GABA and Glutamate in hMT+ Link to Individual Differences in Residual Visual Function After Occipital Stroke.

BACKGROUND: Damage to the primary visual cortex following an occipital stroke causes loss of conscious vision in the contralateral hemifield. Yet, some patients retain the ability to detect moving visual stimuli within their blind field. The present study asked whether such individual differences in blind field perception following loss of primary visual cortex could be explained by the concentration of neurotransmitters γ-aminobutyric acid (GABA) and glutamate or activity of the visual motion processing, human middle temporal complex (hMT+). METHODS: We used magnetic resonance imaging in 19 patients with chronic occipital stroke to measure the concentration of neurotransmitters GABA and glutamate (proton magnetic resonance spectroscopy) and functional activity in hMT+ (functional magnetic resonance imaging). We also tested each participant on a 2-interval forced choice detection task using high-contrast, moving Gabor patches. We then measured and assessed the strength of relationships between participants' residual vision in their blind field and in vivo neurotransmitter concentrations, as well as visually evoked functional magnetic resonance imaging activity in their hMT+. Levels of GABA and glutamate were also measured in a sensorimotor region, which served as a control. RESULTS: Magnetic resonance spectroscopy-derived GABA and glutamate concentrations in hMT+ (but not sensorimotor cortex) strongly predicted blind-field visual detection abilities. Performance was inversely related to levels of both inhibitory and excitatory neurotransmitters in hMT+ but, surprisingly, did not correlate with visually evoked blood oxygenation level-dependent signal change in this motion-sensitive region. CONCLUSIONS: Levels of GABA and glutamate in hMT+ appear to provide superior information about motion detection capabilities inside perimetrically defined blind fields compared to blood oxygenation level-dependent signal changes-in essence, serving as biomarkers for the quality of residual visual processing in the blind-field. Whether they also reflect a potential for successful rehabilitation of visual function remains to be determined.

Generalized models for quantifying laterality using functional transcranial Doppler ultrasound.

We consider how analysis of brain lateralization using functional transcranial Doppler ultrasound (fTCD) data can be brought in line with modern statistical methods typically used in functional magnetic resonance imaging (fMRI). Conventionally, a laterality index is computed in fTCD from the difference between the averages of each hemisphere's signal within a period of interest (POI) over a series of trials. We demonstrate use of generalized linear models (GLMs) and generalized additive models (GAM) to analyze data from individual participants in three published studies (N = 154, 73 and 31), and compare this with results from the conventional POI averaging approach, and with laterality assessed using fMRI (N = 31). The GLM approach was based on classic fMRI analysis that includes a hemodynamic response function as a predictor; the GAM approach estimated the response function from the data, including a term for time relative to epoch start (simple GAM), plus a categorical index corresponding to individual epochs (complex GAM). Individual estimates of the fTCD laterality index are similar across all methods, but error of measurement is lowest using complex GAM. Reliable identification of cases of bilateral language appears to be more accurate with complex GAM. We also show that the GAM-based approach can be used to efficiently analyze more complex designs that incorporate interactions between tasks.

Asymmetry of Auditory-Motor Speech Processing is Determined by Language Experience.

