FLUORESCE: A Pilot Randomized Clinical Trial of Fluoxetine for Vision Recovery After Acute Ischemic Stroke.

BACKGROUND: Poststroke homonymous hemianopia is disabling, and complete spontaneous recovery is rare. In this randomized, placebo-controlled, double-blind, pilot clinical trial, we tested whether fluoxetine enhances vision recovery after stroke. METHODS: We randomized 17 consecutive adults 1:1 to 90 days of fluoxetine 20 mg daily vs placebo within 10 days of an ischemic stroke causing isolated homonymous hemianopia. The primary end point was percent improvement in 24-2 automated perimetry at 6 months. Twelve participants completed the study. Clinical trial registration NCT02737930. RESULTS: Intention-to-treat analysis of the primary end point, percent improvement in perimetric mean deviation, showed a nonsignificant benefit of fluoxetine (64.4%, n = 5) compared with placebo (26.0%, n = 7, one-tailed 95% confidence interval (CI) = (-2.13, ∞), P = 0.06). The original blind field completely recovered in 60% receiving fluoxetine and 14% receiving placebo (odds ratio = 7.22, one-tailed 95% CI = (0.50, ∞)). CONCLUSION: These results suggest a trend in favor of fluoxetine for vision recovery after stroke and have the potential to inform the design of a larger multicenter trial.

What tool representation, intuitive physics, and action have in common: The brain's first-person physics engine.

An overlapping set of brain regions in parietal and frontal cortex are engaged by different types of tasks and stimuli: (i) making inferences about the physical structure and dynamics of the world, (ii) passively viewing, or actively interacting with, manipulable objects, and (iii) planning and execution of reaching and grasping actions. We suggest the observed neural overlap is because a common superordinate computation is engaged by each of those different tasks: A forward model of physical reasoning about how first-person actions will affect the world and be affected by unfolding physical events. This perspective offers an account of why some physical predictions are systematically incorrect - there can be a mismatch between how physical scenarios are experimentally framed and the native format of the inferences generated by the brain's first-person physics engine. This perspective generates new empirical expectations about the conditions under which physical reasoning may exhibit systematic biases.

Interactions between language, thought, and perception: Cognitive and neural perspectives.

ABSTRACT The role that language plays in shaping non-linguistic cognitive and perceptual systems has been the subject of much theoretical and experimental attention over the past half-century. Understanding how language interacts with non-linguistic systems can provide insight into broader constraints on cognitive and brain organization. The papers that form this volume investigate various ways in which linguistic structure can interact with and influence how speakers think about and perceive the world, and the related issue of the constraints that in turn shape linguistic representations. These theoretical and empirical contributions support deeper understanding of the interactions between language, thought, and perception, and motivate new approaches for developing directional predictions at both the neural and cognitive levels.

Domain-Specific Diaschisis: Lesions to Parietal Action Areas Modulate Neural Responses to Tools in the Ventral Stream.

Neural responses to small manipulable objects ("tools") in high-level visual areas in ventral temporal cortex (VTC) provide an opportunity to test how anatomically remote regions modulate ventral stream processing in a domain-specific manner. Prior patient studies indicate that grasp-relevant information can be computed about objects by dorsal stream structures independently of processing in VTC. Prior functional neuroimaging studies indicate privileged functional connectivity between regions of VTC exhibiting tool preferences and regions of parietal cortex supporting object-directed action. Here we test whether lesions to parietal cortex modulate tool preferences within ventral and lateral temporal cortex. We found that lesions to the left anterior intraparietal sulcus, a region that supports hand-shaping during object grasping and manipulation, modulate tool preferences in left VTC and in the left posterior middle temporal gyrus. Control analyses demonstrated that neural responses to "place" stimuli in left VTC were unaffected by lesions to parietal cortex, indicating domain-specific consequences for ventral stream neural responses in the setting of parietal lesions. These findings provide causal evidence that neural specificity for "tools" in ventral and lateral temporal lobe areas may arise, in part, from online inputs to VTC from parietal areas that receive inputs via the dorsal visual pathway.

Survival of retinal ganglion cells after damage to the occipital lobe in humans is activity dependent.

