Predicting Online Behavioural Responses to Transcranial Direct Current Stimulation in Stroke Patients with Anomia.

Anomia, or difficulty naming common objects, is the most common, acquired impairment of language. Effective therapeutic interventions for anomia typically involve massed practice at high doses. This requires significant investment from patients and therapists. Aphasia researchers have increasingly looked to neurostimulation to accelerate these treatment effects, but the evidence behind this intervention is sparse and inconsistent. Here, we hypothesised that group-level neurostimulation effects might belie a more systematic structure at the individual level. We sought to test the hypothesis by attempting to predict the immediate (online), individual-level behavioural effects of anodal and sham neurostimulation in 36 chronic patients with anomia, performing naming and size judgement tasks. Using clinical, (pre-stimulation) behavioural and MRI data, as well as Partial Least Squares regression, we attempted to predict neurostimulation effects on accuracies and reaction times of both tasks. Model performance was assessed via cross-validation. Predictive performances were compared to that of a null model, which predicted the mean neurostimulation effects for all patients. Models derived from pre-stimulation data consistently outperformed the null model when predicting neurostimulation effects on both tasks' performance. Notably, we could predict behavioural declines just as well as improvements. In conclusion, inter-patient variation in online responses to neurostimulation is, to some extent, systematic and predictable. Since declines in performance were just as predictable as improvements, the behavioural effects of neurostimulation in patients with anomia are unlikely to be driven by placebo effects. However, the online effect of the intervention appears to be as likely to interfere with task performance as to improve it.

Better long-term speech outcomes in stroke survivors who received early clinical speech and language therapy: What's driving recovery?

Establishing whether speech and language therapy after stroke has beneficial effects on speaking ability is challenging because of the need to control for multiple non-therapy factors known to influence recovery. We investigated how speaking ability at three time points post-stroke differed in patients who received varying amounts of clinical therapy in the first month post-stroke. In contrast to prior studies, we factored out variance from: initial severity of speaking impairment, amount of later therapy, and left and right hemisphere lesion size and site. We found that speaking ability at one month post-stroke was significantly better in patients who received early therapy (n = 79), versus those who did not (n = 64), and the number of hours of early therapy was positively related to recovery at one year post-stroke. We offer two non-mutually exclusive interpretations of these data: (1) patients may benefit from the early provision of self-management strategies; (2) therapy is more likely to be provided to patients who have a better chance of recovery (e.g., poor physical and/or mental health may impact suitability for therapy and chance of recovery). Both interpretations have implications for future studies aiming to predict individual patients' speech outcomes after stroke, and their response to therapy.

Dissociating the functions of three left posterior superior temporal regions that contribute to speech perception and production.

Prior studies have shown that the left posterior superior temporal sulcus (pSTS) and left temporo-parietal junction (TPJ) both contribute to phonological short-term memory, speech perception and speech production. Here, by conducting a within-subjects multi-factorial fMRI study, we dissociate the response profiles of these regions and a third region - the anterior ascending terminal branch of the left superior temporal sulcus (atSTS), which lies dorsal to pSTS and ventral to TPJ. First, we show that each region was more activated by (i) 1-back matching on visually presented verbal stimuli (words or pseudowords) compared to 1-back matching on visually presented non-verbal stimuli (pictures of objects or non-objects), and (ii) overt speech production than 1-back matching, across 8 types of stimuli (visually presented words, pseudowords, objects and non-objects and aurally presented words, pseudowords, object sounds and meaningless hums). The response properties of the three regions dissociated within the auditory modality. In left TPJ, activation was higher for auditory stimuli that were non-verbal (sounds of objects or meaningless hums) compared to verbal (words and pseudowords), irrespective of task (speech production or 1-back matching). In left pSTS, activation was higher for non-semantic stimuli (pseudowords and hums) than semantic stimuli (words and object sounds) on the dorsal pSTS surface (dpSTS), irrespective of task. In left atSTS, activation was not sensitive to either semantic or verbal content. The contrasting response properties of left TPJ, dpSTS and atSTS was cross-validated in an independent sample of 59 participants, using region-by-condition interactions. We also show that each region participates in non-overlapping networks of frontal, parietal and cerebellar regions. Our results challenge previous claims about functional specialisation in the left posterior superior temporal lobe and motivate future studies to determine the timing and directionality of information flow in the brain networks involved in speech perception and production.