Speech processing relies on interactions between auditory and motor systems and is asymmetrically organized in the human brain. The left auditory system is specialized for processing of phonemes, whereas the right is specialized for processing of pitch changes in speech affecting prosody. In speakers of tonal languages, however, processing of pitch (i.e., tone) changes that alter word meaning is left-lateralized indicating that linguistic function and language experience shape speech processing asymmetries. Here, we investigated the asymmetry of motor contributions to auditory speech processing in male and female speakers of tonal and non-tonal languages. We temporarily disrupted the right or left speech motor cortex using transcranial magnetic stimulation (TMS) and measured the impact of these disruptions on auditory discrimination (mismatch negativity; MMN) responses to phoneme and tone changes in sequences of syllables using electroencephalography (EEG). We found that the effect of motor disruptions on processing of tone changes differed between language groups: disruption of the right speech motor cortex suppressed responses to tone changes in non-tonal language speakers, whereas disruption of the left speech motor cortex suppressed responses to tone changes in tonal language speakers. In non-tonal language speakers, the effects of disruption of left speech motor cortex on responses to tone changes were inconclusive. For phoneme changes, disruption of left but not right speech motor cortex suppressed responses in both language groups. We conclude that the contributions of the right and left speech motor cortex to auditory speech processing are determined by the functional roles of acoustic cues in the listener's native language.SIGNIFICANCE STATEMENT The principles underlying hemispheric asymmetries of auditory speech processing remain debated. The asymmetry of processing of speech sounds is affected by low-level acoustic cues, but also by their linguistic function. By combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG), we investigated the asymmetry of motor contributions to auditory speech processing in tonal and non-tonal language speakers. We provide causal evidence that the functional role of the acoustic cues in the listener's native language affects the asymmetry of motor influences on auditory speech discrimination ability [indexed by mismatch negativity (MMN) responses]. Lateralized top-down motor influences can affect asymmetry of speech processing in the auditory system.

Elevated iron concentration in putamen and cortical speech motor network in developmental stuttering.

Theoretical accounts of developmental stuttering implicate dysfunctional cortico-striatal-thalamo-cortical motor loops through the putamen. However, the analysis of conventional MRI brain scans in individuals who stutter has failed to yield strong support for this theory in terms of reliable differences in the structure or function of the basal ganglia. Here, we performed quantitative mapping of brain tissue, which can be used to measure iron content alongside markers sensitive to myelin and thereby offers particular sensitivity to the measurement of iron-rich structures such as the basal ganglia. Analysis of these quantitative maps in 41 men and women who stutter and 32 individuals who are typically fluent revealed significant group differences in maps of R2*, indicative of higher iron content in individuals who stutter in the left putamen and in left hemisphere cortical regions important for speech motor control. Higher iron levels in brain tissue in individuals who stutter could reflect elevated dopamine levels or lysosomal dysfunction, both of which are implicated in stuttering. This study represents the first use of these quantitative measures in developmental stuttering and provides new evidence of microstructural differences in the basal ganglia and connected frontal cortical regions.

Functional organisation for verb generation in children with developmental language disorder.

Developmental language disorder (DLD) is characterised by difficulties in learning one's native language for no apparent reason. These language difficulties occur in 7% of children and are known to limit future academic and social achievement. Our understanding of the brain abnormalities associated with DLD is limited. Here, we used a simple four-minute verb generation task (children saw a picture of an object and were instructed to say an action that goes with that object) to test children between the ages of 10-15 years (DLD N = 50, typically developing N = 67). We also tested 26 children with poor language ability who did not meet our criteria for DLD. Contrary to our registered predictions, we found that children with DLD did not have (i) reduced activity in language relevant regions such as the left inferior frontal cortex; (ii) dysfunctional striatal activity during overt production; or (iii) a reduction in left-lateralised activity in frontal cortex. Indeed, performance of this simple language task evoked activity in children with DLD in the same regions and to a similar level as in typically developing children. Consistent with previous reports, we found sub-threshold group differences in the left inferior frontal gyrus and caudate nuclei, but only when analysis was limited to a subsample of the DLD group (N = 14) who had the poorest performance on the task. Additionally, we used a two-factor model to capture variation in all children studied (N = 143) on a range of neuropsychological tests and found that these language and verbal memory factors correlated with activity in different brain regions. Our findings indicate a lack of support for some neurological models of atypical language learning, such as the procedural deficit hypothesis or the atypical lateralization hypothesis, at least when using simple language tasks that children can perform. These results also emphasise the importance of controlling for and monitoring task performance.

Mapping Human Laryngeal Motor Cortex during Vocalization.

