The Graded Incomplete Letters Test (GILT): a rapid test to detect cortical visual loss, with UK Biobank implementation.

Impairments of object recognition are core features of neurodegenerative syndromes, in particular posterior cortical atrophy (PCA; the 'visual-variant Alzheimer's disease'). These impairments arise from damage to higher-level cortical visual regions and are often missed or misattributed to common ophthalmological conditions. Consequently, diagnosis can be delayed for years with considerable implications for patients. We report a new test for the rapid measurement of cortical visual loss - the Graded Incomplete Letters Test (GILT). The GILT is an optimised psychophysical variation of a test used to diagnose cortical visual impairment, which measures thresholds for recognising letters under levels of increasing visual degradation (decreasing "completeness") in a similar fashion to ophthalmic tests. The GILT was administered to UK Biobank participants (total n=2,359) and participants with neurodegenerative conditions characterised by initial cortical visual (PCA, n=18) or memory loss (typical Alzheimer's disease, n=9). UK Biobank participants, including both typical adults and those with ophthalmological conditions, were able to recognise letters under low levels of completeness. In contrast, participants with PCA consistently made errors with only modest decreases in completeness. GILT sensitivity to PCA was 83.3% for participants reaching the 80% accuracy cut-off, increasing to 88.9% using alternative cut-offs (60% or 100% accuracy). Specificity values were consistently over 94% when compared to UK Biobank participants without or with documented visual conditions, regardless of accuracy cut-off. These first-release UK Biobank and clinical verification data suggest the GILT has utility in both rapidly detecting visual perceptual losses following posterior cortical damage and differentiating perceptual losses from common eye-related conditions.

Dynamic causal modelling for functional near-infrared spectroscopy.

Functional near-infrared spectroscopy (fNIRS) is an emerging technique for measuring changes in cerebral hemoglobin concentration via optical absorption changes. Although there is great interest in using fNIRS to study brain connectivity, current methods are unable to infer the directionality of neuronal connections. In this paper, we apply Dynamic Causal Modelling (DCM) to fNIRS data. Specifically, we present a generative model of how observed fNIRS data are caused by interactions among hidden neuronal states. Inversion of this generative model, using an established Bayesian framework (variational Laplace), then enables inference about changes in directed connectivity at the neuronal level. Using experimental data acquired during motor imagery and motor execution tasks, we show that directed (i.e., effective) connectivity from the supplementary motor area to the primary motor cortex is negatively modulated by motor imagery, and this suppressive influence causes reduced activity in the primary motor cortex during motor imagery. These results are consistent with findings of previous functional magnetic resonance imaging (fMRI) studies, suggesting that the proposed method enables one to infer directed interactions in the brain mediated by neuronal dynamics from measurements of optical density changes.

Reading front to back: MEG evidence for early feedback effects during word recognition.

Magnetoencephalography studies in humans have shown word-selective activity in the left inferior frontal gyrus (IFG) approximately 130 ms after word presentation ( Pammer et al. 2004; Cornelissen et al. 2009; Wheat et al. 2010). The role of this early frontal response is currently not known. We tested the hypothesis that the IFG provides top-down constraints on word recognition using dynamic causal modeling of magnetoencephalography data collected, while subjects viewed written words and false font stimuli. Subject-specific dipoles in left and right occipital, ventral occipitotemporal and frontal cortices were identified using Variational Bayesian Equivalent Current Dipole source reconstruction. A connectivity analysis tested how words and false font stimuli differentially modulated activity between these regions within the first 300 ms after stimulus presentation. We found that left inferior frontal activity showed stronger sensitivity to words than false font and a stronger feedback connection onto the left ventral occipitotemporal cortex (vOT) in the first 200 ms. Subsequently, the effect of words relative to false font was observed on feedforward connections from left occipital to ventral occipitotemporal and frontal regions. These findings demonstrate that left inferior frontal activity modulates vOT in the early stages of word processing and provides a mechanistic account of top-down effects during word recognition.

A dynamical pattern recognition model of γ activity in auditory cortex.

