Improving sleep and learning in rehabilitation after stroke, part 2 (INSPIRES2): study protocol for a home-based randomised control trial of digital cognitive behavioural therapy (dCBT) for insomnia.

INTRODUCTION: Consolidation of motor skill learning, a key component of rehabilitation post-stroke, is known to be sleep dependent. However, disrupted sleep is highly prevalent after stroke and is often associated with poor motor recovery and quality of life. Previous research has shown that digital cognitive behavioural therapy (dCBT) for insomnia can be effective at improving sleep quality after stroke. Therefore, the aim of this trial is to evaluate the potential for sleep improvement using a dCBT programme, to improve rehabilitation outcomes after stroke. METHODS AND ANALYSIS: We will conduct a parallel-arm randomised controlled trial of dCBT (Sleepio) versus treatment as usual among individuals following stroke affecting the upper limb. Up to 100 participants will be randomly allocated (2:1) into either the intervention (6-8 week dCBT) or control (continued treatment as usual) group. The primary outcome of the study will be change in insomnia symptoms pre to post intervention compared with treatment as usual. Secondary outcomes include improvement in overnight motor memory consolidation and sleep measures between intervention groups, correlations between changes in sleep behaviour and overnight motor memory consolidation in the dCBT group and changes in symptoms of depression and fatigue between the dCBT and control groups. Analysis of covariance models and correlations will be used to analyse data from the primary and secondary outcomes. ETHICS AND DISSEMINATION: The study has received approval from the National Research Ethics Service (22/EM/0080), Health Research Authority (HRA) and Health and Care Research Wales (HCRW), IRAS ID: 306 291. The results of this trial will be disseminated via presentations at scientific conferences, peer-reviewed publication, public engagement events, stakeholder organisations and other forms of media where appropriate. TRIAL REGISTRATION NUMBER: NCT05511285.

Managing painful shoulder after neurological injury.

Shoulder pain is common after neurological injury and can be disabling, lead to poor functional outcomes and increase care costs. Its cause is multifactoral and several pathologies contribute to the presentation. Astute diagnostic skills and a multidisciplinary approach are required to recognise what is clinically relevant and to implement appropriate stepwise management. In the absence of large clinical trial data, we aim to provide a comprehensive, practical and pragmatic overview of shoulder pain in patients with neurological conditions. We use available evidence to produce a management guideline, taking into account specialty opinions from neurology, rehabilitation medicine, orthopaedics and physiotherapy.

The Need for Head Protection Protocols for Craniectomy Patients during Rest, Transfers and Turning.

After craniectomy, patients are generally advised to wear a helmet when mobilising to protect the unshielded brain from damage. However, there exists limited guidance regarding head protection for patients at rest and when being transferred or turned. Here, we emphasise the need for such protocols and utilise evidence from several sources to affirm our viewpoint. A literature search was first performed using MEDLINE and EMBASE, looking for published material relating to head protection for patients post-craniectomy during rest, transfer or turning. No articles were identified using a wide-ranging search strategy. Next, we surveyed and interviewed staff and patients from our neurosurgical centre to ascertain how often their craniectomy site was exposed to external pressure and the precautions taken to prevent this. 59% of patients admitted resting in contact with the craniectomy site, in agreement with the observations of 67% of staff. In 63% of these patients, this occurred on a daily basis and for some, was associated with symptoms suggestive of raised intracranial pressure. 44% of staff did not use a method to prevent craniectomy site contact while 65% utilised no additional precautions during transfer or turning. 63% of patients received no information about avoiding craniectomy site contact upon discharge, and almost all surveyed wished for resting head protection if it were available. We argue that pragmatic guidelines are needed and that our results support this perspective. As such, we offer a simple, practical protocol which can be adopted and iteratively improved as further evidence becomes available in this area.

Exploring the use of dopaminergic medication to treat hemispatial inattention during in-patient post-stroke neurorehabilitation.