The representations of the articulators involved in human speech production are organized somatotopically in primary motor cortex. The neural representation of the larynx, however, remains debated. Both a dorsal and a ventral larynx representation have been previously described. It is unknown, however, whether both representations are located in primary motor cortex. Here, we mapped the motor representations of the human larynx using functional magnetic resonance imaging and characterized the cortical microstructure underlying the activated regions. We isolated brain activity related to laryngeal activity during vocalization while controlling for breathing. We also mapped the articulators (the lips and tongue) and the hand area. We found two separate activations during vocalization-a dorsal and a ventral larynx representation. Structural and quantitative neuroimaging revealed that myelin content and cortical thickness underlying the dorsal, but not the ventral larynx representation, are similar to those of other primary motor representations. This finding confirms that the dorsal larynx representation is located in primary motor cortex and that the ventral one is not. We further speculate that the location of the ventral larynx representation is in premotor cortex, as seen in other primates. It remains unclear, however, whether and how these two representations differentially contribute to laryngeal motor control.

Evasion of host defenses by intracellular Staphylococcus aureus.

Staphylococcus aureus is one of the leading causes of hospital and community-acquired infections worldwide. The increasing occurrence of antibiotic resistant strains and the high rates of recurrent staphylococcal infections have placed several treatment challenges on healthcare systems. In recent years, it has become evident that S. aureus is a facultative intracellular pathogen, able to invade and survive in a range of cell types. The ability to survive intracellularly provides this pathogen with yet another way to evade antibiotics and immune responses during infection. Intracellular S. aureus have been strongly linked to several recurrent infections, including severe bone infections and septicemias. S. aureus is armed with an array of virulence factors as well as an intricate network of regulators that enable it to survive, replicate and escape from a number of immune and nonimmune host cells. It is able to successfully manipulate host cell pathways and use it as a niche to multiply, disseminate, as well as persist during an infection. This bacterium is also known to adapt to the intracellular environment by forming small colony variants, which are metabolically inactive. In this review we will discuss the clinical evidence, the molecular pathways involved in S. aureus intracellular persistence, and new treatment strategies for targeting intracellular S. aureus.

Transcranial direct current stimulation over left inferior frontal cortex improves speech fluency in adults who stutter.

See Crinion (doi:10.1093/brain/awy075) for a scientific commentary on this article.Stuttering is a neurodevelopmental condition affecting 5% of children, and persisting in 1% of adults. Promoting lasting fluency improvement in adults who stutter is a particular challenge. Novel interventions to improve outcomes are of value, therefore. Previous work in patients with acquired motor and language disorders reported enhanced benefits of behavioural therapies when paired with transcranial direct current stimulation. Here, we report the results of the first trial investigating whether transcranial direct current stimulation can improve speech fluency in adults who stutter. We predicted that applying anodal stimulation to the left inferior frontal cortex during speech production with temporary fluency inducers would result in longer-lasting fluency improvements. Thirty male adults who stutter completed a randomized, double-blind, controlled trial of anodal transcranial direct current stimulation over left inferior frontal cortex. Fifteen participants received 20 min of 1-mA stimulation on five consecutive days while speech fluency was temporarily induced using choral and metronome-timed speech. The other 15 participants received the same speech fluency intervention with sham stimulation. Speech fluency during reading and conversation was assessed at baseline, before and after the stimulation on each day of the 5-day intervention, and at 1 and 6 weeks after the end of the intervention. Anodal stimulation combined with speech fluency training significantly reduced the percentage of disfluent speech measured 1 week after the intervention compared with fluency intervention alone. At 6 weeks after the intervention, this improvement was maintained during reading but not during conversation. Outcome scores at both post-intervention time points on a clinical assessment tool (the Stuttering Severity Instrument, version 4) also showed significant improvement in the group receiving transcranial direct current stimulation compared with the sham group, in whom fluency was unchanged from baseline. We conclude that transcranial direct current stimulation combined with behavioural fluency intervention can improve fluency in adults who stutter. Transcranial direct current stimulation thereby offers a potentially useful adjunct to future speech therapy interventions for this population, for whom fluency therapy outcomes are currently limited.