A functional dissociation of the left frontal regions that contribute to single word production tasks.

Controversy surrounds the interpretation of higher activation for pseudoword compared to word reading in the left precentral gyrus and pars opercularis. Specifically, does activation in these regions reflect: (1) the demands on sublexical assembly of articulatory codes, or (2) retrieval effort because the combinations of articulatory codes are unfamiliar? Using fMRI, in 84 neurologically intact participants, we addressed this issue by comparing reading and repetition of words (W) and pseudowords (P) to naming objects (O) from pictures or sounds. As objects do not provide sublexical articulatory cues, we hypothesis that retrieval effort will be greater for object naming than word repetition/reading (which benefits from both lexical and sublexical cues); while the demands on sublexical assembly will be higher for pseudoword production than object naming. We found that activation was: (i) highest for pseudoword reading [P>O&W in the visual modality] in the anterior part of the ventral precentral gyrus bordering the precentral sulcus (vPCg/vPCs), consistent with the sublexical assembly of articulatory codes; but (ii) as high for object naming as pseudoword production [P&O>W] in dorsal precentral gyrus (dPCg) and the left inferior frontal junction (IFJ), consistent with retrieval demands and cognitive control. In addition, we dissociate the response properties of vPCg/vPCs, dPCg and IFJ from other left frontal lobe regions that are activated during single word speech production. Specifically, in both auditory and visual modalities: a central part of vPCg (head and face area) was more activated for verbal than nonverbal stimuli [P&W>O]; and the pars orbitalis and inferior frontal sulcus were most activated during object naming [O>W&P]. Our findings help to resolve a previous discrepancy in the literature, dissociate three functionally distinct parts of the precentral gyrus, and refine our knowledge of the functional anatomy of speech production in the left frontal lobe.

Clinical Effectiveness of the Queen Square Intensive Comprehensive Aphasia Service for Patients With Poststroke Aphasia.

Background and Purpose: Poststroke aphasia has a major impact on peoples' quality of life. Speech and language therapy interventions work, especially in high doses, but these doses are rarely achieved outside of research studies. Intensive Comprehensive Aphasia Programs (ICAPs) are an option to deliver high doses of therapy to people with aphasia over a short period of time. Methods: Forty-six people with aphasia in the chronic stage poststroke completed the ICAP over a 3-week period, attending for 15 days and averaging 6 hours of therapy per day. Outcome measures included the Comprehensive Aphasia Test, an impairment-based test of the 4 main domains of language (speaking, writing, auditory comprehension, and reading) which was measured at 3 time points (baseline, immediately posttreatment at 3 weeks and follow-up at 12-week post-ICAP); and, the Communicative Effectiveness Index, a carer-reported measure of functional communication skills collected at baseline and 12 weeks. Results: A 2-way repeated measures multivariate ANOVA was conducted. We found a significant domain-by-time interaction, F=12.7, P<0.0005, indicating that the ICAP improved people with aphasia's language scores across all 4 domains, with the largest gains in speaking (Cohen's d=1.3). All gains were maintained or significantly improved further at 12-week post-ICAP. Importantly, patients' functional communication, as indexed by changes on the Communicative Effectiveness Index, also significantly improved at 12-week post-ICAP, t=5.4, P<0.0005, also with a large effect size (Cohen's d=0.9). Conclusions: People with aphasia who participated in the Queen Square ICAP made large and clinically meaningful gains on both impairment-based and functional measures of language. Gains were sustained and in some cases improved further over the subsequent 12 weeks.

