Septo-dentate gyrus cholinergic circuits modulate function and morphogenesis of adult neural stem cells through granule cell intermediaries.

Cholinergic neurons in the basal forebrain play a crucial role in regulating adult hippocampal neurogenesis (AHN). However, the circuit and molecular mechanisms underlying cholinergic modulation of AHN, especially the initial stages of this process related to the generation of newborn progeny from quiescent radial neural stem cells (rNSCs), remain unclear. Here, we report that stimulation of the cholinergic circuits projected from the diagonal band of Broca (DB) to the dentate gyrus (DG) neurogenic niche promotes proliferation and morphological development of rNSCs, resulting in increased neural stem/progenitor pool and rNSCs with longer radial processes and larger busy heads. Interestingly, DG granule cells (GCs) are required for DB-DG cholinergic circuit-dependent modulation of proliferation and morphogenesis of rNSCs. Furthermore, single-nucleus RNA sequencing of DG reveals cell type-specific transcriptional changes in response to cholinergic circuit stimulation, with GCs (among all the DG niche cells) exhibiting the most extensive transcriptional changes. Our findings shed light on how the DB-DG cholinergic circuits orchestrate the key niche components to support neurogenic function and morphogenesis of rNSCs at the circuit and molecular levels.

Neural correlates of semantic-driven syntactic parsing in sentence comprehension.

For sentence comprehension, information carried by semantic relations between constituents must be combined with other information to decode the constituent structure of a sentence, due to atypical and noisy situations of language use. Neural correlates of decoding sentence structure by semantic information have remained largely unexplored. In this functional MRI study, we examine the neural basis of semantic-driven syntactic parsing during sentence reading and compare it with that of other types of syntactic parsing driven by word order and case marking. Chinese transitive sentences of various structures were investigated, differing in word order, case making, and agent-patient semantic relations (i.e., same vs. different in animacy). For the non-canonical unmarked sentences without usable case marking, a semantic-driven effect triggered by agent-patient ambiguity was found in the left inferior frontal gyrus opercularis (IFGoper) and left inferior parietal lobule, with the activity not being modulated by naturalness factors of the sentences. The comparison between each type of non-canonical sentences with canonical sentences revealed that the non-canonicity effect engaged the left posterior frontal and temporal regions, in line with previous studies. No extra neural activity was found responsive to case marking within the non-canonical sentences. A word order effect across all types of sentences was also found in the left IFGoper, suggesting a common neural substrate between different types of parsing. The semantic-driven effect was also observed for the non-canonical marked sentences but not for the canonical sentences, suggesting that semantic information is used in decoding sentence structure in addition to case marking. The current findings illustrate the neural correlates of syntactic parsing with semantics, and provide neural evidence of how semantics facilitates syntax together with other information.

Cell type-specific and frequency-dependent centrifugal modulation in olfactory bulb output neurons in vivo.

Mitral/tufted cells (M/TCs) form complex local circuits with interneurons in the olfactory bulb and are powerfully inhibited by these interneurons. The horizontal limb of the diagonal band of Broca (HDB), the only GABAergic/inhibitory source of centrifugal circuit with the olfactory bulb, is known to target olfactory bulb interneurons, and we have shown targeting also to olfactory bulb glutamatergic neurons in vitro. However, the net efficacy of these circuits under different patterns of activation in vivo and the relative balance between the various targeted intact local and centrifugal circuits was the focus of this study. Here channelrhodopsin-2 (ChR2) was expressed in HDB GABAergic neurons to investigate the short-term plasticity of HDB-activated disinhibitory rebound excitation of M/TCs. Optical activation of HDB interneurons increased spontaneous M/TC firing without odor presentation and increased odor-evoked M/TC firing. HDB activation induced disinhibitory rebound excitation (burst or cluster of spiking) in all classes of M/TCs. This excitation was frequency dependent, with short-term facilitation only at higher HDB stimulation frequency (5 Hz and above). However, frequency-dependent HDB regulation was more potent in the deeper layer M/TCs compared with more superficial layer M/TCs. In all neural circuits the balance between inhibition and excitation in local and centrifugal circuits plays a critical functional role, and this patterned input-dependent regulation of inhibitory centrifugal inputs to the olfactory bulb may help maintain the precise balance across the populations of output neurons in different environmental odors, putatively to sharpen the enhancement of tuning specificity of individual or classes of M/TCs to odors.NEW & NOTEWORTHY Neuronal local circuits in the olfactory bulb are modulated by centrifugal long circuits. In vivo study here shows that inhibitory horizontal limb of the diagonal band of Broca (HDB) modulates all five types of mitral/tufted cells (M/TCs), by direct inhibitory circuits HDB → M/TCs and indirect disinhibitory long circuits HDB → interneurons → M/TCs. The HDB net effect exerts excitation in all types of M/TCs but more powerful in deeper layer output neurons as HDB activation frequency increases, which may sharpen the tuning specificity of classes of M/TCs to odors during sensory processing.

