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The hand area of the primary somatosensory cortex contains detailed finger topography, thought to be shaped and maintained by daily life experience. Here we utilise phantom sensations and ultra high-field neuroimaging to uncover preserved, though latent, representation of amputees’ missing hand. We show that representation of the missing hand’s individual fingers persists in the primary somatosensory cortex even decades after arm amputation. By demonstrating stable topography despite amputation, our finding questions the extent to which continued sensory input is necessary to maintain organisation in sensory cortex, thereby reopening the question what happens to a cortical territory once its main input is lost. The discovery of persistent digit topography of amputees’ missing hand could be exploited for the development of intuitive and fine-grained control of neuroprosthetics, requiring neural signals of individual digits. The brain has a remarkable ability to adapt to changes in circumstances. But what happens to the brain when it loses a key source of input, for example, following the amputation of a limb? A region of the brain known as primary somatosensory cortex processes sensory inputs from all over the body. The more sensitive an area of the body is, the more fine-grained its representation is in the cortex. For example, the hand is represented with a highly detailed map, with each finger represented seperately. The brain is thought to require ongoing sensory signals from the body to maintain these detailed representations in the cortex. Indeed, textbooks typically state that the brain will ‘overwrite’ its representation of a body part if input from that area no longer arrives. According to this view, people who have lost a hand should show little or no activity in the area of primary somatosensory cortex that used to represent it. However, many people who have had a limb amputated continue to experience vivid sensations of the missing limb long after its loss. When asked to move their so-called ‘phantom’ limb, these individuals report being able to feel the movement. Kikkert, Kolasinski et al. now show, using advanced imaging techniques, that the brains of individuals with phantom hands continue to represent the missing hand several decades after its loss. Indeed, asking the subjects to move individual fingers of their phantom hand activates fine-grained representations of those fingers, similar to those seen in two-handed controls. By showing that the brain ‘remembers’ an amputated hand, Kikkert, Kolasinski et al. demonstrate that ongoing sensory input is not required to maintain representations of the body in somatosensory cortex. This, in turn, offers new hope for developing prosthetic limbs that are under direct brain control. If the brain continues to represent individual fingers many years after their loss, it should be possible to exploit those pathways to achieve intuitive fine-grained control of artificial fingers.

Myelination has been increasingly implicated in the function and dysfunction of the adult human brain. Although it is known that axon myelination shapes axon physiology in animal models, it is unclear whether a similar principle applies in the living human brain, and at the level of whole axon bundles in white matter tracts. Here, we hypothesised that in humans, cortico-cortical interactions between two brain areas may be shaped by the amount of myelin in the white matter tract connecting them. As a test bed for this hypothesis, we use a well-defined interhemispheric premotor-to-motor circuit. We combined TMS-derived physiological measures of cortico-cortical interactions during action reprogramming with multimodal myelin markers (MT, R1, R2* and FA), in a large cohort of healthy subjects. We found that physiological metrics of premotor-to-motor interaction are broadly associated with multiple myelin markers, suggesting interindividual differences in tract myelination may play a role in motor network physiology. Moreover, we also demonstrate that myelination metrics link indirectly to action switching by influencing local primary motor cortex dynamics. These findings suggest that myelination levels in white matter tracts may influence millisecond-level cortico-cortical interactions during tasks. They also unveil a link between the physiology of the motor network and the myelination of tracts connecting its components, and provide a putative mechanism mediating the relationship between brain myelination and human behaviour. Myelination is a key regulator of brain function. Here the authors use MR-based myelin measures to examine if cortico-cortical interactions, as assessed by paired pulse transcranial magnetic stimulation, are affected by variations in myelin in the human brain.