Lesions that do or do not impair digit span: a study of 816 stroke survivors.

Prior studies have reported inconsistency in the lesion sites associated with verbal short-term memory impairments. Here we asked: How many different lesion sites can account for selective impairments in verbal short-term memory that persist over time, and how consistently do these lesion sites impair verbal short-term memory? We assessed verbal short-term memory impairments using a forward digit span task from the Comprehensive Aphasia Test. First, we identified the incidence of digit span impairments in a sample of 816 stroke survivors (541 males/275 females; age at stroke onset 56 ± 13 years; time post-stroke 4.4 ± 5.2 years). Second, we studied the lesion sites in a subgroup of these patients (n = 39) with left hemisphere damage and selective digit span impairment-defined as impaired digit span with unimpaired spoken picture naming and spoken word comprehension (tests of speech production and speech perception, respectively). Third, we examined how often these lesion sites were observed in patients who either had no digit span impairments or digit span impairments that co-occurred with difficulties in speech perception and/or production tasks. Digit span impairments were observed in 222/816 patients. Almost all (199/222 = 90%) had left hemisphere damage to five small regions in basal ganglia and/or temporo-parietal areas. Even complete damage to one or more of these five regions was not consistently associated with persistent digit span impairment. However, when the same regions were spared, only 5% (23/455) presented with digit span impairments. These data suggest that verbal short-term memory impairments are most consistently associated with damage to left temporo-parietal and basal ganglia structures. Sparing of these regions very rarely results in persistently poor verbal short-term memory. These findings have clinical implications for predicting recovery of verbal short-term memory after stroke.

Damage to Broca's area does not contribute to long-term speech production outcome after stroke.

Broca's area in the posterior half of the left inferior frontal gyrus has long been thought to be critical for speech production. The current view is that long-term speech production outcome in patients with Broca's area damage is best explained by the combination of damage to Broca's area and neighbouring regions including the underlying white matter, which was also damaged in Paul Broca's two historic cases. Here, we dissociate the effect of damage to Broca's area from the effect of damage to surrounding areas by studying long-term speech production outcome in 134 stroke survivors with relatively circumscribed left frontal lobe lesions that spared posterior speech production areas in lateral inferior parietal and superior temporal association cortices. Collectively, these patients had varying degrees of damage to one or more of nine atlas-based grey or white matter regions: Brodmann areas 44 and 45 (together known as Broca's area), ventral premotor cortex, primary motor cortex, insula, putamen, the anterior segment of the arcuate fasciculus, uncinate fasciculus and frontal aslant tract. Spoken picture description scores from the Comprehensive Aphasia Test were used as the outcome measure. Multiple regression analyses allowed us to tease apart the contribution of other variables influencing speech production abilities such as total lesion volume and time post-stroke. We found that, in our sample of patients with left frontal damage, long-term speech production impairments (lasting beyond 3 months post-stroke) were solely predicted by the degree of damage to white matter, directly above the insula, in the vicinity of the anterior part of the arcuate fasciculus, with no contribution from the degree of damage to Broca's area (as confirmed with Bayesian statistics). The effect of white matter damage cannot be explained by a disconnection of Broca's area, because speech production scores were worse after damage to the anterior arcuate fasciculus with relative sparing of Broca's area than after damage to Broca's area with relative sparing of the anterior arcuate fasciculus. Our findings provide evidence for three novel conclusions: (i) Broca's area damage does not contribute to long-term speech production outcome after left frontal lobe strokes; (ii) persistent speech production impairments after damage to the anterior arcuate fasciculus cannot be explained by a disconnection of Broca's area; and (iii) the prior association between persistent speech production impairments and Broca's area damage can be explained by co-occurring white matter damage, above the insula, in the vicinity of the anterior part of the arcuate fasciculus.