Two models of mind blanking.

Mind blanking is a mental state in which attention does not bring any perceptual input into conscious awareness. As this state is still largely unexplored, we suggest that a comprehensive understanding of mind blanking can be achieved through a multifaceted approach combining self-assessment methods, neuroimaging and neuromodulation. In this article, we explain how electroencephalography and transcranial magnetic stimulation could be combined to help determine whether mind blanking is associated with a lack of mental content or a lack of linguistically or conceptually determinable mental content. We also question whether mind blanking occurs spontaneously or intentionally and whether these two forms are instantiated by the same or different neural correlates.

Transcranial direct-current stimulation of core language areas facilitates novel word acquisition.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that can alter the state of the stimulated brain area and thereby affect neurocognitive processes and resulting behavioural performance. Previous studies have shown disparate results with respect to tDCS effects on language function, particularly with respect to language learning and word acquisition. To fill this gap, this study aimed at systematically addressing the effects of tDCS of core left-hemispheric language cortices on the brain mechanisms underpinning two main neurocognitive strategies of word learning: implicit inference-based Fast Mapping (FM) and direct instruction-based Explicit Encoding (EE). Prior to a word-learning session, 160 healthy participants were given 15 min of either anodal or cathodal tDCS of Wernicke's or Broca's areas, or a control sham (placebo) stimulation, using a between-group design. Each participant then learned 16 novel words (8 through FM and 8 through EE) in a contextual word-picture association session. Moreover, these words were learnt either perceptually via auditory exposure combined with a graphical image of the novel object, or in an articulatory mode, where the participants additionally had to overtly articulate the novel items. These learning conditions were fully counterbalanced across participants, stimuli and tDCS groups. Learning outcomes were tested at both lexical and semantic levels using two tasks: recognition and word-picture matching. EE and FM conditions produced similar outcomes, indicating comparable efficiency of the respective learning strategies. At the same time, articulatory learning produced generally better results than non-articulatory exposure, yielding higher recognition accuracies and shorter latencies in both tasks. Crucially, real tDCS led to global outcome improvements, demonstrated by faster (compared to sham) reactions, as well as some accuracy changes. There was also evidence of more specific tDCS effects: better word-recognition accuracy for EE vs. FM following cathodal stimulation as well as more expressed improvements in recognition accuracy and reaction times for anodal Broca's and cathodal Wernicke's stimulation, particularly for unarticulated FM items. These learning mode-specific effects support the notion of partially distinct brain mechanisms underpinning these two learning strategies. Overall, numerically largest improvements were observed for anodal Broca's tDCS, whereas the least expressed benefits of tDCS for learning were measured after anodal Wernicke stimulation. Finally, we did not find any inhibitory effects of either tDCS polarity in any of the comparisons. We conclude that tDCS of core language areas exerts a general facilitatory effect on new word acquisition with some limited specificity to learning protocols - the result that may be of potential applied value for future research aimed at ameliorating learning deficits and language disorders.

Accelerated neurodegeneration of basal forebrain cholinergic neurons in HIV-1 gp120 transgenic mice: Critical role of the p75 neurotrophin receptor.

