A greater modulation of the visual and fronto-parietal networks for children in a post-media versus pre-media exposure group.

AIM: Media use in children has exploded in the past several decades, most recently fuelled by portable electronic devices. This study aims to explore differences in functional brain connectivity in children during a story-listening functional MRI (fMRI) task using data collected before (1998) and after (2013) the widespread adoption of media. METHODS: Cross-sectional data were collected from English-speaking 5- to 7-year-old children at Cincinnati Children's Hospital Medical Center, USA, of a functional MRI narrative comprehension task completed in 1998 (n = 22) or 2013 (n = 25). Imaging data were processed using a graph theory approach, focusing on executive functions, language and visual processing networks supporting reading. RESULTS: Group differences suggest more efficient processing in the fronto-parietal network in the pre-media group while listening to stories. A modulation of the visual and fronto-parietal networks for the post-media exposure group was found. CONCLUSION: Further studies are needed to assess effects over time in the more exposed group to discern a causal effect of portable devices on cognitive networks.

Maternal education as an environmental factor related to reading in children with reading difficulties: A functional magnetic resonance imaging study.

The expanded simple view of reading (SVR) model suggests that word decoding, language comprehension and executive functions are necessary for reading comprehension. Children with reading difficulties (RDs) often have deficits in critical components of reading established in the expanded SVR model and alterations in brain function of reading-related regions. Maternal education could provide children with advantageous educational opportunities or resources that support reading acquisition. The primary goal of this study was to examine the contributions of maternal education to the behavioural and neurobiological correlates of the expanded SVR model. Seventy-two 8- to 12-year-old children with RDs and typical readers (TRs) completed reading, behavioural and an functional magnetic resonance imaging stories-listening task to determine the functional connectivity of the receptive language network to the whole brain in association with maternal education. Higher maternal education was associated with better vocabulary in children with RDs and positive functional connectivity between the receptive language network and regions related to visual processing in children with RDs versus TRs. These data suggest that maternal education supports the ability to comprehend oral language and engagement of neural networks that support imagination/visualization in children with RDs.

The role of visual attention in dyslexia: Behavioral and neurobiological evidence.

Poor phonological processing has typically been considered the main cause of dyslexia. However, visuo-attentional processing abnormalities have been described as well. The goal of the present study was to determine the involvement of visual attention during fluent reading in children with dyslexia and typical readers. Here, 75 children (8-12 years old; 36 typical readers, 39 children with dyslexia) completed cognitive and reading assessments. Neuroimaging data were acquired while children performed a fluent reading task with (a) a condition where the text remained on the screen (Still) versus (b) a condition in which the letters were being deleted (Deleted). Cognitive assessment data analysis revealed that visual attention, executive functions, and phonological awareness significantly contributed to reading comprehension in both groups. A seed-to-voxel functional connectivity analysis was performed on the fluency functional magnetic resonance imaging task. Typical readers showed greater functional connectivity between the dorsal attention network and the left angular gyrus while performing the Still and Deleted reading tasks versus children with dyslexia. Higher connectivity values were associated with higher reading comprehension. The control group showed increased functional connectivity between the ventral attention network and the fronto-parietal network during the Deleted text condition (compared with the Still condition). Children with dyslexia did not display this pattern. The results suggest that the synchronized activity of executive, visual attention, and reading-related networks is a pattern of functional integration which children with dyslexia fail to achieve. The present evidence points toward a critical role of visual attention in dyslexia.

Cerebral blood flow is lower in youth with type 2 diabetes compared to obese controls: A pilot study.