Hemispatial inattention (HSI), a lateralised impairment of spatial processing, is a common consequence of stroke. It is a poor prognostic indicator for functional recovery and interferes with the progress during in-patient neurorehabilitation. Dopaminergic medication has shown promise in improving HSI in the chronic post-stroke period but is untested in more acute settings, e.g. during in-patient neurorehabilitation. We audited the use of dopaminergic medication in ten sequential patients with post-stroke HSI, on an open-label exploratory basis. Patients' response to medication was assessed individually, using a three-week Off-On-Off protocol. We employed a mixture of bedside and functional measures, and made a multidisciplinary judgement of efficacy in individual patients. In six out of 10 patients, there was a convincing improvement of HSI while on medication, which reversed when it was paused. There was a mean 57% relative increase in target detection in the star cancellation test on the most affected side (on vs. off medication). In the six responders, medication was therefore continued throughout their admission without adverse effects. The star cancellation test was sensitive to HSI in most patients but in two cases failed to detect changes that were picked up by a functional assessment (Kessler Functional Neglect Assessment Protocol). We found this multidisciplinary approach to be feasible in an in-patient neurorehabilitation setting. We suggest further research to explore the efficacy of dopaminergic medication in improving neurorehabilitation outcomes for patients with post-stroke HSI. We suggest that more detailed N-of-1 assessments of treatment response, with internal blinding, may be a productive approach.

Visual Field Reconstruction in Hemianopia Using fMRI Based Mapping Techniques.

PURPOSE: A stroke that includes the primary visual cortex unilaterally leads to a loss of visual field (VF) representation in the hemifield contralateral to the damage. While behavioral procedures for measuring the VF, such as perimetry, may indicate that a patient cannot see in a particular area, detailed psychophysical testing often detects the ability to perform detection or discrimination of visual stimuli ("blindsight"). The aim of this study was to determine whether functional magnetic resonance imaging (fMRI) could be used to determine whether perimetrically blind regions of the VF were still represented in VF maps reconstructed on the basis of visually evoked neural activity. METHODS: Thirteen patients with hemianopia and nine control participants were scanned using 3T MRI while presented with visual stimulation. Two runs of a dynamic "wedge and ring" mapping stimulus, totaling approximately 10 min, were performed while participants fixated centrally. Two different analysis approaches were taken: the conventional population receptive field (pRF) analysis and micro-probing (MP). The latter is a variant of the former that makes fewer assumptions when modeling the visually evoked neural activity. Both methods were used to reconstruct the VF by projecting modeled activity back onto the VF. Following a normalization step, these "coverage maps" can be compared to the VF sensitivity plots obtained using perimetry. RESULTS: While both fMRI-based approaches revealed regions of neural activity within the perimetrically "blind" sections of the VF, the MP approach uncovered more voxels in the lesioned hemisphere in which a modest degree of visual sensitivity was retained. Furthermore, MP-based analysis indicated that both early (V1/V2) and extrastriate visual areas contributed equally to the retained sensitivity in both patients and controls. CONCLUSION: In hemianopic patients, fMRI-based approaches for reconstructing the VF can pick up activity in perimetrically blind regions of the VF. Such regions of the VF may be particularly amenable for rehabilitation to regain visual function. Compared to conventional pRF modeling, MP reveals more voxels with retained visual sensitivity, suggesting it is a more sensitive approach for VF reconstruction.

Optic Tract Shrinkage Limits Visual Restoration After Occipital Stroke.

Background and Purpose: Damage to the adult primary visual cortex (V1) causes vision loss in the contralateral visual hemifield, initiating a process of trans-synaptic retrograde degeneration. The present study examined functional implications of this process, asking if degeneration impacted the amount of visual recovery attainable from visual restoration training in chronic patients, and if restoration training impacted optic tract (OT) shrinkage. Methods: Magnetic resonance imaging was used to measure OT volumes bilaterally in 36 patients with unilateral occipital stroke. From OT volumes, we computed laterality indices (LI), estimating the stroke-induced OT shrinkage in each case. A subset of these chronic patients (n=14, 13±6 months poststroke) underwent an average of nearly 1 year of daily visual restoration training, which repeatedly stimulated vision in their blind field. The amount of visual field recovery was quantified using Humphrey perimetry, and post training magnetic resonance imaging was used to assess the impact of training on OT shrinkage. Results: OT LI was correlated with time since stroke: it was close to 0 (no measurable OT shrinkage) in subacute participants (<6 months poststroke) while chronic participants (>6 months poststroke) exhibited LI >0, but with significant variability. Visual training did not systematically alter LI, but chronic patients with baseline LI≈0 (no OT shrinkage) exhibited greater visual field recovery than those with LI>0. Conclusions: Unilateral OT shrinkage becomes detectable with magnetic resonance imaging by ≈7 months poststroke, albeit with significant interindividual variability. Although visual restoration training did not alter the amount of degeneration already sustained, OT shrinkage appeared to serve as a biomarker of the potential for training-induced visual recovery in chronic cortically blind patients.