Human Immunodeficiency Virus-1 (HIV) infection of the brain induces HIV-associated neurocognitive disorders (HAND). The set of molecular events employed by HIV to drive cognitive impairments in people living with HIV are diverse and remain not completely understood. We have shown that the HIV envelope protein gp120 promotes loss of synapses and decreases performance on cognitive tasks through the p75 neurotrophin receptor (p75NTR). This receptor is abundant on cholinergic neurons of the basal forebrain and contributes to cognitive impairment in various neurological disorders. In this study, we examined cholinergic neurons of gp120 transgenic (gp120tg) mice for signs of degeneration. We observed that the number of choline acetyltransferase-expressing cells is decreased in old (12-14-month-old) gp120tg mice when compared to age matched wild type. In the same animals, we observed an increase in the levels of pro-nerve growth factor, a ligand of p75NTR, as well as a disruption of consolidation of extinction of conditioned fear, a behavior regulated by cholinergic neurons of the basal forebrain. Both biochemical and behavioral outcomes of gp120tg mice were rescued by the deletion of the p75NTR gene, strongly supporting the role that this receptor plays in the neurotoxic effects of gp120. These data indicate that future p75NTR-directed pharmacotherapies could provide an adjunct therapy against synaptic simplification caused by HIV.

Children's syntax is supported by the maturation of BA44 at 4 years, but of the posterior STS at 3 years of age.

Within the first years of life, children learn major aspects of their native language. However, the ability to process complex sentence structures, a core faculty in human language called syntax, emerges only slowly. A milestone in syntax acquisition is reached around the age of 4 years, when children learn a variety of syntactic concepts. Here, we ask which maturational changes in the child's brain underlie the emergence of syntactically complex sentence processing around this critical age. We relate markers of cortical brain maturation to 3- and 4-year-olds' sentence processing in contrast to other language abilities. Our results show that distinct cortical brain areas support sentence processing in the two age groups. Sentence production abilities at 3 years were associated with increased surface area in the most posterior part of the left superior temporal sulcus, whereas 4-year-olds showed an association with cortical thickness in the left posterior part of Broca's area, i.e. BA44. The present findings suggest that sentence processing abilities rely on the maturation of distinct cortical regions in 3- compared to 4-year-olds. The observed shift to more mature regions involved in processing syntactically complex sentences may underlie behavioral milestones in syntax acquisition at around 4 years.

Atypical characteristic changes of surface morphology and structural covariance network in developmental dyslexia.

BACKGROUND: Developmental dyslexia (DD) is a neurodevelopmental disorder that is characterized by difficulties with all aspects of information acquisition in the written word, including slow and inaccurate word recognition. The neural basis behind DD has not been fully elucidated. METHOD: The study included 22 typically developing (TD) children, 16 children with isolated spelling disorder (SpD), and 20 children with DD. The cortical thickness, folding index, and mean curvature of Broca's area, including the triangular part of the left inferior frontal gyrus (IFGtriang) and the opercular part of the left inferior frontal gyrus, were assessed to explore the differences of surface morphology among the TD, SpD, and DD groups. Furthermore, the structural covariance network (SCN) of the triangular part of the left inferior frontal gyrus was analyzed to explore the changes of structural connectivity in the SpD and DD groups. RESULTS: The DD group showed higher curvature and cortical folding of the left IFGtriang than the TD group and SpD group. In addition, compared with the TD group and the SpD group, the structural connectivity between the left IFGtriang and the left middle-frontal gyrus and the right mid-orbital frontal gyrus was increased in the DD group, and the structural connectivity between the left IFGtriang and the right precuneus and anterior cingulate was decreased in the DD group. CONCLUSION: DD had atypical structural connectivity in brain regions related to visual attention, memory and which might impact the information input and integration needed for reading and spelling.

Integrating EEG and Machine Learning to Analyze Brain Changes during the Rehabilitation of Broca's Aphasia.

The fusion of electroencephalography (EEG) with machine learning is transforming rehabilitation. Our study introduces a neural network model proficient in distinguishing pre- and post-rehabilitation states in patients with Broca's aphasia, based on brain connectivity metrics derived from EEG recordings during verbal and spatial working memory tasks. The Granger causality (GC), phase-locking value (PLV), weighted phase-lag index (wPLI), mutual information (MI), and complex Pearson correlation coefficient (CPCC) across the delta, theta, and low- and high-gamma bands were used (excluding GC, which spanned the entire frequency spectrum). Across eight participants, employing leave-one-out validation for each, we evaluated the intersubject prediction accuracy across all connectivity methods and frequency bands. GC, MI theta, and PLV low-gamma emerged as the top performers, achieving 89.4%, 85.8%, and 82.7% accuracy in classifying verbal working memory task data. Intriguingly, measures designed to eliminate volume conduction exhibited the poorest performance in predicting rehabilitation-induced brain changes. This observation, coupled with variations in model performance across frequency bands, implies that different connectivity measures capture distinct brain processes involved in rehabilitation. The results of this paper contribute to current knowledge by presenting a clear strategy of utilizing limited data to achieve valid and meaningful results of machine learning on post-stroke rehabilitation EEG data, and they show that the differences in classification accuracy likely reflect distinct brain processes underlying rehabilitation after stroke.