Guidelines for TMS/tES clinical services and research through the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has broadly disrupted biomedical treatment and research including non-invasive brain stimulation (NIBS). Moreover, the rapid onset of societal disruption and evolving regulatory restrictions may not have allowed for systematic planning of how clinical and research work may continue throughout the pandemic or be restarted as restrictions are abated. The urgency to provide and develop NIBS as an intervention for diverse neurological and mental health indications, and as a catalyst of fundamental brain research, is not dampened by the parallel efforts to address the most life-threatening aspects of COVID-19; rather in many cases the need for NIBS is heightened including the potential to mitigate mental health consequences related to COVID-19. OBJECTIVE: To facilitate the re-establishment of access to NIBS clinical services and research operations during the current COVID-19 pandemic and possible future outbreaks, we develop and discuss a framework for balancing the importance of NIBS operations with safety considerations, while addressing the needs of all stakeholders. We focus on Transcranial Magnetic Stimulation (TMS) and low intensity transcranial Electrical Stimulation (tES) - including transcranial Direct Current Stimulation (tDCS) and transcranial Alternating Current Stimulation (tACS). METHODS: The present consensus paper provides guidelines and good practices for managing and reopening NIBS clinics and laboratories through the immediate and ongoing stages of COVID-19. The document reflects the analysis of experts with domain-relevant expertise spanning NIBS technology, clinical services, and basic and clinical research - with an international perspective. We outline regulatory aspects, human resources, NIBS optimization, as well as accommodations for specific demographics. RESULTS: A model based on three phases (early COVID-19 impact, current practices, and future preparation) with an 11-step checklist (spanning removing or streamlining in-person protocols, incorporating telemedicine, and addressing COVID-19-associated adverse events) is proposed. Recommendations on implementing social distancing and sterilization of NIBS related equipment, specific considerations of COVID-19 positive populations including mental health comorbidities, as well as considerations regarding regulatory and human resource in the era of COVID-19 are outlined. We discuss COVID-19 considerations specifically for clinical (sub-)populations including pediatric, stroke, addiction, and the elderly. Numerous case-examples across the world are described. CONCLUSION: There is an evident, and in cases urgent, need to maintain NIBS operations through the COVID-19 pandemic, including anticipating future pandemic waves and addressing effects of COVID-19 on brain and mind. The proposed robust and structured strategy aims to address the current and anticipated future challenges while maintaining scientific rigor and managing risk.

How Does iReadMore Therapy Change the Reading Network of Patients with Central Alexia?

Central alexia (CA) is an acquired reading disorder co-occurring with a generalized language deficit (aphasia). The roles of perilesional and ipsilesional tissue in recovery from poststroke aphasia are unclear. We investigated the impact of reading training (using iReadMore, a therapy app) on the connections within and between the right and left hemisphere of the reading network of patients with CA. In patients with pure alexia, iReadMore increased feedback from left inferior frontal gyrus (IFG) region to the left occipital (OCC) region. We aimed to identify whether iReadMore therapy was effective through a similar mechanism in patients with CA. Participants with chronic poststroke CA (n = 23) completed 35 h of iReadMore training over 4 weeks. Reading accuracy for trained and untrained words was assessed before and after therapy. The neural response to reading trained and untrained words in the left and right OCC, ventral occipitotemporal, and IFG regions was examined using event-related magnetoencephalography. The training-related modulation in effective connectivity between regions was modeled at the group level with dynamic causal modeling. iReadMore training improved participants' reading accuracy by an average of 8.4% (range, -2.77 to 31.66) while accuracy for untrained words was stable. Training increased regional sensitivity in bilateral frontal and occipital regions, and strengthened feedforward connections within the left hemisphere. Our data suggest that iReadMore training in these patients modulates lower-order visual representations, as opposed to higher-order, more abstract representations, to improve word-reading accuracy.SIGNIFICANCE STATEMENT This is the first study to conduct a network-level analysis of therapy effects in participants with poststroke central alexia. When patients trained with iReadMore (a multimodal, behavioral, mass practice, computer-based therapy), reading accuracy improved by an average 8.4% on trained items. A network analysis of the magnetoencephalography data associated with this improvement revealed an increase in regional sensitivity in bilateral frontal and occipital regions and strengthening of feedforward connections within the left hemisphere. This indicates that in patients with CA iReadMore engages lower-order, intact resources within the left hemisphere (posterior to their lesion locations) to improve word reading. This provides a foundation for future research to investigate reading network modulation in different CA subtypes, or for sentence-level therapy.