Increased Visual Sensitivity and Occipital Activity in Patients With Hemianopia Following Vision Rehabilitation.

Hemianopia, loss of vision in half of the visual field, results from damage to the visual pathway posterior to the optic chiasm. Despite negative effects on quality of life, few rehabilitation options are currently available. Recently, several long-term training programs have been developed that show visual improvement within the blind field. Little is known of the underlying neural changes. Here, we have investigated functional and structural changes in the brain associated with visual rehabilitation. Seven human participants with occipital lobe damage enrolled in a visual training program to distinguish which of two intervals contained a drifting Gabor patch presented within the blind field. Participants performed ∼25 min of training each day for 3-6 months and undertook psychophysical tests and an magnetic resonance imaging scan before and after training. A control group undertook psychophysical tests before and after an equivalent period without training. Participants who were not at ceiling on baseline tests showed on average 9.6% improvement in Gabor detection, 8.3% in detection of moving dots, and 9.9% improvement in direction discrimination after training. Importantly, psychophysical improvement only correlated with improvement in Humphrey perimetry in the trained region of the visual field. Whole-brain analysis showed an increased neural response to moving stimuli in the blind visual field in motion area V5/hMT. Using a region-of-interest approach, training had a significant effect on the blood oxygenation level-dependent signal compared with baseline. Moreover, baseline V5/hMT activity was correlated to the amount of improvement in visual sensitivity using psychophysical and perimetry tests. This study, identifying a critical role for V5/hMT in boosting visual function, may allow us to identify which patients may benefit most from training and design adjunct intervention to increase training effects.SIGNIFICANCE STATEMENTHomonymous visual field loss is a common consequence of brain injury and is estimated to affect more than 230,000 people in the United Kingdom. Despite its high prevalence and well-described impact on quality of life, treatments to improve visual sensitivity remain experimental, and deficits are considered permanent after 6 months. Our study shows that behavioral changes following vision rehabilitation are associated with enhanced visual-evoked occipital activity to stimuli in the blind visual field. Unlike previous behavioral studies, we observe clinical changes that are specific to the trained region of vision. This lends significant weight to such training paradigms and offers a mechanism by which visual function can be improved despite damage to the primary visual pathway.

The Superior Colliculus and Amygdala Support Evaluation of Face Trait in Blindsight.

Humans can respond rapidly to viewed expressions of fear, even in the absence of conscious awareness. This is demonstrated using visual masking paradigms in healthy individuals and in patients with cortical blindness due to damage to the primary visual cortex (V1) - so called affective blindsight. Humans have also been shown to implicitly process facial expressions representing important social dimensions. Two major axes, dominance and trustworthiness, are proposed to characterize the social dimensions of face evaluation. The processing of both types of implicit stimuli is believed to occur via similar subcortical pathways involving the amygdala. However, we do not know whether unconscious processing of more subtle expressions of facial traits can occur in blindsight, and if so, how. To test this, we studied 13 patients with unilateral V1 damage and visual field loss. We assessed their ability to detect and discriminate faces that had been manipulated along two orthogonal axes of trustworthiness and dominance to generate five trait levels inside the blind visual field: dominant, submissive, trustworthy, untrustworthy, and neutral. We compared neural activity and functional connectivity in patients classified as blindsight positive or negative for these stimuli. We found that dominant faces were most likely to be detected above chance, with individuals demonstrating unique interactions between performance and face trait. Only patients with blindsight (n = 8) showed significant preference in the superior colliculus and amygdala for face traits in the blind visual field, and a critical functional connection between the amygdala and superior colliculus in the damaged hemisphere. We also found a significant correlation between behavioral performance and fMRI activity in the amygdala and lateral geniculate nucleus across all participants. Our findings confirm that affective blindsight involving the superior colliculus and amygdala extends to the processing of socially salient but emotionally neutral facial expressions when V1 is damaged. This pathway is distinct from that which supports motion blindsight, as both types of blindsight can exist in the absence of the other with corresponding patterns of residual connectivity.