Damage to the optic radiations or primary visual cortex leads to blindness in all or part of the contralesional visual field. Such damage disconnects the retina from its downstream targets and, over time, leads to trans-synaptic retrograde degeneration of retinal ganglion cells. To date, visual ability is the only predictor of retinal ganglion cell degeneration that has been investigated after geniculostriate damage. Given prior findings that some patients have preserved visual cortex activity for stimuli presented in their blind field, we tested whether that activity explains variability in retinal ganglion cell degeneration over and above visual ability. We prospectively studied 15 patients (four females, mean age = 63.7 years) with homonymous visual field defects secondary to stroke, 10 of whom were tested within the first two months after stroke. Each patient completed automated Humphrey visual field testing, retinotopic mapping with functional magnetic resonance imaging, and spectral-domain optical coherence tomography of the macula. There was a positive relation between ganglion cell complex (GCC) thickness in the blind field and early visual cortex activity for stimuli presented in the blind field. Furthermore, residual visual cortex activity for stimuli presented in the blind field soon after the stroke predicted the degree of retinal GCC thinning six months later. These findings indicate that retinal ganglion cell survival after ischaemic damage to the geniculostriate pathway is activity dependent.

Direct electrical stimulation mapping of cognitive functions in the human brain.

Direct electrical stimulation (DES) is a well-established clinical tool for mapping cognitive functions while patients are undergoing awake neurosurgery or invasive long-term monitoring to identify epileptogenic tissue. Despite the proliferation of a range of invasive and noninvasive methods for mapping sensory, motor and cognitive processes in the human brain, DES remains the clinical gold standard for establishing the margins of brain tissue that can be safely removed while avoiding long-term neurological deficits. In parallel, and principally over the last two decades, DES has emerged as a powerful scientific tool for testing hypotheses of brain organization and mechanistic hypotheses of cognitive function. DES can cause transient "lesions" and thus can support causal inferences about the necessity of stimulated brain regions for specific functions, as well as the separability of sensory, motor and cognitive processes. This Special Issue of Cognitive Neuropsychology emphasizes the use of DES as a research tool to advance understanding of normal brain organization and function.

Direct electrical stimulation of the left frontal aslant tract disrupts sentence planning without affecting articulation.

Sentence production involves mapping from deep structures that specify meaning and thematic roles to surface structures that specify the order and sequencing of production ready elements. We propose that the frontal aslant tract is a key pathway for sequencing complex actions with deep hierarchical structure. In the domain of language, and primarily with respect to the left FAT, we refer to this as the 'Syntagmatic Constraints On Positional Elements' (SCOPE) hypothesis. One prediction made by the SCOPE hypothesis is that disruption of the frontal aslant tract should disrupt sentence production at grammatical phrase boundaries, with no disruption of articulatory processes.  We test this prediction in a patient undergoing direct electrical stimulation mapping of the frontal aslant tract during an awake craniotomy to remove a left frontal brain tumor. We found that stimulation of the left FAT prolonged inter-word durations at the start of grammatical phrases, while inter-word durations internal to noun phrases were unaffected, and there was no effect on intra-word articulatory duration. These results provide initial support for the SCOPE hypothesis, and motivate novel directions for future research to explore the functions of this recently discovered component of the language system.

Abstract Representations of Object-Directed Action in the Left Inferior Parietal Lobule.

Prior neuroimaging and neuropsychological research indicates that the left inferior parietal lobule in the human brain is a critical substrate for representing object manipulation knowledge. In the present functional MRI study we used multivoxel pattern analyses to test whether action similarity among objects can be decoded in the inferior parietal lobule independent of the task applied to objects (identification or pantomime) and stimulus format in which stimuli are presented (pictures or printed words). Participants pantomimed the use of objects, cued by printed words, or identified pictures of objects. Classifiers were trained and tested across task (e.g., training data: pantomime; testing data: identification), stimulus format (e.g., training data: word format; testing format: picture) and specific objects (e.g., training data: scissors vs. corkscrew; testing data: pliers vs. screwdriver). The only brain region in which action relations among objects could be decoded across task, stimulus format and objects was the inferior parietal lobule. By contrast, medial aspects of the ventral surface of the left temporal lobe represented object function, albeit not at the same level of abstractness as actions in the inferior parietal lobule. These results suggest compulsory access to abstract action information in the inferior parietal lobe even when simply identifying objects.