AIM: The cerebral vasculature may be susceptible to the adverse effects of type 2 diabetes. In this pilot study, we compared cerebral blood flow (CBF) in youth with type 2 diabetes to obese, euglycemic controls, and explored the association between CBF and a non-invasive measure of atherosclerosis, carotid intima-medial thickness (IMT). METHODS: Global and regional CBF were compared between youth with type 2 diabetes (mean age 16.7 ± 2.0 years, n = 20) and age, race, and sex similar obese youth without diabetes (17.4 ± 1.9 years, n = 19) using arterial spin labeling magnetic resonance imaging. Mean CBF values were compared between groups. Voxel-wise results were evaluated for statistical significance (p < 0.05) after adjustment for multiple comparisons. Carotid IMT in the type 2 diabetes group was correlated with CBF. RESULTS: Compared to obese controls, the type 2 diabetes group had significantly lower global CBF (49.7 ± 7.2 vs. 63.8 ± 11.5 ml/gm/min, p < 0.001). Significantly lower CBF was observed in multiple brain regions for the type 2 diabetes group, while no regions with higher CBF were identified. In the type 2 diabetes group, carotid IMT was inversely correlated with CBF, both globally (r = -0.70, p = 0.002) and in regional clusters. CONCLUSIONS: In this pilot study, lower CBF was seen in youth with type 2 diabetes compared to youth with obesity and IMT was inversely correlated with CBF. Cerebrovascular impairment may be present in youth with type 2 diabetes. These findings could represent a mechanistic link to explain previously reported brain volume and neurocognitive differences.

Neuronal activation and performance changes in working memory induced by chronic sleep restriction in adolescents.

Most adolescents get less than the recommended 8-10 hr of sleep per night. Functional deficits from lack of sleep include disruption of working memory. Adult neuroimaging studies of sleep deprivation suggest diminished responses in task-related brain networks if performance degrades, but compensatory increased responses with maintained performance. This study utilized functional magnetic resonance imaging to examine compensatory and diminished brain responses in adolescents during working memory performance, comparing chronic sleep restriction and healthy sleep duration. Thirty-six healthy adolescents, 14-17 years old, experienced a 3-week protocol: (a) sleep phase stabilization; (b) sleep restriction (~6.5 hr nightly); and (c) healthy sleep duration (~9 hr nightly). After each sleep manipulation, we acquired functional magnetic resonance imaging with an NBack working memory task with four difficulty levels (0 to 3-back). NBack performance degraded with higher task difficulty, but without a detectable effect of sleep duration. ANOVA revealed main effects of both NBack difficulty and sleep in widespread brain networks. Planned contrasts showed that, compared with healthy sleep, sleep restriction resulted in greater medial prefrontal activation and weaker activation in the precuneus for the most difficult task condition. During sleep restriction, we found compensatory functional responses in brain regions that process sensory input and vigilance. However, adolescents also showed impaired performance and diminished brain responses during the hardest task level under a week of chronic sleep restriction. Chronic sleep restriction during adolescence is common. Understanding the impact of ongoing functional compensation and performance breakdown during this developmental period can have important implications for learning and educational strategies.

Longer Screen Vs. Reading Time is Related to Greater Functional Connections Between the Salience Network and Executive Functions Regions in Children with Reading Difficulties Vs. Typical Readers.

An adverse relationship between screen exposure time and brain functional/structural connectivity was reported in typically developing children, specifically related to neurobiological correlates of reading ability. As children with reading difficulties (RD) suffer from impairments in reading and executive functions (EF), we sought to determine the association between the ratio of screen time duration to reading time duration and functional connectivity of EF networks to the entire brain in children with RD compared to typical readers (TRs) using resting state data. Screen/reading time ratio was related to reduced reading and EF abilities. A larger screen/reading time ratio was correlated with increased functional connectivity between the salience network and frontal-EF regions in children with RD compared to TRs. We suggest that whereas greater screen/reading time ratio is related to excessive stimulation of the visual processing system in TRs, it may be related to decreased efficiency of the cognitive control system in RDs.

Youth-Onset Type 2 Diabetes and the Developing Brain.