Subcortical pathways to extrastriate visual cortex underlie residual vision following bilateral damage to V1.

Residual vision, or blindsight, following damage to the primary visual cortex (V1) has been investigated for almost half a century. While there have been many studies of patients with unilateral damage to V1, far fewer have examined bilateral damage, mainly due to the rarity of such patients. Here we re-examine the residual visual function and underlying pathways of previously studied patient SBR who, as a young adult, suffered bilateral damage restricted to V1 which rendered him cortically blind. While earlier work compared his visual cortex to healthy, sighted participants, here we consider how his visual responses and connections compare to patients with unilateral damage to V1 in addition to sighted participants. Detection of drifting Gabor patches of different contrasts (1%, 5%, 10%, 50% and 100%) was tested in SBR and a group of eight patients with unilateral damage to V1. Performance was compared to the neural activation in motion area hMT+ measured using functional magnetic resonance imaging. Diffusion tractography was also used to determine the white matter microstructure of the visual pathways in all participants. Like the patients with unilateral damage, patient SBR showed increased % BOLD signal change to the high contrast stimuli that he could detect compared to the lower contrast stimuli that were not detectable. Diffusion tractography suggests this information is conveyed by a direct pathway between the lateral geniculate nucleus (LGN) and hMT+ since this pathway had microstructure that was comparable to the healthy control group. In contrast, the pathway between LGN and V1 had reduced integrity compared to controls. A further finding of note was that, unlike control participants, SBR showed similar patterns of contralateral and ipsilateral activity in hMT+, in addition to healthy white matter microstructure in the tract connecting hMT+ between the two hemispheres. This raises the possibility of increased connectivity between the two hemispheres in the absence of V1 input. In conclusion, the pattern of visual function and anatomy in bilateral cortical damage is comparable to that seen in a group of patients with unilateral damage. Thus, while the intact hemisphere may play a role in residual vision in patients with unilateral damage, its influence is not evident with the methodology employed here.

Visual training in hemianopia alters neural activity in the absence of behavioural improvement: a pilot study.

BACKGROUND: Damage to the primary visual cortex (V1) due to stroke often results in permanent loss of sight affecting one side of the visual field (homonymous hemianopia). Some rehabilitation approaches have shown improvement in visual performance in the blind region, but require a significant time investment. METHODS: Seven patients with cortical damage performed 400 trials of a motion direction discrimination task daily for 5 days. Three patients received anodal transcranial direct current stimulation (tDCS) during training, three received sham stimulation and one had no stimulation. Each patient had an assessment of visual performance and a functional magnetic resonance imaging (fMRI) scan before and after training to measure changes in visual performance and cortical activity. RESULTS: No patients showed improvement in visual function due to the training protocol, and application of tDCS had no effect on visual performance. However, following training, the neural response in motion area hMT+ to a moving stimulus was altered. When the stimulus was presented to the sighted hemifield, activity decreased in hMT+ of the damaged hemisphere. There was no change in hMT+ response when the stimulus was presented to the impaired hemifield. There was a decrease in activity in the inferior precuneus after training when the stimulus was presented to either the impaired or sighted hemifield. Preliminary analysis of tDCS data suggested that anodal tDCS interacted with the delivered training, modulating the neural response in hMT+ in the healthy side of the brain. CONCLUSION: Training can affect the neural responses in hMT+ even in the absence of change in visual performance.

Blindsight relies on a functional connection between hMT+ and the lateral geniculate nucleus, not the pulvinar.