Language and executive functions in patients with transcortical motor aphasia and Broca's aphasia.

This study investigated language and executive functions (EF) in people with transcortical motor aphasia (TMA) and Broca's aphasia (BA). Participants included 19 patients with TMA, 19 patients with BA, and 25 healthy controls. Verbal Fluency tests, Stroop tests and Trail-Making tests were administered to all participants, and the Boston Diagnostic Aphasia Examination (BDAE) was administered to participants with aphasia. Results showed that (1) both groups of patients with aphasia had poorer performance on Verbal Fluency tests, Stroop tests and Trail-Making tests than healthy controls; (2) participants with BA had superior performance on Stroop tests and Trail-Making tests, but not on Verbal Fluency tests, than participants with TMA, and (2) the performance on Verbal Fluency tests, Stroop tests and Trail-Making was significantly correlated with the performance on BDAE for participants with TMA, but not for participants with BA. These results suggest that EF deficits are present in both patients with TMA and those with BA. They also show that the relationship between EF deficits and language impairments in people with aphasia might depend on the type of aphasia, aspects of language, and the components of EF measured.

Frequency-dependent centrifugal modulation of the activity of different classes of mitral and tufted cells in olfactory bulb.

Mitral/tufted cells (M/TCs), the principal output neuron classes form complex circuits with bulbar neurons and long-range centrifugal circuits with higher processing areas such as the horizontal limb of the diagonal band of Broca (HDB). The precise excitability of output neurons is sculpted by local inhibitory circuits. Here, light-gated cation channel channelrhodopsin-2 (ChR2) was expressed in HDB GABAergic neurons to investigate the short-term plasticity of evoked postsynaptic currents/potentials of HDB input to all classes of M/TCs and effects on firing in the acute slice preparation. Activation of the HDB directly inhibited all classes of output neurons exhibiting frequency-dependent short-term depression of evoked inhibitory postsynaptic current (eIPSC)/potential (eIPSP), resulting in decreased inhibition of responses to olfactory nerve input as a function of input frequency. In contrast, activation of an indirect circuit of HDB→interneurons→M/TCs induced frequency-dependent disinhibition, resulting in short-term facilitation of evoked excitatory postsynaptic current (eEPSC) eliciting a burst or cluster of spiking in M/TCs. The facilitatory effects of elevated HDB input frequency were strongest on deeper output neurons (deep tufted and mitral cells) and negligible on peripheral output neurons (external and superficial tufted cells). Taken together, GABAergic HDB activation generates frequency-dependent regulation that differentially affects the excitability and responses across the five classes of M/TCs. This regulation may help maintain the precise balance between inhibition and excitation of neuronal circuits across the populations of output neurons in the face of changes in an animal sniffing rate, putatively to enhance and sharpen the tuning specificity of individual or classes of M/TCs to odors.NEW & NOTEWORTHY Neuronal circuits in the olfactory bulb closely modulate olfactory bulb output activity. Activation of GABAergic circuits from the HDB to the olfactory bulb has both direct and indirect action differentially across the five classes of M/TC bulbar output neurons. The net effect enhances the excitability of deeper output neurons as HDB frequency increases, altering the relative inhibition-excitation balance of output circuits. We hypothesize that this sharpens the tuning specificity of classes of M/TCs to odors during sensory processing.

The impact of selective and non-selective medial septum stimulation on hippocampal neuronal oscillations: A study based on modeling and experiments.

