Strain concentration drives the anatomical distribution of injury in acute and chronic traumatic brain injury.

Brain tissue injury caused by mild traumatic brain injury (mTBI) disproportionately concentrates in the midbrain, cerebellum, mesial temporal lobe, and the interface between cortex and white matter at sulcal depths 1-12. The bio-mechanical principles that explain why physical impacts to different parts of the skull translate to common foci of injury concentrated in specific brain structures are unknown. A general and longstanding idea, which has not to date been directly tested in humans, is that different brain regions are differentially susceptible to strain loading11,13-15. We use Magnetic Resonance Elastography (MRE) in healthy participants to develop whole-brain bio-mechanical vulnerability maps that independently define which regions of the brain exhibit disproportionate strain concentration. We then validate those vulnerability maps in a prospective cohort of mTBI patients, using diffusion MRI data collected at three cross-sectional timepoints after injury: acute, sub-acute, chronic. We show that regions that exhibit high strain, measured with MRE, are also the sites of greatest injury, as measured with diffusion MR in mTBI patients. This was the case in acute, subacute, and chronic subgroups of the mTBI cohort. Follow-on analyses decomposed the biomechanical cause of increased strain by showing it is caused jointly by disproportionately higher levels of energy arriving to 'high-strain' structures, as well as the inability of 'high strain' structures to effectively disperse that energy. These findings establish a causal mechanism that explains the anatomy of injury in mTBI based on in vivo rheological properties of the human brain.

Reciprocal interactions among parietal and occipito-temporal representations support everyday object-directed actions.

Everyday interactions with common manipulable objects require the integration of conceptual knowledge about objects and actions with real-time sensory information about the position, orientation and volumetric structure of the grasp target. The ability to successfully interact with everyday objects involves analysis of visual form and shape, surface texture, material properties, conceptual attributes such as identity, function and typical context, and visuomotor processing supporting hand transport, grasp form, and object manipulation. Functionally separable brain regions across the dorsal and ventral visual pathways support the processing of these different object properties and, in cohort, are necessary for functional object use. Object-directed grasps display end-state-comfort: they anticipate in form and force the shape and material properties of the grasp target, and how the object will be manipulated after it is grasped. End-state-comfort is the default for everyday interactions with manipulable objects and implies integration of information across the ventral and dorsal visual pathways. We propose a model of how visuomotor and action representations in parietal cortex interact with object representations in ventral and lateral occipito-temporal cortex. One pathway, from the supramarginal gyrus to the middle and inferior temporal gyrus, supports the integration of action-related information, including hand and limb position (supramarginal gyrus) with conceptual attributes and an appreciation of the action goal (middle temporal gyrus). A second pathway, from posterior IPS to the fusiform gyrus and collateral sulcus supports the integration of grasp parameters (IPS) with the surface texture and material properties (e.g., weight distribution) of the grasp target. Reciprocal interactions among these regions are part of a broader network of regions that support everyday functional object interactions.

Intraoperative cortical localization of music and language reveals signatures of structural complexity in posterior temporal cortex.

Language and music involve the productive combination of basic units into structures. It remains unclear whether brain regions sensitive to linguistic and musical structure are co-localized. We report an intraoperative awake craniotomy in which a left-hemispheric language-dominant professional musician underwent cortical stimulation mapping (CSM) and electrocorticography of music and language perception and production during repetition tasks. Musical sequences were melodic or amelodic, and differed in algorithmic compressibility (Lempel-Ziv complexity). Auditory recordings of sentences differed in syntactic complexity (single vs. multiple phrasal embeddings). CSM of posterior superior temporal gyrus (pSTG) disrupted music perception and production, along with speech production. pSTG and posterior middle temporal gyrus (pMTG) activated for language and music (broadband gamma; 70-150 Hz). pMTG activity was modulated by musical complexity, while pSTG activity was modulated by syntactic complexity. This points to shared resources for music and language comprehension, but distinct neural signatures for the processing of domain-specific structural features.

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.

Domain-specific connectivity drives the organization of object knowledge in the brain.