PURPOSE OF REVIEW: This review describes the literature evaluating the potential adverse effects of youth-onset type 2 diabetes on the developing brain. A summary of recently published articles and the current state of knowledge are covered succinctly in this manuscript. RECENT FINDINGS: Current literature suggests both cognitive and brain structural differences are found in youth with type 2 diabetes. Studies have shown poorer scores in a number of neurocognitive domains, particularly in areas of executive functioning and memory. Additionally, imaging studies have found differences in brain gray matter volume, white matter volume, and microstructural integrity. These findings are largely consistent with the adult literature. Youth with type 2 diabetes demonstrate lower cognitive scores and structural brain differences. Although causality has not yet been established, these findings are important because these individuals are still undergoing neurodevelopmental maturation.

Cardioventilatory Control in Preterm-born Children and the Risk of Obstructive Sleep Apnea.

RATIONALE: The contribution of ventilatory control to the pathogenesis of obstructive sleep apnea (OSA) in preterm-born children is unknown. OBJECTIVES: To characterize phenotypes of ventilatory control that are associated with the presence of OSA in preterm-born children during early childhood. METHODS: Preterm- and term-born children without comorbid conditions were enrolled. They were categorized into an OSA group and a non-OSA group on the basis of polysomnography. MEASUREMENTS AND MAIN RESULTS: Loop gain, controller gain, and plant gain, reflecting ventilatory instability, chemoreceptor sensitivity, and blood gas response to a change in ventilation, respectively, were estimated from spontaneous sighs identified during polysomnography. Cardiorespiratory coupling, a measure of brainstem maturation, was estimated by measuring the interval between inspiration and the preceding electrocardiogram R-wave. Cluster analysis was performed to develop phenotypes based on controller gain, plant gain, cardiorespiratory coupling, and gestational age. The study included 92 children, 63 of whom were born preterm (41% OSA) and 29 of whom were born at term (48% OSA). Three phenotypes of ventilatory control were derived with risks for OSA being 8%, 47%, and 77% in clusters 1, 2, and 3, respectively. There was a stepwise decrease in controller gain and an increase in plant gain from clusters 1 to 3. Children in cluster 1 had significantly higher cardiorespiratory coupling and gestational age than clusters 2 and 3. No difference in loop gain was found between clusters. CONCLUSIONS: The risk for OSA could be stratified according to controller gain, plant gain, cardiorespiratory coupling, and gestational age. These findings could guide personalized care for children at risk for OSA.

Differential effect of reading training on functional connectivity in children with reading difficulties with and without ADHD comorbidity.

A comorbidity of attention deficit hyperactivity disorder (ADHD) with reading difficulties (RD) is common in children. However, children with ADHD+RD have a different reading and executive functions (EF) profile than children with RD alone. We compared the effect of an EF-based intervention on neural circuits related to EF in children with RD and those with ADHD+RD. Functional connectivity MRI data from a lexical decision task suggest that the RD-alone group showed greater improvement in EF and reading tests and greater functional connectivity between networks related to both higher-and lower-level visual processing and those related to ventral attention and dorsal attention, as well as semantic processing. Children with ADHD+RD showed greater connectivity between networks related to attention and dorsal attention and those related to visual processing and EF. Results are consistent with the Cognitive Subtype hypothesis and suggest that RD and ADHD+RD, although related behaviourally, are distinct disorders with regard to network response and connectivity during reading and after an EF-based intervention.

Resting-state functional connectivity of subcortical locomotor centers explains variance in walking capacity.