Alzheimer's disease (AD) is a neurodegenerative disorder with a rising socioeconomic impact on societies. The hippocampus (HPC), which plays an important role in AD, is affected in the early stages. The medial septum (MS) in the forebrain provides major cholinergic input to the HPC and has been shown to play a significant role in generating oscillations in hippocampal neurons. Cholinergic neurons in the basal forebrain are particularly vulnerable to neurodegeneration in AD. To better understand the role of MS neurons including the cholinergic, glutamatergic, and GABAergic subpopulations in generating the well-known brain rhythms in HPC including delta, theta, slow gamma, and fast gamma oscillations, we designed a detailed computational model of the septohippocampal pathway. We validated the results of our model, using electrophysiological recordings in HPC with and without stimulation of the cholinergic neurons in MS using designer receptors exclusively activated by designer drugs (DREADDs) in healthy male ChAT-cre rats. Then, we eliminated 75% of the MS cholinergic neurons in the model to simulate degeneration in AD. A series of selective and non-selective stimulations of the remaining MS neurons were performed to understand the dynamics of oscillation regulation in the HPC during the degenerated state. In this way, appropriate stimulation strategies able to normalize the aberrant oscillations are proposed. We found that selectively stimulating the remaining healthy cholinergic neurons was sufficient for network recovery and compare this to stimulating other subpopulations and a non-selective stimulation of all MS neurons. Our data provide valuable information for the development of new therapeutic strategies in AD and a tool to test and predict the outcome of potential theranostic manipulations.

Atypical development of Broca's area in a large family with inherited stuttering.

Developmental stuttering is a condition of speech dysfluency, characterized by pauses, blocks, prolongations and sound or syllable repetitions. It affects around 1% of the population, with potential detrimental effects on mental health and long-term employment. Accumulating evidence points to a genetic aetiology, yet gene-brain associations remain poorly understood due to a lack of MRI studies in affected families. Here we report the first neuroimaging study of developmental stuttering in a family with autosomal dominant inheritance of persistent stuttering. We studied a four-generation family, 16 family members were included in genotyping analysis. T1-weighted and diffusion-weighted MRI scans were conducted on seven family members (six male; aged 9-63 years) with two age and sex matched controls without stuttering (n = 14). Using Freesurfer, we analysed cortical morphology (cortical thickness, surface area and local gyrification index) and basal ganglia volumes. White matter integrity in key speech and language tracts (i.e. frontal aslant tract and arcuate fasciculus) was also analysed using MRtrix and probabilistic tractography. We identified a significant age by group interaction effect for cortical thickness in the left hemisphere pars opercularis (Broca's area). In affected family members this region failed to follow the typical trajectory of age-related thinning observed in controls. Surface area analysis revealed the middle frontal gyrus region was reduced bilaterally in the family (all cortical morphometry significance levels set at a vertex-wise threshold of P < 0.01, corrected for multiple comparisons). Both the left and right globus pallidus were larger in the family than in the control group (left P = 0.017; right P = 0.037), and a larger right globus pallidus was associated with more severe stuttering (rho = 0.86, P = 0.01). No white matter differences were identified. Genotyping identified novel loci on chromosomes 1 and 4 that map with the stuttering phenotype. Our findings denote disruption within the cortico-basal ganglia-thalamo-cortical network. The lack of typical development of these structures reflects the anatomical basis of the abnormal inhibitory control network between Broca's area and the striatum underpinning stuttering in these individuals. This is the first evidence of a neural phenotype in a family with an autosomal dominantly inherited stuttering.

Cognitive control of orofacial motor and vocal responses in the ventrolateral and dorsomedial human frontal cortex.

In the primate brain, a set of areas in the ventrolateral frontal (VLF) cortex and the dorsomedial frontal (DMF) cortex appear to control vocalizations. The basic role of this network in the human brain and how it may have evolved to enable complex speech remain unknown. In the present functional neuroimaging study of the human brain, a multidomain protocol was utilized to investigate the roles of the various areas that comprise the VLF-DMF network in learning rule-based cognitive selections between different types of motor actions: manual, orofacial, nonspeech vocal, and speech vocal actions. Ventrolateral area 44 (a key component of the Broca's language production region in the human brain) is involved in the cognitive selection of orofacial, as well as, speech and nonspeech vocal responses; and the midcingulate cortex is involved in the analysis of speech and nonspeech vocal feedback driving adaptation of these responses. By contrast, the cognitive selection of speech vocal information requires this former network and the additional recruitment of area 45 and the presupplementary motor area. We propose that the basic function expressed by the VLF-DMF network is to exert cognitive control of orofacial and vocal acts and, in the language dominant hemisphere of the human brain, has been adapted to serve higher speech function. These results pave the way to understand the potential changes that could have occurred in this network across primate evolution to enable speech production.

Comparing the efficiency of speech and language therapy and transcranial magnetic stimulation for treating Broca's aphasia.