Cortico-cerebellar Networks Drive Sensorimotor Learning in Speech.

The motor cortex and cerebellum are thought to be critical for learning and maintaining motor behaviors. Here we use transcranial direct current stimulation (tDCS) to test the role of the motor cortex and cerebellum in sensorimotor learning in speech. During productions of "head," "bed," and "dead," the first formant of the vowel sound was altered in real time toward the first formant of the vowel sound in "had," "bad," and "dad." Compensatory changes in first and second formant production were used as a measure of motor adaptation. tDCS to either the motor cortex or the cerebellum improved sensorimotor learning in speech compared with sham stimulation ( n = 20 in each group). However, in the case of cerebellar tDCS, production changes were restricted to the source of the acoustical error (i.e., the first formant). Motor cortex tDCS drove production changes that offset errors in the first formant, but unlike cerebellar tDCS, adaptive changes in the second formant also occurred. The results suggest that motor cortex and cerebellar tDCS have both shared and dissociable effects on motor adaptation. The study provides initial causal evidence in speech production that the motor cortex and the cerebellum support different aspects of sensorimotor learning. We propose that motor cortex tDCS drives sensorimotor learning toward previously learned patterns of movement, whereas cerebellar tDCS focuses sensorimotor learning on error correction.

Separation of trait and state in stuttering.

Stuttering is a disorder in which the smooth flow of speech is interrupted. People who stutter show structural and functional abnormalities in the speech and motor system. It is unclear whether functional differences reflect general traits of the disorder or are specifically related to the dysfluent speech state. We used a hierarchical approach to separate state and trait effects within stuttering. We collected sparse-sampled functional MRI during two overt speech tasks (sentence reading and picture description) in 17 people who stutter and 16 fluent controls. Separate analyses identified indicators of: (1) general traits of people who stutter; (2) frequency of dysfluent speech states in subgroups of people who stutter; and (3) the differences between fluent and dysfluent states in people who stutter. We found that reduced activation of left auditory cortex, inferior frontal cortex bilaterally, and medial cerebellum were general traits that distinguished fluent speech in people who stutter from that of controls. The stuttering subgroup with higher frequency of dysfluent states during scanning (n = 9) had reduced activation in the right subcortical grey matter, left temporo-occipital cortex, the cingulate cortex, and medial parieto-occipital cortex relative to the subgroup who were more fluent (n = 8). Finally, during dysfluent states relative to fluent ones, there was greater activation of inferior frontal and premotor cortex extending into the frontal operculum, bilaterally. The above differences were seen across both tasks. Subcortical state effects differed according to the task. Overall, our data emphasise the independence of trait and state effects in stuttering.

Resting-State Retinotopic Organization in the Absence of Retinal Input and Visual Experience.

Early visual areas have neuronal receptive fields that form a sampling mosaic of visual space, resulting in a series of retinotopic maps in which the same region of space is represented in multiple visual areas. It is not clear to what extent the development and maintenance of this retinotopic organization in humans depend on retinal waves and/or visual experience. We examined the corticocortical receptive field organization of resting-state BOLD data in normally sighted, early blind, and anophthalmic (in which both eyes fail to develop) individuals and found that resting-state correlations between V1 and V2/V3 were retinotopically organized for all subject groups. These results show that the gross retinotopic pattern of resting-state connectivity across V1-V3 requires neither retinal waves nor visual experience to develop and persist into adulthood. Significance statement: Evidence from resting-state BOLD data suggests that the connections between early visual areas develop and are maintained even in the absence of retinal waves and visual experience.

Attention fine-tunes auditory-motor processing of speech sounds.