A Role for the Frontal Aslant Tract in Speech Planning: A Neurosurgical Case Study.

Frontal and temporal white matter pathways play key roles in language processing, but the specific computations supported by different tracts remain a matter of study. A role in speech planning has been proposed for a recently described pathway, the frontal aslant tract (FAT), which connects the posterior inferior frontal gyrus to the pre-SMA. Here, we use longitudinal functional and structural MRI and behavioral testing to evaluate the behavioral consequences of a lesion to the left FAT that was incurred during surgical resection of a frontal glioma in a 60-year-old woman, Patient AF. The pattern of performance in AF is compared, using the same measures, with that in a 37-year-old individual who underwent a left anterior temporal resection and hippocampectomy (Patient AG). AF and AG were both cognitively intact preoperatively but exhibited specific and doubly dissociable behavioral deficits postoperatively: AF had dysfluent speech but no word finding difficulty, whereas AG had word finding difficulty but otherwise fluent speech. Probabilistic tractography showed that the left FAT was lesioned postoperatively in AF (but not AG) whereas the inferior longitudinal fasciculus was lesioned in AG (but not AF). Those structural changes were supported by corresponding changes in functional connectivity to the posterior inferior frontal gyrus: decreased functional connectivity postoperatively between the posterior inferior frontal gyrus and pre-SMA in AF (but not AG) and decreased functional connectivity between the posterior inferior frontal gyrus and the middle temporal gyrus in AG (but not AF). We suggest from these findings that the left FAT serves as a key communicative link between sentence planning and lexical access processes.

Spontaneous in-flight accommodation of hand orientation to unseen grasp targets: A case of action blindsight.

The division of labour between the dorsal and ventral visual pathways is well established. The ventral stream supports object identification, while the dorsal stream supports online processing of visual information in the service of visually guided actions. Here, we report a case of an individual with a right inferior quadrantanopia who exhibited accurate spontaneous rotation of his wrist when grasping a target object in his blind visual field. His accurate wrist orientation was observed despite the fact that he exhibited no sensitivity to the orientation of the handle in a perceptual matching task. These findings indicate that non-geniculostriate visual pathways process basic volumetric information relevant to grasping, and reinforce the observation that phenomenal awareness is not necessary for an object's volumetric properties to influence visuomotor performance.

Visual and visuomotor processing of hands and tools as a case study of cross talk between the dorsal and ventral streams.

A major principle of organization of the visual system is between a dorsal stream that processes visuomotor information and a ventral stream that supports object recognition. Most research has focused on dissociating processing across these two streams. Here we focus on how the two streams interact. We tested neurologically-intact and impaired participants in an object categorization task over two classes of objects that depend on processing within both streams-hands and tools. We measured how unconscious processing of images from one of these categories (e.g., tools) affects the recognition of images from the other category (i.e., hands). Our findings with neurologically-intact participants demonstrated that processing an image of a hand hampers the subsequent processing of an image of a tool, and vice versa. These results were not present in apraxic patients (N = 3). These findings suggest local and global inhibitory processes working in tandem to co-register information across the two streams.

The Representation of Object-Directed Action and Function Knowledge in the Human Brain.

The appropriate use of everyday objects requires the integration of action and function knowledge. Previous research suggests that action knowledge is represented in frontoparietal areas while function knowledge is represented in temporal lobe regions. Here we used multivoxel pattern analysis to investigate the representation of object-directed action and function knowledge while participants executed pantomimes of familiar tool actions. A novel approach for decoding object knowledge was used in which classifiers were trained on one pair of objects and then tested on a distinct pair; this permitted a measurement of classification accuracy over and above object-specific information. Region of interest (ROI) analyses showed that object-directed actions could be decoded in tool-preferring regions of both parietal and temporal cortex, while no independently defined tool-preferring ROI showed successful decoding of object function. However, a whole-brain searchlight analysis revealed that while frontoparietal motor and peri-motor regions are engaged in the representation of object-directed actions, medial temporal lobe areas in the left hemisphere are involved in the representation of function knowledge. These results indicate that both action and function knowledge are represented in a topographically coherent manner that is amenable to study with multivariate approaches, and that the left medial temporal cortex represents knowledge of object function.