How right hemisphere damage after stroke can impair speech comprehension.

Acquired language disorders after stroke are strongly associated with left hemisphere damage. When language difficulties are observed in the context of right hemisphere strokes, patients are usually considered to have atypical functional anatomy. By systematically integrating behavioural and lesion data from brain damaged patients with functional MRI data from neurologically normal participants, we investigated when and why right hemisphere strokes cause language disorders. Experiment 1 studied right-handed patients with unilateral strokes that damaged the right (n = 109) or left (n = 369) hemispheres. The most frequently impaired language task was: auditory sentence-to-picture matching after right hemisphere strokes; and spoken picture description after left hemisphere strokes. For those with auditory sentence-to-picture matching impairments after right hemisphere strokes, the majority (n = 9) had normal performance on tests of perceptual (visual or auditory) and linguistic (semantic, phonological or syntactic) processing. Experiment 2 found that these nine patients had significantly more damage to dorsal parts of the superior longitudinal fasciculus and the right inferior frontal sulcus compared to 75 other patients who also had right hemisphere strokes but were not impaired on the auditory sentence-to-picture matching task. Damage to these right hemisphere regions caused long-term speech comprehension difficulties in 67% of patients. Experiments 3 and 4 used functional MRI in two groups of 25 neurologically normal individuals to show that within the regions identified by Experiment 2, the right inferior frontal sulcus was normally activated by (i) auditory sentence-to-picture matching; and (ii) one-back matching when the demands on linguistic and non-linguistic working memory were high. Together, these experiments demonstrate that the right inferior frontal cortex contributes to linguistic and non-linguistic working memory capacity (executive function) that is needed for normal speech comprehension. Our results link previously unrelated literatures on the role of the right inferior frontal cortex in executive processing and the role of executive processing in sentence comprehension; which in turn helps to explain why right inferior frontal activity has previously been reported to increase during recovery of language function after left hemisphere stroke. The clinical relevance of our findings is that the detrimental effect of right hemisphere strokes on language is (i) much greater than expected; (ii) frequently observed after damage to the right inferior frontal sulcus; (iii) task dependent; (iv) different to the type of impairments observed after left hemisphere strokes; and (v) can result in long-lasting deficits that are (vi) not the consequence of atypical language lateralization.

Dorsal and ventral visual stream contributions to preserved reading ability in patients with central alexia.

We investigated the role of the left temporo-parietal regions in supporting reading abilities of 23 patients with central alexia (CA). For the behavioural data, we employed principal components analysis (PCA), which identified two components: 'reading aloud' and 'reading for meaning'. Voxel-based morphometry of the PCA results showed an association between reading aloud and grey matter density in the left supramarginal gyrus, part of the dorsal visual stream. By contrast, reading for meaning was associated with a large cluster in the left ventral visual stream, from the collateral sulcus to the anterior temporal pole. Most of the peaks were within the group lesion map, indicating that sparing of these areas results in better preservation of reading ability. However, one white matter (WM) cluster in the medial occipitotemporal lobe was outside the lesioned area. A post-hoc test demonstrated that WM density here was equivalent to controls, suggesting that this was not driven by lesion effects. The two likeliest explanations for this correlation are: 1) that pre-morbid, inter-individual differences in brain structure mitigate the effects of CA; 2) that post-morbid practice-based with reading caused compensatory plasticity. We hope to adjudicate between these explanations with longitudinal therapy data collected in this cohort.

Randomized trial of iReadMore word reading training and brain stimulation in central alexia.