The earliest stages of cortical processing of speech sounds take place in the auditory cortex. Transcranial magnetic stimulation (TMS) studies have provided evidence that the human articulatory motor cortex contributes also to speech processing. For example, stimulation of the motor lip representation influences specifically discrimination of lip-articulated speech sounds. However, the timing of the neural mechanisms underlying these articulator-specific motor contributions to speech processing is unknown. Furthermore, it is unclear whether they depend on attention. Here, we used magnetoencephalography and TMS to investigate the effect of attention on specificity and timing of interactions between the auditory and motor cortex during processing of speech sounds. We found that TMS-induced disruption of the motor lip representation modulated specifically the early auditory-cortex responses to lip-articulated speech sounds when they were attended. These articulator-specific modulations were left-lateralized and remarkably early, occurring 60-100 ms after sound onset. When speech sounds were ignored, the effect of this motor disruption on auditory-cortex responses was nonspecific and bilateral, and it started later, 170 ms after sound onset. The findings indicate that articulatory motor cortex can contribute to auditory processing of speech sounds even in the absence of behavioral tasks and when the sounds are not in the focus of attention. Importantly, the findings also show that attention can selectively facilitate the interaction of the auditory cortex with specific articulator representations during speech processing.

Neural activation in speech production and reading aloud in native and non-native languages.

We used fMRI to investigate neural activation in reading aloud in bilinguals differing in age of acquisition. Three groups were compared: French-English bilinguals who acquired two languages from birth (simultaneous), French-English bilinguals who learned their L2 after the age of 5 years (sequential), and English-speaking monolinguals. While the bilingual groups contrasted in age of acquisition, they were matched for language proficiency, although sequential bilinguals produced speech with a less native-like accent in their L2 than in their L1. Simultaneous bilinguals activated similar brain regions to an equivalent degree when reading in their two languages. In contrast, sequential bilinguals more strongly activated areas related to speech-motor control and orthographic to phonological mapping, the left inferior frontal gyrus, left premotor cortex, and left fusiform gyrus, when reading aloud in L2 compared to L1. In addition, the activity in these regions showed a significant positive correlation with age of acquisition. The results provide evidence for the engagement of overlapping neural substrates for processing two languages when acquired in native context from birth. However, it appears that the maturation of certain brain regions for both speech production and phonological encoding is limited by a sensitive period for L2 acquisition regardless of language proficiency.

Subcortical functional reorganization due to early blindness.

Lack of visual input early in life results in occipital cortical responses to auditory and tactile stimuli. However, it remains unclear whether cross-modal plasticity also occurs in subcortical pathways. With the use of functional magnetic resonance imaging, auditory responses were compared across individuals with congenital anophthalmia (absence of eyes), those with early onset (in the first few years of life) blindness, and normally sighted individuals. We find that the superior colliculus, a "visual" subcortical structure, is recruited by the auditory system in congenital and early onset blindness. Additionally, auditory subcortical responses to monaural stimuli were altered as a result of blindness. Specifically, responses in the auditory thalamus were equally strong to contralateral and ipsilateral stimulation in both groups of blind subjects, whereas sighted controls showed stronger responses to contralateral stimulation. These findings suggest that early blindness results in substantial reorganization of subcortical auditory responses.

Neurochemical changes in the pericalcarine cortex in congenital blindness attributable to bilateral anophthalmia.

Congenital blindness leads to large-scale functional and structural reorganization in the occipital cortex, but relatively little is known about the neurochemical changes underlying this cross-modal plasticity. To investigate the effect of complete and early visual deafferentation on the concentration of metabolites in the pericalcarine cortex, (1)H magnetic resonance spectroscopy was performed in 14 sighted subjects and 5 subjects with bilateral anophthalmia, a condition in which both eyes fail to develop. In the pericalcarine cortex, where primary visual cortex is normally located, the proportion of gray matter was significantly greater, and levels of choline, glutamate, glutamine, myo-inositol, and total creatine were elevated in anophthalmic relative to sighted subjects. Anophthalmia had no effect on the structure or neurochemistry of a sensorimotor cortex control region. More gray matter, combined with high levels of choline and myo-inositol, resembles the profile of the cortex at birth and suggests that the lack of visual input from the eyes might have delayed or arrested the maturation of this cortical region. High levels of choline and glutamate/glutamine are consistent with enhanced excitatory circuits in the anophthalmic occipital cortex, which could reflect a shift toward enhanced plasticity or sensitivity that could in turn mediate or unmask cross-modal responses. Finally, it is possible that the change in function of the occipital cortex results in biochemical profiles that resemble those of auditory, language, or somatosensory cortex.