This paper describes a dynamical process which serves both as a model of temporal pattern recognition in the brain and as a forward model of neuroimaging data. This process is considered at two separate levels of analysis: the algorithmic and implementation levels. At an algorithmic level, recognition is based on the use of Occurrence Time features. Using a speech digit database we show that for noisy recognition environments, these features rival standard cepstral coefficient features. At an implementation level, the model is defined using a Weakly Coupled Oscillator (WCO) framework and uses a transient synchronization mechanism to signal a recognition event. In a second set of experiments, we use the strength of the synchronization event to predict the high gamma (75-150 Hz) activity produced by the brain in response to word versus non-word stimuli. Quantitative model fits allow us to make inferences about parameters governing pattern recognition dynamics in the brain.

How number processing survives left occipito-temporal damage.

We investigated the neural systems that support number processing in a patient (JL) who had damage to the left ventral occipito-temporal cortex (LvOT). JL had severely impaired written word recognition but he was remarkably accurate in number tasks, albeit slower than normal. This suggests LvOT activation is necessary for efficient but not for accurate number decisions. Here we investigated how JL made accurate number decisions using fMRI; we compared JL's brain activation to that in healthy controls and in two patients with frontal lobe damage who, like JL, made slow but accurate responses in number tasks. For semantic relative to perceptual decisions on numbers, JL did not activate the left occipito-temporal area that was involved in all other subjects. However, JL had significantly increased activation in a left posterior middle temporal region. In addition, during semantic and perceptual decisions on numbers, JL showed increased activation in: (1) the right occipito-temporal cortex, (2) right caudate, and (3) bilateral frontal regions. These effects were unique to JL and cannot be explained in terms of abnormally long response times because they were not observed in the other patients who made slow but accurate number decisions. Together these results show that although the LvOT usually contributes to efficient number processing, activation in this region is not essential for accurate performance because (i) perceptual processing of numbers can be supported by right occipital, right caudate, and bilateral frontal activation and (ii) semantic processing of numbers can be supported by increased left posterior middle temporal activation associated with hand actions.

Data warehousing methods and processing infrastructure for brain recovery research.

In order to accelerate translational neuroscience with the goal of improving clinical care it has become important to support rapid accumulation and analysis of large, heterogeneous neuroimaging samples and their metadata from both normal control and patient groups. We propose a multi-centre, multinational approach to accelerate the data mining of large samples and facilitate data-led clinical translation of neuroimaging results in stroke. Such data-driven approaches are likely to have an early impact on clinically relevant brain recovery while we simultaneously pursue the much more challenging model-based approaches that depend on a deep understanding of the complex neural circuitry and physiological processes that support brain function and recovery. We present a brief overview of three (potentially converging) approaches to neuroimaging data warehousing and processing that aim to support these diverse methods for facilitating prediction of cognitive and behavioral recovery after stroke, or other types of brain injury or disease.

Lesion sites that predict the ability to gesture how an object is used.

We used a two stage procedure to predict which stroke patients would have chronic difficulties gesturing how to use an object when object recognition and hand movements were intact. First, we searched our PLORAS database by behavior and identified 5 patients who had chronic difficulty gesturing object use but no difficulty recognising objects, comprehending words or moving their hands. High definition lesion analyses showed that all 5 patients had damage to the white matter underlying the left ventral supramarginal gyrus, (A) close to the cortex, (B) deep towards the midline and (C) extending into the temporal lobe. In addition, 2 patients had damage to (D) the left posterior middle temporal cortex, and 3 patients had damage to (E) the left dorsal supramarginal gyrus and (F) the left premotor cortex. Second, we searched our database by lesion location for patients who had damage to any part of regions ABCDEF. The incidence of gesturing difficulties was higher in patients with damage to ABCD (7/9), ABCE (7/10) or ABCDE (10/13) than ABCF (7/13), ABC (8/16) or partial damage to ABCF (6/32). Thus behaviour was best predicted by the combination of regions that were damaged (a "network-lesion") rather than on the basis of each region alone or overall lesion size. Our results identify which parts of the temporal and parietal lobes impair the ability to gesture object use and which parts need to be intact to support it after damage. Our methods provide a framework for future studies aiming to predict the consequences of brain damage.

Changing meaning causes coupling changes within higher levels of the cortical hierarchy.