Limb apraxia is a syndrome often observed after stroke that affects the ability to perform skilled actions despite intact elementary motor and sensory systems. In a large cohort of unselected stroke patients with lesions to the left, right, and bilateral hemispheres, we used voxel-based lesion-symptom mapping (VLSM) on clinical CT head images to identify the neuroanatomical correlates of the impairment of performance in three tasks investigating praxis skills in patient populations. These included a meaningless gesture imitation task, a gesture production task involving pantomiming transitive and intransitive gestures, and a gesture recognition task involving recognition of these same categories of gestures. Neocortical lesions associated with poor performance in these tasks were all in the left hemisphere. They involved the pre-striate and medial temporal cortices, the superior temporal sulcus, inferior parietal area PGi, the superior longitudinal fasciculus underlying the primary motor cortex, and the uncinate fasciculus, subserving connections between temporal and frontal regions. No significant lesions were identified when language deficits, as indicated via a picture naming task, were controlled for. The implication of the superior temporal sulcus and the anatomically connected prestriate and inferior parietal regions challenges traditional models of the disorder. The network identified has been implicated in studies of action observation, which might share cognitive functions sub-serving praxis and language skills.

Limb apraxia is a syndrome that affects the ability to perform skilful actions, despite intact elementary motor and sensory systems. Using voxel-based lesion symptom mapping in a large cohort of 387 stroke patients we determined the neuroanatomy of three tasks traditionally used to study praxis skills in patient populations: these included a meaningless gesture imitation task, a gesture production task involving pantomime of transitive and intransitive gestures and a gesture recognition task, involving recognition of these same categories of gestures. Lesions associated with reduced performance in these tasks involved an integrated network previously described in biological motion, with input areas comprising left pre-striate and occipital regions, left superior temporal sulcus and motor output areas comprising left premotor area, left striatum and the white matter underlying the left primary motor cortex. This study confirms a role for the left hemisphere in limb apraxia and supports the hypothesis it is a white matter disconnection syndrome, whilst shedding new light into the nature of the behavioural deficits described in the disorder comprising parts of an integrated network of brain areas described in biological motion.

Experience-dependent reorganisation of functional maps in the cerebral cortex is well described in the primary sensory cortices. However, there is relatively little evidence for such cortical reorganisation over the short-term. Using human somatosensory cortex as a model, we investigated the effects of a 24 hr gluing manipulation in which the right index and right middle fingers (digits 2 and 3) were adjoined with surgical glue. Somatotopic representations, assessed with two 7 tesla fMRI protocols, revealed rapid off-target reorganisation in the non-manipulated fingers following gluing, with the representation of the ring finger (digit 4) shifted towards the little finger (digit 5) and away from the middle finger (digit 3). These shifts were also evident in two behavioural tasks conducted in an independent cohort, showing reduced sensitivity for discriminating the temporal order of stimuli to the ring and little fingers, and increased substitution errors across this pair on a speeded reaction time task. The areas of the brain that receive inputs from our senses have a map-like structure. In an area called the visual cortex this map represents our field of vision; in the auditory cortex, it represents the range of different tones we can hear. The sense of touch is processed in the somatosensory cortex: an area of the brain that is organised around a map of the body, with adjacent regions of the cortex representing adjacent regions of the body. The clear structure of these brain regions makes them ideal for exploring how the organisation of the brain changes over time. How quickly can changes to the touch inputs that the brain receives cause the map in the somatosensory cortex to reorganise? Can these effects be produced in just 24 hours? And would this remapping affect how we perceive touch? To investigate these questions, Kolasinski et al. glued together the right index and right middle fingers of healthy human volunteers. This separated the middle and ring fingers: a pair that usually move together due to the anatomical structure of the hand. Functional magnetic resonance imaging of the brain’s activity revealed that within 24 hours of the gluing, the brain’s representation of the ring finger moved away from that of the middle finger, and towards the representation of the little finger. A perceptual judgment task mirrored this finding: after 24 hours of gluing, the participants became better at distinguishing between the middle and ring fingers and worse at distinguishing between the ring and little fingers. This is a powerful demonstration of the human brain’s potential to adapt and reorganise rapidly to changes to sensory inputs. The sense of touch declines gradually with age and may also be reduced as a result of disease such as stroke. A long-term challenge is to understand how the sensory regions of the brain change during this loss of sensation. Further research could then investigate how to maintain the structure of the cortical map to prolong or restore high quality touch sensation.