Central alexia is an acquired reading disorder co-occurring with a generalized language deficit (aphasia). We tested the impact of a novel training app, 'iReadMore', and anodal transcranial direct current stimulation of the left inferior frontal gyrus, on word reading ability in central alexia. The trial was registered at www.clinicaltrials.gov (NCT02062619). Twenty-one chronic stroke patients with central alexia participated. A baseline-controlled, repeated-measures, crossover design was used. Participants completed two 4-week blocks of iReadMore training, one with anodal stimulation and one with sham stimulation (order counterbalanced between participants). Each block comprised 34 h of iReadMore training and 11 stimulation sessions. Outcome measures were assessed before, between and after the two blocks. The primary outcome measures were reading ability for trained and untrained words. Secondary outcome measures included semantic word matching, sentence reading, text reading and a self-report measure. iReadMore training resulted in an 8.7% improvement in reading accuracy for trained words (95% confidence interval 6.0 to 11.4; Cohen's d = 1.38) but did not generalize to untrained words. Reaction times also improved. Reading accuracy gains were still significant (but reduced) 3 months after training cessation. Anodal transcranial direct current stimulation (compared to sham), delivered concurrently with iReadMore, resulted in a 2.6% (95% confidence interval -0.1 to 5.3; d = 0.41) facilitation for reading accuracy, both for trained and untrained words. iReadMore also improved performance on the semantic word-matching test. There was a non-significant trend towards improved self-reported reading ability. However, no significant changes were seen at the sentence or text reading level. In summary, iReadMore training in post-stroke central alexia improved reading ability for trained words, with good maintenance of the therapy effect. Anodal stimulation resulted in a small facilitation (d = 0.41) of learning and also generalized to untrained items.10.1093/brain/awy138_video1awy138media15796149281001.

How distributed processing produces false negatives in voxel-based lesion-deficit analyses.

In this study, we hypothesized that if the same deficit can be caused by damage to one or another part of a distributed neural system, then voxel-based analyses might miss critical lesion sites because preservation of each site will not be consistently associated with preserved function. The first part of our investigation used voxel-based multiple regression analyses of data from 359 right-handed stroke survivors to identify brain regions where lesion load is associated with picture naming abilities after factoring out variance related to object recognition, semantics and speech articulation so as to focus on deficits arising at the word retrieval level. A highly significant lesion-deficit relationship was identified in left temporal and frontal/premotor regions. Post-hoc analyses showed that damage to either of these sites caused the deficit of interest in less than half the affected patients (76/162 = 47%). After excluding all patients with damage to one or both of the identified regions, our second analysis revealed a new region, in the anterior part of the left putamen, which had not been previously detected because many patients had the deficit of interest after temporal or frontal damage that preserved the left putamen. The results illustrate how (i) false negative results arise when the same deficit can be caused by different lesion sites; (ii) some of the missed effects can be unveiled by adopting an iterative approach that systematically excludes patients with lesions to the areas identified in previous analyses, (iii) statistically significant voxel-based lesion-deficit mappings can be driven by a subset of patients; (iv) focal lesions to the identified regions are needed to determine whether the deficit of interest is the consequence of focal damage or much more extensive damage that includes the identified region; and, finally, (v) univariate voxel-based lesion-deficit mappings cannot, in isolation, be used to predict outcome in other patients.

Less is more: neural mechanisms underlying anomia treatment in chronic aphasic patients.