Processing of speech and nonspeech sounds occurs bilaterally within primary auditory cortex and surrounding regions of the superior temporal gyrus; however, the manner in which these regions interact during speech and nonspeech processing is not well understood. Here, we investigate the underlying neuronal architecture of the auditory system with magnetoencephalography and a mismatch paradigm. We used a spoken word as a repeating "standard" and periodically introduced 3 "oddball" stimuli that differed in the frequency spectrum of the word's vowel. The closest deviant was perceived as the same vowel as the standard, whereas the other 2 deviants were perceived as belonging to different vowel categories. The neuronal responses to these vowel stimuli were compared with responses elicited by perceptually matched tone stimuli under the same paradigm. For both speech and tones, deviant stimuli induced coupling changes within the same bilateral temporal lobe system. However, vowel oddball effects increased coupling within the left posterior superior temporal gyrus, whereas perceptually equivalent nonspeech oddball effects increased coupling within the right primary auditory cortex. Thus, we show a dissociation in neuronal interactions, occurring at both different hierarchal levels of the auditory system (superior temporal versus primary auditory cortex) and in different hemispheres (left versus right). This hierarchical specificity depends on whether auditory stimuli are embedded in a perceptual context (i.e., a word). Furthermore, our lateralization results suggest left hemisphere specificity for the processing of phonological stimuli, regardless of their elemental (i.e., spectrotemporal) characteristics.

The role of the thalamus in amnesia: a tractography, high-resolution MRI and neuropsychological study.

Although it is well established that thalamic lesions may lead to profound amnesia, the precise contribution of thalamic sub-regions to memory remains unclear. In an influential article Aggleton and Brown proposed that recognition memory depends on two processes supported by distinct thalamic and cortical structures. Familiarity is mediated by the mediodorsal (MD) thalamic nucleus and the entorhinal/perirhinal cortex. Recollection is mediated by the anterior thalamic nucleus (AN), the mamillothalamic tract (MTT) and the hippocampus. The authors also suggested that the lateral dorsal nucleus (LD) may contribute to the thalamic/hippocampus system, thereby implying that the LD may play a role in recollection. Given the finding that material specific amnesia can occur following thalamic lesions, we tested an extension of the Aggleton and Brown model. We predicted that patients with bilateral lesions with a bias to the left or right MD or AN/MTT/LD may exhibit impaired familiarity or recollection on verbal or non-verbal memoranda. We report two patients with highly focal thalamic lesions and profound memory impairments affecting verbal and non-verbal memoranda. For the first time, diffusion-weighted imaging was employed to perform tractography of the MTT along with high-resolution anatomical MRI and detailed assessments of verbal and non-verbal memory. Our data support only some aspects of the Aggleton and Brown model. Both patients had left MD nucleus and AN/MTT lesions and performed poorly on familiarity and recall for verbal memoranda, just as predicted by the model. However, both patients' performance for non-verbal memoranda (human faces and topography) is more difficult to reconcile with the model. Patient 1 had damage to the right AN/MTT/LD with sparing of the MD: familiarity should therefore have been preserved but was not. Patient 2 had damage to the right MD with sparing of AN/MTT: recollection should have been preserved but was not. This finding raises the possibility that fractionation of familiarity and recollection to separate thalamic nuclei may not fully capture the role of thalamic sub-regions in memory function.

Optokinetic therapy improves text reading in patients with hemianopic alexia: a controlled trial.

OBJECTIVE: An acquired right-sided homonymous hemianopia can result in slowed left-to-right text reading, called hemianopic alexia (HA). Patients with HA lack essential visual information to help guide ensuing reading fixations. We tested two hypotheses: first, that practice with a visual rehabilitation method that induced small-field optokinetic nystagmus (OKN) would improve reading speeds in patients with HA when compared to a sham visual rehabilitation therapy; second, that this therapy would preferentially affect reading saccades into the blind field. METHODS: Nineteen patients with HA were entered into a two-armed study with two therapy blocks in each arm: one group practiced reading moving text (MT) that scrolled from right to left daily for two 4-week blocks (Group1), while the other had sham therapy (spot the difference) for the first block and then crossed over to MT for the second. RESULTS: Group 1 showed significant improvements in static text reading speed over both therapy blocks (18% improvement), while Group 2 did not significantly improve over the first block (5% improvement) but did when they crossed over to the MT block (23% improvement). MT therapy was associated with a direction-specific effect on saccadic amplitude for rightward but not leftward reading saccades. CONCLUSION: Optokinetic nystagmus inducing therapy preferentially affects reading saccades in the direction of the induced (involuntary) saccadic component. This is the first study to demonstrate the effectiveness of a specific eye movement based therapy in patients with hemianopic alexia (HA) in the context of a therapy-controlled trial. A free Web-based version of the therapy used in this study is available online to suitable patients with HA.