Development of Tool Representations in the Dorsal and Ventral Visual Object Processing Pathways.

Tools represent a special class of objects, because they are processed across both the dorsal and ventral visual object processing pathways. Three core regions are known to be involved in tool processing: the left posterior middle temporal gyrus, the medial fusiform gyrus (bilaterally), and the left inferior parietal lobule. A critical and relatively unexplored issue concerns whether, in development, tool preferences emerge at the same time and to a similar degree across all regions of the tool-processing network. To test this issue, we used functional magnetic resonance imaging to measure the neural amplitude, peak location, and the dispersion of tool-related neural responses in the youngest sample of children tested to date in this domain (ages 4-8 years). We show that children recruit overlapping regions of the adult tool-processing network and also exhibit similar patterns of co-activation across the network to adults. The amplitude and co-activation data show that the core components of the tool-processing network are established by age 4. Our findings on the distributions of peak location and dispersion of activation indicate that the tool network undergoes refinement between ages 4 and 8 years.

Temporal Frequency Tuning Reveals Interactions between the Dorsal and Ventral Visual Streams.

Visual processing of complex objects is supported by the ventral visual pathway in the service of object identification and by the dorsal visual pathway in the service of object-directed reaching and grasping. Here, we address how these two streams interact during tool processing, by exploiting the known asymmetry in projections of subcortical magnocellular and parvocellular inputs to the dorsal and ventral streams. The ventral visual pathway receives both parvocellular and magnocellular input, whereas the dorsal visual pathway receives largely magnocellular input. We used fMRI to measure tool preferences in parietal cortex when the images were presented at either high or low temporal frequencies, exploiting the fact that parvocellular channels project principally to the ventral but not dorsal visual pathway. We reason that regions of parietal cortex that exhibit tool preferences for stimuli presented at frequencies characteristic of the parvocellular pathway receive their inputs from the ventral stream. We found that the left inferior parietal lobule, in the vicinity of the supramarginal gyrus, exhibited tool preferences for images presented at low temporal frequencies, whereas superior and posterior parietal regions exhibited tool preferences for images present at high temporal frequencies. These data indicate that object identity, processed within the ventral stream, is communicated to the left inferior parietal lobule and may there combine with inputs from the dorsal visual pathway to allow for functionally appropriate object manipulation.

Multisensory Part-based Representations of Objects in Human Lateral Occipital Cortex.

The format of high-level object representations in temporal-occipital cortex is a fundamental and as yet unresolved issue. Here we use fMRI to show that human lateral occipital cortex (LOC) encodes novel 3-D objects in a multisensory and part-based format. We show that visual and haptic exploration of objects leads to similar patterns of neural activity in human LOC and that the shared variance between visually and haptically induced patterns of BOLD contrast in LOC reflects the part structure of the objects. We also show that linear classifiers trained on neural data from LOC on a subset of the objects successfully predict a novel object based on its component part structure. These data demonstrate a multisensory code for object representations in LOC that specifies the part structure of objects.

Decoding Visual Location From Neural Patterns in the Auditory Cortex of the Congenitally Deaf.

Sensory cortices of individuals who are congenitally deprived of a sense can exhibit considerable plasticity and be recruited to process information from the senses that remain intact. Here, we explored whether the auditory cortex of congenitally deaf individuals represents visual field location of a stimulus-a dimension that is represented in early visual areas. We used functional MRI to measure neural activity in auditory and visual cortices of congenitally deaf and hearing humans while they observed stimuli typically used for mapping visual field preferences in visual cortex. We found that the location of a visual stimulus can be successfully decoded from the patterns of neural activity in auditory cortex of congenitally deaf but not hearing individuals. This is particularly true for locations within the horizontal plane and within peripheral vision. These data show that the representations stored within neuroplastically changed auditory cortex can align with dimensions that are typically represented in visual cortex.