OBJECTIVES: Aphasia is an acquired language-cognitive disorder that highly affects an individual's speech, language, and communication skills. Recovery from aphasia requires attentive treatment since it is a long and dynamic process. This study aimed to show interactive benefits of combining classical intervention strategies with new technological approaches and demonstrating their effectiveness. MATERIALS AND METHODS: A total of 40 individuals with Broca's aphasia were included in the study. The participants were divided into Application-1 Speech and Language Therapy, Application-2 Transcranial Magnetic Stimulation, Application-3 (consecutive Transcranial Magnetic Stimulation and Speech and Language Therapy), and Application-4 (Control Group) experimental groups, with 10 participants in each group. RESULTS: Analysis indicated that individuals in the group in which Transcranial Magnetic Stimulation and Speech and Language Therapy were applied consecutively had further increases in speech fluency, repetition, and naming scores from pre-test to post-test (p<0.01). Picture naming and quality-of-life communication scores of individuals in the group in which Speech and Language Therapy was performed increased further from pre-test to post-test (p<0.01). CONCLUSIONS: The results of the study showed a positive effect on language skills, naming scores, and participation in social life of Turkish-speaking aphasic individuals with the Speech and Language Therapy and Transcranial Magnetic Stimulation methods. The use of Transcranial Magnetic Stimulation alone is insufficient in this context. Although Speech and Language Therapy alone is effective in naming ability, Transcranial Magnetic Stimulation in addition to Speech and Language Therapy significantly increases the gain obtained with therapies.

Individual Variability of Broca's Area of the Brain in Women.

In this article, we studied individual features of the macroscopic structure of Broca's area of the brains in 9 women (18 hemispheres) aged from 20 to 30 years, without any mental or neurological disorders. By using MRI, the structures of the sulci and gyri of the pars triangularis and pars opercularis of Broca's area were studied: the anterior and ascending rami of the lateral sulcus, the radial, diagonal, precentral, inferior frontal, and lateral sulci. We also studied the relationship between the pars triangularis and pars opercularis as well as their relationships with neighboring cortical structures. We measured the volume of the pars triangularis and pars opercularis and the thickness of their cortex. Significant individual variability in the location and relationships between the anterior ramus of the lateral sulcus and the ascending ramus of the lateral sulcus, as well as structural features of the pars triangularis and pars opercularis of Broca's area were demonstrated.

The human language effective connectome.

To advance understanding of brain networks involved in language, the effective connectivity between 26 cortical regions implicated in language by a community analysis and 360 cortical regions was measured in 171 humans from the Human Connectome Project, and complemented with functional connectivity and diffusion tractography, all using the HCP multimodal parcellation atlas. A (semantic) network (Group 1) involving inferior cortical regions of the superior temporal sulcus cortex (STS) with the adjacent inferior temporal visual cortex TE1a and temporal pole TG, and the connected parietal PGi region, has effective connectivity with inferior temporal visual cortex (TE) regions; with parietal PFm which also has visual connectivity; with posterior cingulate cortex memory-related regions; with the frontal pole, orbitofrontal cortex, and medial prefrontal cortex; with the dorsolateral prefrontal cortex; and with 44 and 45 for output regions. It is proposed that this system can build in its temporal lobe (STS and TG) and parietal parts (PGi and PGs) semantic representations of objects incorporating especially their visual and reward properties. Another (semantic) network (Group 3) involving superior regions of the superior temporal sulcus cortex and more superior temporal lobe regions including STGa, auditory A5, TPOJ1, the STV and the Peri-Sylvian Language area (PSL) has effective connectivity with auditory areas (A1, A4, A5, Pbelt); with relatively early visual areas involved in motion, e.g., MT and MST, and faces/words (FFC); with somatosensory regions (frontal opercular FOP, insula and parietal PF); with other TPOJ regions; and with the inferior frontal gyrus regions (IFJa and IFSp). It is proposed that this system builds semantic representations specialising in auditory and related facial motion information useful in theory of mind and somatosensory / body image information, with outputs directed not only to regions 44 and 45, but also to premotor 55b and midcingulate premotor cortex. Both semantic networks (Groups 1 and 3) have access to the hippocampal episodic memory system via parahippocampal TF. A third largely frontal network (Group 2) (44, 45, 47l; 55b; the Superior Frontal Language region SFL; and including temporal pole TGv) receives effective connectivity from the two semantic systems, and is implicated in syntax and speech output.