Walking capacity influences the quality of life and disability in normal aging and neurological disease, but the neural correlates remain unclear and subcortical locomotor regions identified in animals have been more challenging to assess in humans. Here we test whether resting-state functional MRI connectivity (rsFC) of midbrain and cerebellar locomotor regions (MLR and CLR) is associated with walking capacity among healthy adults. Using phenotypic and MRI data from the Nathan Kline Institute Rockland Sample (n =119, age 18-85), the association between walking capacity (6-min walk test distance) and rsFC was calculated from subcortical locomotor regions to 81 other gait-related regions of interest across the brain. Additional analyses assessed the independence and specificity of the results. Walking capacity was associated with higher rsFC between the MLR and superior frontal gyrus adjacent to the anterior cingulate cortex, higher rsFC between the MLR and paravermal cerebellum, and lower rsFC between the CLR and primary motor cortex foot area. These rsFC correlates were more strongly associated with walking capacity than phenotypic variables such as age, and together explained 25% of the variance in walking capacity. Results were specific to locomotor regions compared with the other brain regions. The rsFC of locomotor centers correlates with walking capacity among healthy adults. These locomotion-related biomarkers may prove useful in future work aimed at helping patients with reduced walking capacity.

Age-related changes in baroreflex sensitivity and cardiac autonomic tone in children mirrored by regional brain gray matter volume trajectories.

BackgroundThe baroreflex and central autonomic brain regions together control the cardiovascular system. Baroreflex sensitivity (BRS) decreases with age in adults. Age-related changes in brain regions for cardiovascular control in children are unknown. We studied age-related changes in BRS, cardiac autonomic tone, and gray matter volume (GMV) of brain regions associated with cardiovascular control.MethodsBeat-to-beat blood pressure and heart rate (HR) were recorded in 49 children (6-14 years old). Spontaneous BRS was calculated by the sequence method. Cardiac autonomic tone was measured by spectral analysis of HR variability. GMV was measured using voxel-based morphometryin 112 healthy children (5-18 years old).ResultsAge-related changes in BRS were significantly different in children <10 years and ≥10 years. Age-related changes in GMV in regions of interest (ROI) were also significantly different between children <10 and ≥10 years and between children <11 and ≥11 years. However, age-related changes in cardiac autonomic tone were progressive.ConclusionsSignificant changes in BRS trajectories between <10 and ≥10 years may be associated with similar age-related changes of GMV in brain ROI. This new knowledge will guide future studies examining whether childhood cardiovascular disruption manifests as deviated maturation trajectories of specific brain regions.

The Involvement of Speed-of-Processing in Story Listening in Preschool Children: A Functional and Structural Connectivity Study.

Story listening in children relies on brain regions supporting speech perception, auditory word recognition, syntax, semantics, and discourse abilities, along with the ability to attend and process information (part of executive functions). Speed-of-processing is an early-developed executive function. We used functional and structural magnetic resonance imaging (MRI) to demonstrate the relationship between story listening and speed-of-processing in preschool-age children. Eighteen participants performed story-listening tasks during MRI scans. Functional and structural connectivity analysis was performed using the speed-of-processing scores as regressors. Activation in the superior frontal gyrus during story listening positively correlated with speed-of-processing scores. This region was functionally connected with the superior temporal gyrus, insula, and hippocampus. Fractional anisotropy in the inferior frontooccipital fasciculus, which connects the superior frontal and temporal gyri, was positively correlated with speed-of-processing scores. Our results suggest that speed-of-processing skills in preschool-age children are reflected in functional activation and connectivity during story listening and may act as a biomarker for future academic abilities.

Brain morphometric changes associated with childhood-onset systemic lupus erythematosus and neurocognitive deficit.