See Thompson and Woollams (doi:10.1093/brain/awx264) for a scientific commentary on this article. Previous research with aphasic patients has shown that picture naming can be facilitated by concurrent phonemic cueing [e.g. initial phoneme(s) of the word that the patient is trying to retrieve], both as an immediate word retrieval technique, and when practiced repeatedly over time as a long-term anomia treatment. Here, to investigate the neural mechanisms supporting word retrieval, we adopted­for the first time­a functional magnetic resonance imaging task using the same naming procedure as it occurs during the anomia treatment process. Before and directly after a 6-week anomia treatment programme, 18 chronic aphasic stroke patients completed our functional magnetic resonance imaging protocol­a picture naming task aided by three different types of phonemic cues (whole words, initial phonemes, final phonemes) and a noise-control condition. Patients completed a naming task based on the training materials, and a more general comprehensive battery of language tests both before and after the anomia treatment, to determine the effectiveness and specificity of the therapy. Our results demonstrate that the anomia treatment was effective and specific to speech production, significantly improving both patients' naming accuracy and reaction time immediately post-treatment (unstandardized effect size: 29% and 17%, respectively; Cohen's d: 3.45 and 1.83). Longer term gains in naming were maintained 3 months later. Functional imaging results showed that both immediate and long-term facilitation of naming involved a largely overlapping bilateral frontal network including the right anterior insula, inferior frontal and dorsal anterior cingulate cortices, and the left premotor cortex. These areas were associated with a neural priming effect (i.e. reduced blood oxygen level-dependent signal) during both immediate (phonemically-cued versus control-cue conditions), and long-term facilitation of naming (i.e. treated versus untreated items). Of note is that different brain regions were sensitive to different phonemic cue types. Processing of whole word cues was associated with increased activity in the right angular gyrus; whereas partial word cues (initial and final phonemes) recruited the left supplementary motor area, and right anterior insula, inferior frontal cortex, and basal ganglia. The recruitment of multiple and bilateral areas may help explain why phonemic cueing is such a successful behavioural facilitation tool for anomia treatment. Our results have important implications for optimizing current anomia treatment approaches, developing new treatments, and improving speech outcome for aphasic patients.

Using functional imaging to understand therapeutic effects in poststroke aphasia.

PURPOSE OF REVIEW: The evidence base for the treatment of poststroke aphasia continues to grow, so too does interest in the neural mechanisms that underlie these therapy-driven improvements. Although the majority of patients respond to therapy, not all of those who do improve do so in a predictable way. Here, we review 17 of the most recent articles that have attempted to deal with this important question, dividing them into those that target speech perception and production. RECENT FINDINGS: There are many methodological differences between the studies, but some neuroimaging patterns have emerged: whether the in-scanner language task is speech perception or production, left hemisphere fronto-temporal cortex is often activated/correlated with language improvement and; right inferior frontal gyrus is frequently identified although what this represents is still hotly contested. We are concerned that many studies are not well controlled making it difficult to ascribe neuroimaging changes directly to the therapeutic intervention. SUMMARY: Encouragingly, there are many more functional imaging studies in this challenging area of research. Behaviour, either alone or paired with structural imaging data, only goes part way in explaining aphasic patients' responses to therapy. An important emerging theme is exploring the role that nonlanguage cognitive processes play in aphasia recovery.

Changes in auditory feedback connections determine the severity of speech processing deficits after stroke.

We compared brain structure and function in two subgroups of 21 stroke patients with either moderate or severe chronic speech comprehension impairment. Both groups had damage to the supratemporal plane; however, the severe group suffered greater damage to two unimodal auditory areas: primary auditory cortex and the planum temporale. The effects of this damage were investigated using fMRI while patients listened to speech and speech-like sounds. Pronounced changes in connectivity were found in both groups in undamaged parts of the auditory hierarchy. Compared to controls, moderate patients had significantly stronger feedback connections from planum temporale to primary auditory cortex bilaterally, while in severe patients this connection was significantly weaker in the undamaged right hemisphere. This suggests that predictive feedback mechanisms compensate in moderately affected patients but not in severely affected patients. The key pathomechanism in humans with persistent speech comprehension impairments may be impaired feedback connectivity to unimodal auditory areas.

A deficit of spatial remapping in constructional apraxia after right-hemisphere stroke.