Corticogenesis is underpinned by a complex process of subcortical neuroproliferation, followed by highly orchestrated cellular migration. A greater appreciation of the processes involved in human fetal corticogenesis is vital to gaining an understanding of how developmental disturbances originating in gestation could establish a variety of complex neuropathology manifesting in childhood, or even in adult life. Magnetic resonance imaging modalities offer a unique insight into anatomical structure, and increasingly infer information regarding underlying microstructure in the human brain. In this study we applied a combination of high-resolution structural and diffusion-weighted magnetic resonance imaging to a unique cohort of three post-mortem fetal brain specimens, aged between 19 and 22 post-conceptual weeks. Specifically, we sought to assess patterns of diffusion coherence associated with subcortical neuroproliferative structures: the pallial ventricular/subventricular zone and subpallial ganglionic eminence. Two distinct three-dimensional patterns of diffusion coherence were evident: a clear radial pattern originating in ventricular/subventricular zone, and a tangentio-radial patterns originating in ganglionic eminence. These patterns appeared to regress in a caudo-rostral and lateral-ventral to medial-dorsal direction across the short period of fetal development under study. Our findings demonstrate for the first time distinct patterns of diffusion coherence associated with known anatomical proliferative structures. The radial pattern associated with dorsopallial ventricular/subventricular zone and the tangentio-radial pattern associated with subpallial ganglionic eminence are consistent with reports of radial–glial mediated neuronal migration pathways identified during human corticogenesis, supported by our prior studies of comparative fetal diffusion MRI and histology. The ability to assess such pathways in the fetal brain using MR imaging offers a unique insight into three-dimensional trajectories beyond those visualized using traditional histological techniques. Our results suggest that ex-vivo fetal MRI is a potentially useful modality in understanding normal human development and various disease processes whose etiology may originate in aberrant fetal neuronal migration. •We apply ex-vivo structural and diffusion MRI to study the human fetal brain.•We examine diffusion coherence associated with neuroproliferative structures.•A radial coherence pattern originated from ventricular/subventricular zone.•A tangentio-radial coherence pattern was associated with ganglionic eminence.•These patterns concur with histological descriptions of neuronal migration.

The organizing principle of human motor cortex does not follow an anatomical body map, but rather a distributed representational structure in which motor primitives are combined to produce motor outputs. Electrophysiological recordings in primates and human imaging data suggest that M1 encodes kinematic features of movements, such as joint position and velocity. However, M1 exhibits well-documented sensory responses to cutaneous and proprioceptive stimuli, raising questions regarding the origins of kinematic motor representations: are they relevant in top-down motor control, or are they an epiphenomenon of bottom-up sensory feedback during movement? Here we provide evidence for spatially and temporally distinct encoding of kinematic and muscle information in human M1 during the production of a wide variety of naturalistic hand movements. Using a powerful combination of high-field functional magnetic resonance imaging and magnetoencephalography, a spatial and temporal multivariate representational similarity analysis revealed encoding of kinematic information in more caudal regions of M1, over 200 ms before movement onset. In contrast, patterns of muscle activity were encoded in more rostral motor regions much later after movements began. We provide compelling evidence that top-down control of dexterous movement engages kinematic representations in caudal regions of M1 prior to movement production.