OBJECTIVE: To use structural magnetic resonance imaging (MRI) to characterize changes in gray matter and white matter volumes between patients with childhood-onset systemic lupus erythematosus (SLE) and matched controls, between patients with childhood-onset SLE with and those without neurocognitive deficit, and in relation to disease duration and treatment with steroids. METHODS: Twenty-two patients with childhood-onset SLE and 19 healthy controls underwent high-resolution structural MRI. Probability density maps for gray matter and white matter were compared between groups. RESULTS: Neuropsychological testing confirmed the presence of neurocognitive deficit in 8 patients with childhood-onset SLE. Multiple brain regions had reduced gray matter volume in the patients with childhood- onset SLE with neurocognitive deficit versus controls or patients with childhood-onset SLE without neurocognitive deficit. Neither disease duration nor cumulative oral or intravenous steroid doses accounted for decreases in gray matter. White matter volume was also reduced in patients with childhood-onset SLE with neurocognitive deficit, and the reduction was positively associated with both disease duration and cumulative oral steroid dose. Conversely, higher cumulative intravenous steroid doses were associated with higher white matter volumes. CONCLUSION: Neurocognitive deficit in patients with childhood-onset SLE is associated with multifocal decreases in both gray and white matter volumes. Since only white matter volume changes are related to disease duration and cumulative oral steroid use, this may suggest that gray and white matter alterations relate to different underlying mechanisms. Further work is needed to understand the relationship between gray and white matter alterations in childhood-onset SLE, whether the underlying mechanisms relate to immunologic, vascular, or other causes, and whether the changes are reversible or preventable. Likewise, the protective properties of intravenous steroids in maintaining white matter volumes require confirmation in larger cohorts.

Altered neuronal response to visual food stimuli in adolescents undergoing chronic sleep restriction.

STUDY OBJECTIVES: Poor sleep in adolescents can increase the risk of obesity, possibly due to changes in dietary patterns. Prior neuroimaging evidence, mostly in adults, suggests that lacking sleep results in increased response to food cues in reward-processing brain regions. Needed is a clarification of the mechanisms by which food reward processing is altered by the kind of chronic sleep restriction (SR) typically experienced by adolescents. This study aimed to elucidate the impact of sleep duration on response to visual food stimuli in healthy adolescents using functional neuroimaging, hypothesizing increased reward processing response after SR compared to a well-rested condition. METHODS: Thirty-nine healthy adolescents, 14-17 years old, completed a 3-week protocol: (1) sleep phase stabilization; (2) SR (~6.5 h nightly); and (3) healthy sleep (HS) duration (~9 h nightly). Participants underwent functional MRI while performing a visual food paradigm. Contrasts of food versus nonfood responses were compared within-subject between conditions of SR and HS. RESULTS: Under SR, there was a greater response to food stimuli compared to HS in a voxel cluster including the left ventral tegmental area and substantia nigra. No change in food appeal rating due to the sleep manipulation was detected. CONCLUSIONS: Outcomes of this study suggest that SR, as commonly experienced by healthy adolescents, results in the elevated dopaminergic drive of the reward network that may augment motivation to seek food in the context of individual food appeal and inhibitory profiles. Countermeasures that reduce food salience could include promoting consistent HS habits.

Circadian blood pressure dysregulation in children with obstructive sleep apnea.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) adversely affects normal blood pressure (BP) and may disrupt circadian BP patterns. We sought to examine 24-hour circadian BP rhythms in children with OSA and healthy controls. METHODS: Children 5-14 years with OSA and healthy controls underwent 24-hour BP monitoring and actigraphy to quantify sleep. Shape invariant statistical models compared circadian BP patterns (e.g. times of BP peaks, time arrived at peak BP velocity [TAPV]) in the OSA and control groups. RESULTS: The analytic sample included 219 children (mild OSA: n = 52; moderate-to-severe OSA (MS-OSA): n = 50; controls: n = 117). In the morning, the MS-OSA group had earlier TAPV for DBP than controls (51 minutes, p < 0.001). TAPV in the evening was earlier for the MS-OSA group than controls (SBP: 95 minutes, p < 0.001; DBP: 28 minutes, p = 0.028). At mid-day, SBP and DBP velocity nadirs were earlier for the MS-OSA group than controls (SBP: 57 minutes, p < 0.001; DBP: 38 minutes, p < 0.01). The MS-OSA group reached most BP values significantly earlier than controls; the largest differences were 118 minutes (SBP) and 43 minutes (DBP) (p < 0.001). SBP and DBP were elevated in the MS-OSA group (hours 18-21 and 7--12, respectively, p < 0.01) compared to controls. The MS-OSA group was prone to "non-dipping" compared to controls (SBP: odds ratio [OR] = 2.16, 95% CI: 1.09, 4.29; DBP: OR = 3.45, 95% CI: 1.21, 10.23). CONCLUSIONS: Children with MS-OSA had changes in circadian BP patterns, namely earlier TAPV and BP peaks and nadirs than controls. Circadian disturbances in BP rhythms may be key to mapping the natural history of BP dysregulation in children with OSA.