When the primary visual cortex (V1) is damaged, the principal visual pathway is lost, causing a loss of vision in the opposite visual field. While conscious vision is impaired, patients can still respond to certain images; this is known as 'blindsight'. Recently, a direct anatomical connection between the lateral geniculate nucleus (LGN) and human motion area hMT+ has been implicated in blindsight. However, a functional connection between these structures has not been demonstrated. We quantified functional MRI responses to motion in 14 patients with unilateral V1 damage (with and without blindsight). Patients with blindsight showed significant activity and a preserved sensitivity to speed in motion area hMT+, which was absent in patients without blindsight. We then compared functional connectivity between motion area hMT+ and a number of structures implicated in blindsight, including the ventral pulvinar. Only patients with blindsight showed an intact functional connection with the LGN but not the other structures, supporting a specific functional role for the LGN in blindsight.

Blindsight and Unconscious Vision: What They Teach Us about the Human Visual System.

Damage to the primary visual cortex removes the major input from the eyes to the brain, causing significant visual loss as patients are unable to perceive the side of the world contralateral to the damage. Some patients, however, retain the ability to detect visual information within this blind region; this is known as blindsight. By studying the visual pathways that underlie this residual vision in patients, we can uncover additional aspects of the human visual system that likely contribute to normal visual function but cannot be revealed under physiological conditions. In this review, we discuss the residual abilities and neural activity that have been described in blindsight and the implications of these findings for understanding the intact system.

Human blindsight is mediated by an intact geniculo-extrastriate pathway.

Although damage to the primary visual cortex (V1) causes hemianopia, many patients retain some residual vision; known as blindsight. We show that blindsight may be facilitated by an intact white-matter pathway between the lateral geniculate nucleus and motion area hMT+. Visual psychophysics, diffusion-weighted magnetic resonance imaging and fibre tractography were applied in 17 patients with V1 damage acquired during adulthood and 9 age-matched controls. Individuals with V1 damage were subdivided into blindsight positive (preserved residual vision) and negative (no residual vision) according to psychophysical performance. All blindsight positive individuals showed intact geniculo-hMT+ pathways, while this pathway was significantly impaired or not measurable in blindsight negative individuals. Two white matter pathways previously implicated in blindsight: (i) superior colliculus to hMT+ and (ii) between hMT+ in each hemisphere were not consistently present in blindsight positive cases. Understanding the visual pathways crucial for residual vision may direct future rehabilitation strategies for hemianopia patients.

Abnormal contrast responses in the extrastriate cortex of blindsight patients.

When the human primary visual cortex (V1) is damaged, the dominant geniculo-striate pathway can no longer convey visual information to the occipital cortex. However, many patients with such damage retain some residual visual function that must rely on an alternative pathway directly to extrastriate occipital regions. This residual vision is most robust for moving stimuli, suggesting a role for motion area hMT+. However, residual vision also requires high-contrast stimuli, which is inconsistent with hMT+ sensitivity to contrast in which even low-contrast levels elicit near-maximal neural activation. We sought to investigate this discrepancy by measuring behavioral and neural responses to increasing contrast in patients with V1 damage. Eight patients underwent behavioral testing and functional magnetic resonance imaging to record contrast sensitivity in hMT+ of their damaged hemisphere, using Gabor stimuli with a spatial frequency of 1 cycle/°. The responses from hMT+ of the blind hemisphere were compared with hMT+ and V1 responses in the sighted hemisphere of patients and a group of age-matched controls. Unlike hMT+, neural responses in V1 tend to increase linearly with increasing contrast, likely reflecting a dominant parvocellular channel input. Across all patients, the responses in hMT+ of the blind hemisphere no longer showed early saturation but increased linearly with contrast. Given the spatiotemporal parameters used in this study and the known direct subcortical projections from the koniocellular layers of the lateral geniculate nucleus to hMT+, we propose that this altered contrast sensitivity in hMT+ could be consistent with input from the koniocellular pathway.

Motion area V5/MT+ response to global motion in the absence of V1 resembles early visual cortex.