The neurobiology of language beyond single words.

A hallmark of human language is that we combine lexical building blocks retrieved from memory in endless new ways. This combinatorial aspect of language is referred to as unification. Here we focus on the neurobiological infrastructure for syntactic and semantic unification. Unification is characterized by a high-speed temporal profile including both prediction and integration of retrieved lexical elements. A meta-analysis of numerous neuroimaging studies reveals a clear dorsal/ventral gradient in both left inferior frontal cortex and left posterior temporal cortex, with dorsal foci for syntactic processing and ventral foci for semantic processing. In addition to core areas for unification, further networks need to be recruited to realize language-driven communication to its full extent. One example is the theory of mind network, which allows listeners and readers to infer the intended message (speaker meaning) from the coded meaning of the linguistic utterance. This indicates that sensorimotor simulation cannot handle all of language processing.

Mutational spectrum of breast cancer susceptibility genes among women ascertained in a cancer risk clinic in Northeast Brazil.

PURPOSE: There is a paucity of data on the spectrum and prevalence of pathogenic variants among women of African ancestry in the Northeast region of Brazil. METHODS: We performed BROCA panel sequencing to identify inherited loss-of-function variants in breast cancer susceptibility genes among 292 Brazilian women referred to a single institution cancer risk assessment program. RESULTS: The study included a convenient cohort of 173 women with invasive breast cancer (cases) and 119 women who were cancer-free at the time of ascertainment. The majority of the women self-reported as African-descended (67% for cases and 90.8% for unaffected volunteers). Thirty-seven pathogenic variants were found in 36 (20.8%) patients. While the spectrum of pathogenic variants was heterogeneous, the majority (70.3%) of the pathogenic variants were detected in high-risk genes BRCA1, BRCA2, PALB2, and TP53. Pathogenic variants were also found in the ATM, BARD1, BRIP1, FAM175A, FANCM, NBN, and SLX4 genes in 6.4% of the affected women. Four recurrent pathogenic variants were detected in 11 patients of African ancestry. Only one unaffected woman had a pathogenic variant in the RAD51C gene. Different risk assessment models examined performed well in predicting risk of carrying germline loss-of-function variants in BRCA1 and/or BRCA2 in breast cancer cases. CONCLUSION: The high prevalence and heterogenous spectrum of pathogenic variants identified among self-reported African descendants in Northeast Brazil is consistent with studies in other African ancestry populations with a high burden of aggressive young onset breast cancer. It underscores the need to integrate comprehensive cancer risk assessment and genomic testing in the management of newly diagnosed Black women with breast cancer across the African Diaspora, enabling improved cancer control in admixed underserved and understudied populations.

Broca's area involvement in abstract and concrete word acquisition: tDCS evidence.

Broca's area in the left hemisphere of the human neocortex has been suggested as a major hub for acquisition, storage, and access of linguistic information, abstract words in particular. Direct causal evidence for the latter, however, is still scarce; filling this gap was the goal of the present study. Using transcranial direct current stimulation (tDCS) of Broca's region, we aimed to delineate the involvement of this area in abstract and concrete word acquisition. The experiment used a between-subject design and involved 15 min of anodal or cathodal tDCS over Broca's area, or a sham/placebo control condition. The stimulation procedure was followed by a contextual learning session, in which participants were exposed to new concrete and abstract words embedded into short five-sentence texts. Finally, a set of behavioural assessment tasks was run to assess the learning outcomes immediately after the training (Day 1) and with a 24-hour delay (Day 2). The results showed that participants recognised novel abstract words more accurately after both anodal and cathodal tDCS in comparison with the sham condition on Day 1, which was also accompanied by longer recognition times (presumably due to deeper lexico-semantic processing), supporting the role of Broca's region in acquisition of abstract semantics. They were also more successful when recalling concrete words after cathodal tDCS, which indicates a degree of Broca's area involvement in forming memory circuits for concrete words as well. A decrease in the accuracy of recall of word forms and their meanings, as well as in recognition, was observed for all stimulation groups and both types of semantics on Day 2. The results suggest that both anodal and cathodal tDCS of Broca's area improves immediate contextual learning of novel vocabulary, predominantly affecting abstract semantics.