The goal of this chapter is to review neuropsychological and functional MRI findings that inform a theory of the causes of functional specialization for semantic categories within occipito-temporal cortex-the ventral visual processing pathway. The occipito-temporal pathway supports visual object processing and recognition. The theoretical framework that drives this review considers visual object recognition through the lens of how "downstream" systems interact with the outputs of visual recognition processes. Those downstream processes include conceptual interpretation, grasping and object use, navigating and orienting in an environment, physical reasoning about the world, and inferring future actions and the inner mental states of agents. The core argument of this chapter is that innately constrained connectivity between occipito-temporal areas and other regions of the brain is the basis for the emergence of neural specificity for a limited number of semantic domains in the brain.

Empty Sella Syndrome as a Window Into the Neuroprotective Effects of Prolactin.

Background: The goal of this study was to relate diffusion MR measures of white matter integrity of the retinofugal visual pathway with prolactin levels in a patient with downward herniation of the optic chiasm secondary to medical treatment of a prolactinoma. Methods: A 36-year-old woman with a prolactinoma presented with progressive bilateral visual field defects 9 years after initial diagnosis and medical treatment. She was diagnosed with empty-sella syndrome and instructed to stop cabergoline. Hormone testing was conducted in tandem with routine clinical evaluations over 1 year and the patient was followed with diffusion magnetic resonance imaging (dMRI), optical coherence tomography (OCT), and automated perimetry at three time points. Five healthy controls underwent a complementary battery of clinical and neuroimaging tests at a single time point. Results: Shortly after discontinuing cabergoline, diffusion metrics in the optic tracts were within the range of values observed in healthy controls. However, following a brief period where the patient resumed cabergoline (of her own volition), there was a decrease in serum prolactin with a corresponding decrease in visual ability and increase in radial diffusivity (p < 0.001). Those measures again returned to their baseline ranges after discontinuing cabergoline a second time. Conclusions: These results demonstrate the sensitivity of dMRI to detect rapid and functionally significant microstructural changes in white matter tracts secondary to alterations in serum prolactin levels. The inverse relations between prolactin and measures of white matter integrity and visual function are consistent with the hypothesis that prolactin can play a neuroprotective role in the injured nervous system.

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.

Selective serotonin reuptake inhibitors for functional recovery after stroke: similarities with the critical period and the role of experience-dependent plasticity.

There has been a growing interest in the potential for plasticity-inducing pharmacological interventions to enhance post-stroke recovery. One group of drugs that continues to garner a great deal of attention in this regard is a class of antidepressants called the selective serotonin reuptake inhibitors. Here we propose a model for the mechanism by which these drugs may enhance plasticity after ischemic brain injury. First, we review the research in animal models demonstrating how selective serotonin reuptake inhibitors reopen the critical period for ocular dominance plasticity in adulthood. We then compare this period of heightened plasticity to the cellular and biochemical milieu of perilesional tissue after an ischemic event in the adult brain. We argue that selective serotonin reuptake inhibitors administered acutely after an ischemic stroke alter excitatory-inhibitory balance in perilesional tissue and reinstate a type of plasticity reminiscent of the critical period in development. Finally, we discuss opportunities for future research in this area in both the preclinical and clinical realms.

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.

Brain Mapping: Understanding the Ins and Outs of Brain Regions.

A recent study in which primary motor cortex activity was imaged with sub-laminar resolution has found that, while overt motor actions led to activity in both superficial and deep cortical layers, motor imagery engaged only superficial layers.

Reorganized language network connectivity after left arcuate fasciculus resection: A case study.