The sensorimotor network receives a rich variety of somesthetic afferents and outputs considerable motor efferents, both of which drive experience-dependent plasticity in the system. It remains unclear to what extent subtle changes in somaesthesis and motor function extrinsic to the brain drive plasticity in the functional organisation and anatomy of the sensorimotor network. This thesis contains a series of multimodal MRI experiments to investigate how altered-use and disuse can induce plastic changes in the sensorimotor network of the human brain. In Chapter 3, a method of mapping digit somatotopy in primary somatosensory cortex at the single-subject level using 7.0 tesla fMRI was developed and applied for a study of healthy participants. Using a phase-encoding paradigm, digit representations were accurately mapped in under 10 minutes. These maps were reproducible over time and comparable to a standard block design. In Chapter 4, a further fMRI study assessed the potential for short-term reorganisation of digit representations in primary somatosensory cortex following a manipulation whereby the right index and right middle fingers were glued together for 24 hours. There was a marked shift in the cortical overlap of adjacent digits after the glued manipulation, not seen across an equivalent control period, providing strong evidence for short-term remapping of primary somatosensory cortex. In Chapter 5, a patient study investigated plasticity associated with chronic unilateral disuse of the upper limb. A cross-sectional comparison with control participants showed reduced grey matter density in the posterior right temporoparietal junction, and increased radial diffusivity in the white matter of the right superior longitudinal fasciculus, consistent with change in the right ventral attention network. A complementary longitudinal study in Chapter 6 investigated structural plasticity associated with rehabilitation of the disused limb. There were localised increases in grey matter density, notably in the right temporoparietal junction, further implicating a potential role for regions responsible for egocentric attention in regaining upper limb use. In Chapter 7, a further patient study investigated candidate predictive biomarkers at the sub-acute stage of stroke recovery, identifying CST-lesion cross-section and sensorimotor network strength as correlates of motor function, which warrant further study. The results of the studies presented in this thesis provide a novel insight into the nature and time frame of functional and structural plasticity associated with altered use and disuse. Further study of how subtle changes in our sensory and motor use shape the sensorimotor network is warranted, particularly in the context of disuse in non-neurological clinical populations.

Human machine interfaces are increasingly designed to reduce our reliance on the dominantly used senses of vision and audition. Many emerging technologies are attempting to convey complex spatiotemporal information via tactile percepts shown to be effective in the visual domain, such as shape and motion. Despite the intuitive appeal of touch as a method of feedback, we do not know to what extent the hand can substitute for the retina in this way. Here we ask whether the tactile system can be used to perceive complex whole hand motion stimuli, and whether it exhibits the same kind of established perceptual biases as reported in the visual domain. Using ultrasound stimulation, we were able to project complex moving dot percepts onto the palm in mid-air, over 30cm above an emitter device. We generated dot kinetogram stimuli involving motion in three different directional axes ('Horizontal', 'Vertical', and 'Oblique') on the ventral surface of the hand. We found clear evidence that participants were able to discriminate tactile motion direction. Furthermore, there was a marked directional bias in motion perception: participants were better and more confident at discriminating motion in the vertical and horizontal axes of the hand, compared to those stimuli moving obliquely. This pattern directly mirrors the perceptional biases that have been robustly reported in the visual field, termed the 'Oblique Effect'. These data show the existence of biases in motion perception that transcend sensory modality. Furthermore, we extend the Oblique Effect to a whole hand scale, using motion stimuli presented on the broad and relatively low acuity surface of the palm, away from the densely innervated and much studied fingertips. These findings also highlight targeted ultrasound stimulation as a versatile means by which to convey potentially complex spatial and temporal information without the need for a user to wear or touch a device. This ability is particularly attractive as a potential feedback mechanism for application in contact-free human machine interfaces. Competing Interest Statement The authors have declared no competing interest.

Myelination has been increasingly implicated in the function and dysfunction of the adult human brain. Although it is known that axon myelination shapes axon physiology in animal models, it is unclear whether a similar principle applies in the living human brain, and at the level of whole axon bundles in white matter tracts. Here, we hypothesised that in humans, cortico-cortical interactions between two brain areas may be shaped by the amount of myelin in the white matter tract connecting them. As a test bed for this hypothesis, we use a well-defined interhemispheric premotor-to-motor circuit. We combined TMS-derived physiological measures of cortico-cortical interactions during action reprogramming with multimodal myelin markers (MT, R1, R2* and FA), in a large cohort of healthy subjects. We found that physiological metrics of premotor-to-motor interaction are broadly associated with multiple myelin markers, suggesting interindividual differences in tract myelination may play a role in motor network physiology. Moreover, we also demonstrate that myelination metrics link indirectly to action switching by influencing local primary motor cortex dynamics. These findings suggest that myelination levels in white matter tracts may influence millisecond-level cortico-cortical interactions during tasks. They also unveil a link between the physiology of the motor network and the myelination of tracts connecting its components, and provide a putative mechanism mediating the relationship between brain myelination and human behaviour.