A causal test of the motor theory of speech perception: a case of impaired speech production and spared speech perception.

The debate about the causal role of the motor system in speech perception has been reignited by demonstrations that motor processes are engaged during the processing of speech sounds. Here, we evaluate which aspects of auditory speech processing are affected, and which are not, in a stroke patient with dysfunction of the speech motor system. We found that the patient showed a normal phonemic categorical boundary when discriminating two non-words that differ by a minimal pair (e.g., ADA-AGA). However, using the same stimuli, the patient was unable to identify or label the non-word stimuli (using a button-press response). A control task showed that he could identify speech sounds by speaker gender, ruling out a general labelling impairment. These data suggest that while the motor system is not causally involved in perception of the speech signal, it may be used when other cues (e.g., meaning, context) are not available.

A bimodal tuning curve for spatial frequency across left and right human orbital frontal cortex during object recognition.

Orbital frontal cortex (OFC) is known to play a role in object recognition by generating "first-pass" hypotheses about the identity of naturalistic images based on low spatial frequency (SF) information. These hypotheses are evaluated by more detailed (and slower) ventral visual pathway processes. While it has been suggested on theoretical grounds, it remains unknown whether OFC also receives postrecognition feedback about stimulus identity. We used a novel paradigm in the context of functional magnetic resonance imaging that permits the first few hundred milliseconds of object recognition to be spread out over 120 s. OFC shows a robust response to low and relatively high SFs, whereas ventral stream regions display unimodal response distributions shifted toward high SFs. These findings in OFC were modulated by hemisphere, with right OFC differentially responding to low SFs and left OFC differentially responding to high SFs. Psychophysical experiments confirmed that the same ranges of SFs preferred by ventral stream regions are critical for determining the accuracy and speed of object recognition. Our findings indicate that OFC accesses global form (low SF information, right OFC) and object identity (high SF information, left OFC), and suggest that OFC receives feedback about the accuracy of its initial hypothesis regarding stimulus identity.

With or without semantic mediation: retrieval of lexical representations in sign production.

How are lexical representations retrieved during sign production? Similar to spoken languages, lexical representation in sign language must be accessed through semantics when naming pictures. However, it remains an open issue whether lexical representations in sign language can be accessed via routes that bypass semantics when retrieval is elicited by written words. Here we address this issue by exploring under which circumstances sign retrieval is sensitive to semantic context. To this end we replicate in sign language production the cumulative semantic cost: The observation that naming latencies increase monotonically with each additional within-category item that is named in a sequence of pictures. In the experiment reported here, deaf participants signed sequences of pictures or signed sequences of Italian written words using Italian Sign Language. The results showed a cumulative semantic cost in picture naming but, strikingly, not in word naming. This suggests that only picture naming required access to semantics, whereas deaf signers accessed the sign language lexicon directly (i.e., bypassing semantics) when naming written words. The implications of these findings for the architecture of the sign production system are discussed in the context of current models of lexical access in spoken language production.

Grasping with the eyes: the role of elongation in visual recognition of manipulable objects.

Processing within the dorsal visual stream subserves object-directed action, whereas visual object recognition is mediated by the ventral visual stream. Recent findings suggest that the computations performed by the dorsal stream can nevertheless influence object recognition. Little is known, however, about the type of dorsal stream information that is available to assist in object recognition. Here, we present a series of experiments that explored different psychophysical manipulations known to bias the processing of a stimulus toward the dorsal visual stream in order to isolate its contribution to object recognition. We show that elongated-shaped stimuli, regardless of their semantic category and familiarity, when processed by the dorsal stream, elicit visuomotor grasp-related information that affects how we categorize manipulable objects. Elongated stimuli may reduce ambiguity during grasp preparation by providing a coarse cue to hand shaping and orientation that is sufficient to support action planning. We propose that this dorsal-stream-based analysis of elongation along a principal axis is the basis for how the dorsal visual object processing stream can affect categorization of manipulable objects.