Understanding the neural mechanisms that support spontaneous recovery of cognitive abilities can place important constraints on mechanistic theories of brain organization and function, and holds potential to inform clinical interventions. Connectivity-based MRI measures have emerged as a way to study how recovery from brain injury is modulated by changes in intra- and inter-hemispheric connectivity. Here we report a detailed and multi-modal case study of a 26 year-old male who presented with a left inferior parietal glioma infiltrating the left arcuate fasciculus. The patient underwent pre- and post-operative functional MRI and Diffusion Tensor Imaging, as well as behavioral assessments of language, motor, vision and praxis. The surgery for removal of the tumor was carried out with the patient awake, and direct electrical stimulation mapping was used to evaluate cortical language centers. The patient developed a specific difficulty with repeating sentences toward the end of the surgery, after resection of the tumor and partial transection of the arcuate fasciculus. The patient recovered from the sentence repetition impairments over several months after the operation. Coincident with the patient's cognitive recovery, we document a pattern whereby intra-hemispheric functional connectivity was reduced in the left hemisphere, while inter-hemispheric connectivity increased between classic left hemisphere language regions and their right hemisphere homologues. These findings suggest that increased synchrony between the two hemispheres, in the setting of focal transection of the left arcuate fasciculus, can facilitate functional recovery.

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.

A common neural signature of brain injury in concussion and subconcussion.

The midbrain is biomechanically susceptible to force loading from repetitive subconcussive head impacts (RSHI), is a site of tauopathy in chronic traumatic encephalopathy (CTE), and regulates functions (e.g., eye movements) often disrupted in concussion. In a prospective longitudinal design, we demonstrate there are reductions in midbrain white matter integrity due to a single season of collegiate football, and that the amount of reduction in midbrain white matter integrity is related to the amount of rotational acceleration to which players' brains are exposed. We then replicate the observation of reduced midbrain white matter integrity in a retrospective cohort of individuals with frank concussion, and further show that variance in white matter integrity is correlated with levels of serum-based tau, a marker of blood-brain barrier disruption. These findings mean that noninvasive structural MRI of the midbrain is a succinct index of both clinically silent white matter injury as well as frank concussion.

Translational Brain Mapping at the University of Rochester Medical Center: Preserving the Mind Through Personalized Brain Mapping.

The Translational Brain Mapping Program at the University of Rochester is an interdisciplinary effort that integrates cognitive science, neurophysiology, neuroanesthesia, and neurosurgery. Patients who have tumors or epileptogenic tissue in eloquent brain areas are studied preoperatively with functional and structural MRI, and intraoperatively with direct electrical stimulation mapping. Post-operative neural and cognitive outcome measures fuel basic science studies about the factors that mediate good versus poor outcome after surgery, and how brain mapping can be further optimized to ensure the best outcome for future patients. In this article, we describe the interdisciplinary workflow that allows our team to meet the synergistic goals of optimizing patient outcome and advancing scientific understanding of the human brain.

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.

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.

Action at a distance on object-related ventral temporal representations.

The representation of objects in ventral temporal cortex is relatively resilient to transformations in the stimuli. There is emerging recognition that ventral temporal object representations are forged via interactions among a broader network of regions that receive independent inputs about a stimulus. Here we test whether ventral temporal representations are causally modulated by disrupting processing in distal associative areas. We used transcranial direct current stimulation (tDCS) to stimulate left parietal areas and functional Magnetic Resonance Imaging (fMRI) to measure object-related neural responses in the ventral stream. We find that representational geometries and category discriminability within ventral temporal cortex, as well as functional connectivity between ventral temporal and parietal areas, are enhanced by anodal compared to cathodal stimulation of left parietal associative cortex. These results demonstrate that ventral temporal representations can be causally modulated by processing distal to the ventral stream.

Using Vision to Study Poststroke Recovery and Test Hypotheses About Neurorehabilitation.

Approximately one-third of stroke patients suffer visual field impairment as a result of their strokes. However, studies using the visual pathway as a paradigm for studying poststroke recovery are limited. In this article, we propose that the visual pathway has many features that make it an excellent model system for studying poststroke neuroplasticity and assessing the efficacy of therapeutic interventions. First, the functional anatomy of the visual pathway is well characterized, which makes it well suited for functional neuroimaging studies of poststroke recovery. Second, there are multiple highly standardized and clinically available diagnostic tools and outcome measures that can be used to assess visual function in stroke patients. Finally, as a sensory modality, the assessment of vision is arguably less likely to be affected by confounding factors such as functional compensation and patient motivation. Given these advantages, and the general similarities between poststroke visual field recovery and recovery in other functional domains, future neurorehabilitation studies should consider using the visual pathway to better understand the physiology of neurorecovery and test potential therapeutics.