Constructional apraxia refers to the inability of patients to copy accurately drawings or three-dimensional constructions. It is a common disorder after right parietal stroke, often persisting after initial problems such as visuospatial neglect have resolved. However, there has been very little experimental investigation regarding mechanisms that might contribute to the syndrome. Here, we examined whether a key deficit might be failure to integrate visual information correctly from one fixation to the next. Specifically, we tested whether this deficit might concern remapping of spatial locations across saccades. Right-hemisphere stroke patients with constructional apraxia were compared to patients without constructional problems and neurologically healthy controls. Participants judged whether a pattern shifted position (spatial task) or changed in pattern (non-spatial task) across two saccades, compared to a control condition with an equivalent delay but without intervening eye movements. Patients with constructional apraxia were found to be significantly impaired in position judgements with intervening saccades, particularly when the first saccade of the sequence was to the right. The importance of these remapping deficits in constructional apraxia was confirmed through a highly significant correlation between saccade task performance and constructional impairment on standard neuropsychological tasks. A second study revealed that even single saccades to the right can impair constructional apraxia patients' perception of location shifts. These data are consistent with the view that rightward eye movements result in loss of remembered spatial information from previous fixations, presumably due to constructional apraxia patients' damage to the right-hemisphere regions involved in remapping locations across saccades. These findings provide the first evidence for a deficit in remapping visual information across saccades underlying right-hemisphere constructional apraxia.

The left superior temporal gyrus is a shared substrate for auditory short-term memory and speech comprehension: evidence from 210 patients with stroke.

Competing theories of short-term memory function make specific predictions about the functional anatomy of auditory short-term memory and its role in language comprehension. We analysed high-resolution structural magnetic resonance images from 210 stroke patients and employed a novel voxel based analysis to test the relationship between auditory short-term memory and speech comprehension. Using digit span as an index of auditory short-term memory capacity we found that the structural integrity of a posterior region of the superior temporal gyrus and sulcus predicted auditory short-term memory capacity, even when performance on a range of other measures was factored out. We show that the integrity of this region also predicts the ability to comprehend spoken sentences. Our results therefore support cognitive models that posit a shared substrate between auditory short-term memory capacity and speech comprehension ability. The method applied here will be particularly useful for modelling structure-function relationships within other complex cognitive domains.

Anterior temporal lobe connectivity correlates with functional outcome after aphasic stroke.

Focal brain lesions are assumed to produce language deficits by two basic mechanisms: local cortical dysfunction at the lesion site, and remote cortical dysfunction due to disruption of the transfer and integration of information between connected brain regions. However, functional imaging studies investigating language outcome after aphasic stroke have tended to focus only on the role of local cortical function. In this positron emission tomography functional imaging study, we explored relationships between language comprehension performance after aphasic stroke and the functional connectivity of a key speech-processing region in left anterolateral superior temporal cortex. We compared the organization of left anterolateral superior temporal cortex functional connections during narrative speech comprehension in normal subjects with left anterolateral superior temporal cortex connectivity in a group of chronic aphasic stroke patients. We then evaluated the language deficits associated with altered left anterolateral superior temporal cortex connectivity in aphasic stroke. During normal narrative speech comprehension, left anterolateral superior temporal cortex displayed positive functional connections with left anterior basal temporal cortex, left inferior frontal gyrus and homotopic cortex in right anterolateral superior temporal cortex. As a group, aphasic patients demonstrated a selective disruption of the normal functional connection between left and right anterolateral superior temporal cortices. We observed that deficits in auditory single word and sentence comprehension correlated both with the degree of disruption of left-right anterolateral superior temporal cortical connectivity and with local activation in the anterolateral superior temporal cortex. Subgroup analysis revealed that aphasic patients with preserved positive intertemporal connectivity displayed better receptive language function; these patients also showed greater than normal left inferior frontal gyrus activity, suggesting a possible 'top-down' compensatory mechanism. These results demonstrate that functional connectivity between anterolateral superior temporal cortex and right anterior superior temporal cortex is a marker of receptive language outcome after aphasic stroke, and illustrate that language system organization after focal brain lesions may be marked by complex signatures of altered local and pathway-level function.