BOLD fMRI in infants under sedation: Comparing the impact of pentobarbital and propofol on auditory and language activation.

PURPOSE: To elucidate differences in the disruption of language network function, as measured by blood oxygenation level-dependent (BOLD) contrast functional MRI (fMRI), attributable to two common sedative agents administered to infants under clinical imaging protocols. MATERIALS AND METHODS: The sedatives pentobarbital (Nembutal) and Propofol, administered clinically to infants at 1 year of age, were compared with respect to BOLD activation profiles in response to passive story-listening stimulation. An intermittent event-related imaging protocol was used with which the temporal evolution of language processing resulting from this stimulation was explored. RESULTS: Propofol and Nembutal were found to have distinct and complementary responses to story-listening. Propofol exhibited more activation in higher processing networks with increasing response toward the end of narrative stimulus. Nembutal, in contrast, had much more robust activation of primary and secondary sensory cortices but a decreasing response over time in fronto-parietal default-mode regions. This may suggest a breakdown of top-down feedback for Propofol versus the lack of bottom-up feed-forward processing for Nembutal. CONCLUSION: Two popular sedative agents for use in children for clinical fMRI were found to induce distinct alteration of activation patterns from a language stimulus. This has ramifications for clinical fMRI of sedated infants and encourages further study to build a framework for more confident interpretation.

Reduced default mode network connectivity in treatment-resistant idiopathic generalized epilepsy.

PURPOSE: Idiopathic generalized epilepsy (IGE) resistant to treatment is common, but its neuronal correlates are not entirely understood. Therefore, the aim of this study was to examine resting-state default mode network (DMN) functional connectivity in patients with treatment-resistant IGE. METHODS: Treatment resistance was defined as continuing seizures despite an adequate dose of valproic acid (valproate, VPA). Data from 60 epilepsy patients and 38 healthy controls who underwent simultaneous electroencephalography (EEG) and resting-state functional magnetic resonance imaging (fMRI) were included (EEG/fMRI). Independent component analysis (ICA) and dual regression were used to quantify DMN connectivity. Confirmatory analysis using seed-based voxel correlation was performed. KEY FINDINGS: There was a significant reduction of DMN connectivity in patients with treatment-resistant epilepsy when compared to patients who were treatment responsive and healthy controls. Connectivity was negatively correlated with duration of epilepsy. SIGNIFICANCE: Our findings in this large sample of patients with IGE indicate the presence of reduced DMN connectivity in IGE and show that connectivity is further reduced in treatment-resistant epilepsy. DMN connectivity may be useful as a biomarker for treatment resistance.

[Formula: see text] Higher access to screens is related to decreased functional connectivity between neural networks associated with basic attention skills and cognitive control in children.

Screen-based media has become a prevailing part of children's lives. Different technologies provide limitless access to a wide range of content. This accessibility has immensely increased screen exposure among children, showing that this exposure is associated with decreased cognitive abilities. This study was designed to evaluate how the neurobiological correlates for different sub-components of screen exposure, such as level of access, content, and frequency, are related to different cognitive abilities. Resting-state functional MRI data were collected in 29 native English-speaking children (8-12 years old), in addition to cognitive-behavioral measures. Functional connectivity measures within and between several networks related to cognitive control and attention were calculated [fronto-parietal (FP), cingulo-opercular (CO), dorsal attention (DAN), ventral attention (VAN), salience, default mode (DMN), cerebellar networks]. Sub-components of screen exposure were measured using the Screen-Q questionnaire. Higher access to screens was related to lower functional connectivity between neural networks associated with basic attention skills and cognitive control (i.e., DAN and salience). In addition, higher levels of parent-child interaction during screen exposure were related to increased functional connectivity between networks related to cognitive control and learning (i.e., CO and cerebellar). These findings suggest that screen exposure may reduce the engagement of basic attention and modulation of cognitive control networks and that higher levels of parent-child interaction engage cognitive control networks. An enhanced understanding of these processes can provide an important scientific basis for future educational and medical approaches regarding screen exposure.

