connections to explain cross-modal interactions in the blind. Rather, latent pathways that participate in multisensory percepts in sighted subjects might be unmasked and may be potentiated in the event of complete loss of visual input. These issues have important implications for the development of visual prosthesis aimed at restoring some degree of vision in the blind.
Merabet L, Thut G, Murray B, Andrews J, Hsiao S, Pascual-Leone A. Feeling by sight or seeing by touch?. Neuron. 2004;42 (1) :173-9.Abstract
We have addressed the role of occipital and somatosensory cortex in a tactile discrimination task. Sight-ed and congenitally blind subjects rated the roughness and distance spacing for a series of raised dot patterns. When judging roughness, intermediate dot spacings were perceived as being the most rough, while distance judgments generated a linear relation. Low-frequency rTMS applied to somatosensory cortex disrupted roughness without affecting distance judgments, while rTMS to occipital cortex disrupted distance but not roughness judgments. We also tested an early blind patient with bilateral occipital cortex damage. Her performance on the roughness determination task was normal; however, she was greatly impaired with distance judgments. The findings suggest a double-dissociation effect in which roughness and distance are primarily processed in somatosensory and occipital cortex, respectively. The differential effect of rTMS on task performance and corroborative clinical evidence suggest that occipital cortex is engaged in tactile tasks requiring fine spatial discrimination.
Fregni F, Merabet L, Pascual-Leone A, Marcolin MA. Modulation in motor threshold after a severe episode of gastrointestinal distress. J ECT. 2004;20 (1) :50-1.
Théoret H, Halligan E, Kobayashi M, Merabet L, Pascual-Leone A. Unconscious modulation of motor cortex excitability revealed with transcranial magnetic stimulation. Exp Brain Res. 2004;155 (2) :261-4.Abstract
The neuronal effects of sensory events that do not enter conscious awareness have been reported in numerous pathological conditions and in normal subjects. In the present study, unconscious modulation of corticospinal excitability was probed in healthy volunteers with transcranial magnetic stimulation (TMS). TMS-induced motor evoked potentials (MEPs) were collected from the first dorsal interosseus muscle while subjects performed a masked semantic priming task that has been shown to elicit covert motor cortex activations. Our data show that the amplitude of the MEPs is modulated by an unseen prime, in line with temporal patterns revealed with event related potentials. These data confirm previous reports showing specific motor neural responses associated with an unseen visual stimulus and establish TMS as a valuable tool in the study of the neural correlates of consciousness.
Théoret H, Kobayashi M, Merabet L, Wagner T, Tormos JM, Pascual-Leone A. Modulation of right motor cortex excitability without awareness following presentation of masked self-images. Brain Res Cogn Brain Res. 2004;20 (1) :54-7.Abstract
The neural substrates of self-awareness have been studied with a variety of neurophysiological and behavioral tools. In the present study, unconscious modulation of corticospinal excitability following presentation of self-images was probed with transcranial magnetic stimulation (TMS). TMS-induced motor evoked potentials (MEP) were collected from the contralateral first dorsal interosseus (FDI) muscle while subjects viewed masked pictures of their own face. MEP amplitudes were compared to those obtained when pictures of strangers were masked. Masked self-images induced a relative increase in corticospinal excitability when TMS was applied to the right primary motor cortex. These results demonstrate the utility of TMS to probe unconscious processing and support the notion of hemispheric asymmetry in the processing of self-images.
Merabet LB, Maguire D, Warde A, Alterescu K, Stickgold R, Pascual-Leone A. Visual hallucinations during prolonged blindfolding in sighted subjects. J Neuroophthalmol. 2004;24 (2) :109-13.Abstract
The authors report the occurrence of visual hallucinations of varying complexity in 13 normal subjects after sudden, complete, and prolonged visual deprivation. The subjects were all healthy individuals with no history of cognitive dysfunction, psychosis, or ocular pathology. They wore a specially designed blindfold for a period of five consecutive days (96 hours) and were asked to record their daily experiences using a hand-held microcassette recorder. Ten (77%) of the subjects reported visual hallucinations, which were both simple (bright spots of light) and complex (faces, landscapes, ornate objects). The onset of hallucinations was generally after the first day of blindfolding. Subjects were insightful as to their unreal nature. These results indicate that rapid and complete visual deprivation is sufficient to induce visual hallucinations in normal subjects.
Pascual-Leone A, Merabet L, Theoret H. Behavioral and neuroplastic changes in the blind: evidence for functionally relevant cross-modal interactions. Journal of physiology, Paris. 2004;98 :221-33. Publisher's VersionAbstract

The study of blind individuals provides insight into the brain re-organization and behavioral compensations that occur following sensory deprivation. While behavioral studies have yielded conflicting results in terms of performance levels within the remaining senses, deafferentation of visual cortical areas through peripheral blindness results in clear neuroplastic changes. Most striking is the activation of occipital cortex in response to auditory and tactile stimulation. Indeed, parts of the "unimodal" visual cortex are recruited by other sensory modalities to process sensory information in a functionally relevant manner. In addition, a larger area of the sensorimotor cortex is devoted to the representation of the reading finger in blind Braille readers. The "visual" function of the deafferented occipital cortex is also altered, where transcranial magnetic stimulation-induced phosphenes can be elicited in only 20% of blind subjects. The neural mechanisms underlying these changes remain elusive but recent data showing rapid cross-modal plasticity in blindfolded, sighted subjects argue against the establishment of new connections to explain cross-modal interactions in the blind. Rather, latent pathways that participate in multisensory percepts in sighted subjects might be unmasked and may be potentiated in the event of complete loss of visual input. These issues have important implications for the development of visual prosthesis aimed at restoring some degree of vision in the blind.

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