Structural anatomy of pure and hemianopic alexia.

BACKGROUND: The two most common types of acquired reading disorder resulting from damage to the territory of the dominant posterior cerebral artery are hemianopic and pure alexia. Patients with pronounced hemianopic alexia have a right homonymous hemianopia that encroaches into central or parafoveal vision; they read individual words well, but generate inefficient reading saccades when reading along a line of text. Patients with pure alexia also often have a hemianopia but are more disabled, making frequent errors on individual words; they have sustained damage to a brain region that supports efficient word identification. OBJECTIVE: To investigate the differences in lesion site between hemianopic alexia and pure alexia groups, as rehabilitative techniques differ between the two conditions. METHODS: High-resolution magnetic resonance images were obtained from seven patients with hemianopic alexia and from six patients with pure alexia caused by a left occipital stroke. The boundary of each lesion was defined and lesion volumes were then transformed into a standard stereotactic space so that regional comparisons could be made. RESULTS: The two patient groups did not differ in terms of damage to the medial left occipital lobe, but those with pure alexia had additional lateral damage to the posterior fusiform gyrus and adjacent tissue. CONCLUSIONS: Clinicians will be able to predict the type of reading disorder patients with left occipital lesions have from simple tests of reading speed and the distribution of damage to the left occipital lobe on brain imaging. This information will aid management decisions, including recommendations for reading rehabilitation.

"Bottom-up" and "top-down" effects on reading saccades: a case study.

OBJECTIVE: To investigate the role right foveal/parafoveal sparing plays in reading single words, word arrays, and eye movement patterns in a single case with an incongruous hemianopia. METHODS: The patient, a 48-year-old right handed male with a macular sparing hemianopia in his left eye and a macular splitting hemianopia in his right eye, performed various reading tasks. Single word reading speeds were monitored using a "voice-trigger" system. Eye movements were recorded while reading three passages of text, and PET data were gathered while the subject performed a variety of reading tasks in the camera. RESULTS: The patient was faster at reading single words and text with his left eye compared with his right. A small word length effect was present in his right eye but not his left. His eye movement patterns were more orderly when reading text with his left eye, making fewer saccades. The PET data provided evidence of "top-down" processes involved in reading. Binocular single word reading produced activity in the representation of foveal V1 bilaterally; however, text reading with the left eye only was associated with activation in left but not right parafoveal V1, despite there being visual stimuli in both visual fields. CONCLUSIONS: The presence of a word length effect (typically associated with pure alexia) can be caused by a macular splitting hemianopia. Right parafoveal vision is not critically involved in single word identification, but is when planning left to right reading saccades. The influence of top-down attentional processes during text reading can be visualised in parafoveal V1 using PET.

The planning and guiding of reading saccades: a repetitive transcranial magnetic stimulation study.

A previous positron emission tomography study that investigated the cortical areas involved in directing eye movements during text reading showed two areas of extra-occipital asymmetry: left > right posterior parietal cortex (PPC), and right > left frontal eye-field (FEF). We used the temporal resolution of repetitive TMS (rTMS) to isolate the contributions of the left and right PPC and FEF to the planning and execution of rightward reading saccades. We present eye-movement data collected during text reading, which involves the initiation and maintenance of a series of saccades (scanpath). rTMS over the left but not right PPC slowed reading speeds for the whole array of words, indicating that this area is involved throughout the scanpath. rTMS over the right but not the left FEF slowed the time to make the first saccade, but only when triggered before the stimuli appeared, demonstrating that the role of this region is in the preparation of the scanpath. Our results are compatible with the hypotheses that the left PPC maintains reading saccades along a line of text while the right FEF is involved in the preparation of the motor plan for the scanpath at the start of each new line of text.

Spatial normalization of brain images with focal lesions using cost function masking.