Early auditory processing in area V5/MT+ of the congenitally blind brain.

Previous imaging studies of congenital blindness have studied individuals with heterogeneous causes of blindness, which may influence the nature and extent of cross-modal plasticity. Here, we scanned a homogeneous group of blind people with bilateral congenital anophthalmia, a condition in which both eyes fail to develop, and, as a result, the visual pathway is not stimulated by either light or retinal waves. This model of congenital blindness presents an opportunity to investigate the effects of very early visual deafferentation on the functional organization of the brain. In anophthalmic animals, the occipital cortex receives direct subcortical auditory input. We hypothesized that this pattern of subcortical reorganization ought to result in a topographic mapping of auditory frequency information in the occipital cortex of anophthalmic people. Using functional MRI, we examined auditory-evoked activity to pure tones of high, medium, and low frequencies. Activity in the superior temporal cortex was significantly reduced in anophthalmic compared with sighted participants. In the occipital cortex, a region corresponding to the cytoarchitectural area V5/MT+ was activated in the anophthalmic participants but not in sighted controls. Whereas previous studies in the blind indicate that this cortical area is activated to auditory motion, our data show it is also active for trains of pure tone stimuli and in some anophthalmic participants shows a topographic mapping (tonotopy). Therefore, this region appears to be performing early sensory processing, possibly served by direct subcortical input from the pulvinar to V5/MT+.

Auditory-motor processing of speech sounds.

The motor regions that control movements of the articulators activate during listening to speech and contribute to performance in demanding speech recognition and discrimination tasks. Whether the articulatory motor cortex modulates auditory processing of speech sounds is unknown. Here, we aimed to determine whether the articulatory motor cortex affects the auditory mechanisms underlying discrimination of speech sounds in the absence of demanding speech tasks. Using electroencephalography, we recorded responses to changes in sound sequences, while participants watched a silent video. We also disrupted the lip or the hand representation in left motor cortex using transcranial magnetic stimulation. Disruption of the lip representation suppressed responses to changes in speech sounds, but not piano tones. In contrast, disruption of the hand representation had no effect on responses to changes in speech sounds. These findings show that disruptions within, but not outside, the articulatory motor cortex impair automatic auditory discrimination of speech sounds. The findings provide evidence for the importance of auditory-motor processes in efficient neural analysis of speech sounds.

Approaches to Measuring Language Lateralisation: An Exploratory Study Comparing Two fMRI Methods and Functional Transcranial Doppler Ultrasound.

In this exploratory study we compare and contrast two methods for deriving a laterality index (LI) from functional magnetic resonance imaging (fMRI) data: the weighted bootstrapped mean from the LI Toolbox (toolbox method), and a novel method that uses subtraction of activations from homologous regions in left and right hemispheres to give an array of difference scores (mirror method). Data came from 31 individuals who had been selected to include a high proportion of people with atypical laterality when tested with functional transcranial Doppler ultrasound (fTCD). On two tasks, word generation and semantic matching, the mirror method generally gave better agreement with fTCD laterality than the toolbox method, both for individual regions of interest, and for a large region corresponding to the middle cerebral artery. LI estimates from this method had much smaller confidence intervals (CIs) than those from the toolbox method; with the mirror method, most participants were reliably lateralised to left or right, whereas with the toolbox method, a higher proportion were categorised as bilateral (i.e., the CI for the LI spanned zero). Reasons for discrepancies between fMRI methods are discussed: one issue is that the toolbox method averages the LI across a wide range of thresholds. Furthermore, examination of task-related t-statistic maps from the two hemispheres showed that language lateralisation is evident in regions characterised by deactivation, and so key information may be lost by ignoring voxel activations below zero, as is done with conventional estimates of the LI.