Mapping the human corticoreticular pathway with multimodal delineation of the gigantocellular reticular nucleus and high-resolution diffusion tractography.

The corticoreticular pathway (CRP) is a major motor tract that transmits cortical input to the reticular formation motor nuclei and may be an important mediator of motor recovery after central nervous system damage. However, its cortical origins, trajectory and laterality are incompletely understood in humans. This study aimed to map the human CRP and generate an average CRP template in standard MRI space. Following recently established guidelines, we manually delineated the primary reticular formation motor nucleus (gigantocellular reticular nucleus [GRN]) using several group-mean MRI contrasts from the Human Connectome Project (HCP). CRP tractography was then performed with HCP diffusion-weighted MRI data (N = 1065) by selecting diffusion streamlines that reached both the cortex and GRN. Corticospinal tract (CST) tractography was also performed for comparison. Results suggest that the human CRP has widespread origins, which overlap with the CST across most of the motor cortex and include additional exclusive inputs from the medial and anterior prefrontal cortices. The estimated CRP projected through the anterior and posterior limbs of the internal capsule before partially decussating in the midbrain tegmentum and converging bilaterally on the pontomedullary reticular formation. Thus, the CRP trajectory appears to partially overlap the CST, while being more distributed and anteromedial to the CST in the cerebrum before moving posterior to the CST in the brainstem. These findings have important implications for neurophysiologic testing, cortical stimulation and movement recovery after brain lesions. We expect that our GRN and tract maps will also facilitate future CRP research.

Excitatory repetitive transcranial magnetic stimulation induces improvements in chronic post-stroke aphasia.

BACKGROUND: Aphasia affects 1/3 of stroke patients with improvements noted only in some of them. The goal of this exploratory study was to provide preliminary evidence regarding safety and efficacy of fMRI-guided excitatory repetitive transcranial magnetic stimulation (rTMS) applied to the residual left-hemispheric Broca's area for chronic aphasia treatment. MATERIAL/METHODS: We enrolled 8 patients with moderate or severe aphasia >1 year after LMCA stroke. Linguistic battery was administered pre-/post-rTMS; a semantic decision/tone decision (SDTD) fMRI task was used to localize left-hemispheric Broca's area. RTMS protocol consisted of 10 daily treatments of 200 seconds each using an excitatory stimulation protocol called intermittent theta burst stimulation (iTBS). Coil placement was targeted individually to the left Broca's. RESULTS: 6/8 patients showed significant pre-/post-rTMS improvements in semantic fluency (p=0.028); they were able to generate more appropriate words when prompted with a semantic category. Pre-/post-rTMS fMRI maps showed increases in left fronto-temporo-parietal language networks with a significant left-hemispheric shift in the left frontal (p=0.025), left temporo-parietal (p=0.038) regions and global language LI (p=0.018). Patients tended to report subjective improvement on Communicative Activities Log (mini-CAL; p=0.075). None of the subjects reported ill effects of rTMS. CONCLUSIONS: FMRI-guided, excitatory rTMS applied to the affected Broca's area improved language skills in patients with chronic post-stroke aphasia; these improvements correlated with increased language lateralization to the left hemisphere. This rTMS protocol appears to be safe and should be further tested in blinded studies assessing its short- and long-term safety/efficacy for post-stroke aphasia rehabilitation.