In studies of patients with focal brain lesions, it is often useful to coregister an image of the patient's brain to that of another subject or a standard template. We refer to this process as spatial normalization. Spatial normalization can improve the presentation and analysis of lesion location in neuropsychological studies; it can also allow other data, for example from functional imaging, to be compared to data from other patients or normal controls. In functional imaging, the standard procedure for spatial normalization is to use an automated algorithm, which minimizes a measure of difference between image and template, based on image intensity values. These algorithms usually optimize both linear (translations, rotations, zooms, and shears) and nonlinear transforms. In the presence of a focal lesion, automated algorithms attempt to reduce image mismatch between template and image at the site of the lesion. This can lead to significant inappropriate image distortion, especially when nonlinear transforms are used. One solution is to use cost-function masking-masking the areas used in the calculation of image difference-to exclude the area of the lesion, so that the lesion does not bias the transformations. We introduce and evaluate this technique using normalizations of a selection of brains with focal lesions and normal brains with simulated lesions. Our results suggest that cost-function masking is superior to the standard approach to this problem, which is affine-only normalization; we propose that cost-function masking should be used routinely for normalizations of brains with focal lesions.

The functional anatomy of single-word reading in patients with hemianopic and pure alexia.

We investigated single-word reading in normal subjects and patients with alexia following a left occipital infarct, using PET. The most posterior brain region to show a lateralized response was at the left occipitotemporal junction, in the inferior temporal gyrus. This region was activated when normal subjects, patients with hemianopic alexia and patients with an incomplete right homonymous hemianopia, but no reading deficit, viewed single words presented at increasing rates. This same area was damaged in a patient with pure alexia ("alexia without agraphia") and no hemianopia, who read words slowly using a letter-by-letter strategy. Although the exact level of the functional deficit is controversial, pure alexia is the result of an inability to map a percept of all the letters in a familiar letter string on to the mental representation of the whole word form. However, the commonest deficit associated with "pure" alexia is a right homonymous field defect; an impairment that may, by itself, interfere with single-word reading because of inability to see the letters towards the end of a word. The relative contributions of pure and hemianopic alexia in individual patients needs to be assessed, as the latter has been shown to respond well to specific rehabilitation programmes.

Statistical modeling of positron emission tomography images in wavelet space.

A new method is introduced for the analysis of multiple studies measured with emission tomography. Traditional models of statistical analysis (ANOVA, ANCOVA and other linear models) are applied not directly on images but on their correspondent wavelet transforms. Maps of model effects estimated from these models are filtered using a thresholding procedure based on a simple Bonferroni correction and then reconstructed. This procedure inherently represents a complete modeling approach and therefore obtains estimates of the effects of interest (condition effect, difference between conditions, covariate of interest, and so on) under the specified statistical risk. By performing the statistical modeling step in wavelet space. the procedure allows the direct estimation of the error for each wavelet coefficient; hence, the local noise characteristics are accounted for in the subsequent filtering. The method was validated by use of a null dataset and then applied to typical examples of neuroimaging studies to highlight conceptual and practical differences from existing statistical parametric mapping approaches.

Impaired reading in patients with right hemianopia.

A left occipital stroke may result in alexia for two reasons, which may coexist depending on the distribution of the lesion. A lesion of the left lateroventral prestriate cortex or its afferents impairs word recognition ("pure" alexia). If the left primary visual cortex or its afferents are destroyed, resulting in a complete right homonymous hemianopia, rightward saccades during text reading are disrupted ("hemianopic" alexia). By using functional imaging, we showed two separate but interdependent systems involved in reading. The first, subserving word recognition, involved the representation of foveal vision in the left and right primary visual cortex and the ventral prestriate cortex. The second system, responsible for the planning and execution of reading saccades, consisted of the representation of right parafoveal vision in the left visual cortex, the bilateral posterior parietal cortex (left > right), and the frontal eye fields (right > left). Disruption of this distributed neural system was demonstrated in patients with severe right homonymous hemianopia, commensurate with their inability to perform normal reading eye movements. Text reading, before processes involved in comprehension, requires the integration of perceptual and motor processes. We have demonstrated these distributed neural systems in normal readers and have shown how a right homonymous hemianopia disrupts the motor preparation of reading saccades during text reading.

Complex partial status epilepticus in late-onset MELAS.

A patient with recurrent episodes of complex partial status epilepticus and a distinctive pattern of periodic lateralized epileptiform discharges (PLEDs) is presented. The patient was subsequently shown to have a mitochondrial disorder of the MELAS type, a hitherto unreported association. The case illustrates that CPSE should be added to the list of possible causes of acute neurological deterioration in MELAS patients.