Motion area V5/MT+ shows a variety of characteristic visual responses, often linked to perception, which are heavily influenced by its rich connectivity with the primary visual cortex (V1). This human motion area also receives a number of inputs from other visual regions, including direct subcortical connections and callosal connections with the contralateral hemisphere. Little is currently known about such alternative inputs to V5/MT+ and how they may drive and influence its activity. Using functional magnetic resonance imaging, the response of human V5/MT+ to increasing the proportion of coherent motion was measured in seven patients with unilateral V1 damage acquired during adulthood, and a group of healthy age-matched controls. When V1 was damaged, the typical V5/MT+ response to increasing coherence was lost. Rather, V5/MT+ in patients showed a negative trend with coherence that was similar to coherence-related activity in V1 of healthy control subjects. This shift to a response-pattern more typical of early visual cortex suggests that in the absence of V1, V5/MT+ activity may be shaped by similar direct subcortical input. This is likely to reflect intact residual pathways rather than a change in connectivity, and has important implications for blindsight function. It also confirms predictions that V1 is critically involved in normal V5/MT+ global motion processing, consistent with a convergent model of V1 input to V5/MT+. Historically, most attempts to model cortical visual responses do not consider the contribution of direct subcortical inputs that may bypass striate cortex, such as input to V5/MT+. We have shown that the signal change driven by these non-striate pathways can be measured, and suggest that models of the intact visual system may benefit from considering their contribution.

Novel brain imaging approaches to understand acquired and congenital neuro-ophthalmological conditions.

PURPOSE OF REVIEW: The arrival of large datasets and the on-going refinement of neuroimaging technology have led to a number of recent advances in our understanding of visual pathway disorders. This work can broadly be classified into two areas, both of which are important when considering the optimal management strategies. The first looks at the delineation of damage, teasing out subtle changes to (specific components of) the visual pathway, which may help evaluate the severity and extent of disease. The second uses neuroimaging to investigate neuroplasticity, via changes in connectivity, cortical thickness, and retinotopic maps within the visual cortex. RECENT FINDINGS: Here, we give consideration to both acquired and congenital patients with damage to the visual pathway, and how they differ. Congenital disorders of the peripheral visual system can provide insight into the large-scale reorganization of the visual cortex: these are investigated with reference to disorders of the optic chiasm and anophthalmia (absence of the eyes). In acquired conditions, we consider the recent work describing patterns of degeneration, both following single insult and in neurodegenerative conditions. We also discuss the developments in functional neuroimaging, with particular reference to work on hemianopia and the controversial suggestion of cortical reorganization following acquired retinal injury. SUMMARY: Techniques for comparing neuro-ophthalmological conditions with healthy visual systems provide sensitive metrics to uncover subtle differences in grey and white matter structure of the brain. It is now possible to compare the massive reorganization present in congenital conditions with the apparent lack of plasticity following acquired damage.

Unconscious evaluation of faces on social dimensions.

It has been proposed that two major axes, dominance and trustworthiness, characterize the social dimensions of face evaluation. Whether evaluation of faces on these social dimensions is restricted to conscious appraisal or happens at a preconscious level is unknown. Here we provide behavioral evidence that such preconscious evaluations exist and that they are likely to be interpretations arising from interactions between the face stimuli and observer-specific traits. Monocularly viewed faces that varied independently along two social dimensions of trust and dominance were rendered invisible by continuous flash suppression (CFS) when a flashing pattern was presented to the other eye. Participants pressed a button as soon as they saw the face emerge from suppression to indicate whether the previously hidden face was located slightly to the left or right of central fixation. Dominant and untrustworthy faces took significantly longer time to emerge (T2E) compared with neutral faces. A control experiment showed these findings could not reflect delayed motor responses to conscious faces. Finally, we showed that participants' self-reported propensity to trust was strongly predictive of untrust avoidance (i.e., difference in T2E for untrustworthy vs neutral faces) as well as dominance avoidance (i.e., difference in T2E for dominant vs neutral faces). Dominance avoidance was also correlated with submissive behavior. We suggest that such prolongation of suppression for threatening faces may result from a passive fear response, leading to slowed visual perception.