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Background: Growing health care challenges resulting from a rapidly expanding aging population necessitate examining effective rehabilitation techniques that mitigate age-related comorbidity and improve quality of life. To date, exercise is one of a few proven interventions known to attenuate age-related declines in cognitive and sensorimotor functions critical to sustained independence., Objective: This work aims to implement a multimodal imaging approach to better understand the mechanistic underpinnings of the beneficial exercise-induced adaptations to sedentary older adults' brains and behaviors. Due to the complex cerebral and vascular dynamics that encompass neuroplastic change with aging and exercise, we propose an imaging protocol that will model exercise-induced changes to cerebral perfusion, cerebral vascular reactivity (CVR), and cognitive and sensorimotor task-dependent functional magnetic resonance imaging (fMRI) after prescribed exercise., Methods: Sedentary older adults (aged 65-80 years) were randomly assigned to either a 12-week aerobic-based interval-based cycling intervention or a 12-week balance and stretching intervention. Assessments of cardiovascular fitness used the YMCA submaximal VO 2 test, basal cerebral perfusion using arterial spin labeling (ASL), CVR using hypercapnic fMRI, and cortical activation using fMRI during verbal fluency and motor tapping tasks. A battery of cognitive-executive and motor function tasks outside the scanning environment will be performed before and after the interventions., Results: Our studies and others show that improved cardiovascular fitness in older adults results in improved outcomes related to physical and cognitive health as well as quality of life. A consistent but unexplained finding in many of these studies is a change in cortical activation patterns during task-based fMRI, which corresponds with improved task performance (cognitive-executive and motor). We hypothesize that the 12-week aerobic exercise intervention will increase basal perfusion and improve CVR through a greater magnitude of reactivity in brain areas susceptible to neural and vascular decline (inferior frontal and motor cortices) in previously sedentary older adults. To differentiate between neural and vascular adaptations in these regions, we will map changes in basal perfusion and CVR over the inferior frontal and the motor cortices-regions we have previously shown to be beneficially altered during fMRI BOLD (blood oxygen level dependent), such as verbal fluency and motor tapping, through improved cardiovascular fitness., Conclusions: Exercise is one of the most impactful interventions for improving physical and cognitive health in aging. This study aims to better understand the mechanistic underpinnings of improved health and function of the cerebrovascular system. If our hypothesis of improved perfusion and cerebrovascular reactivity following a 12-week aerobic exercise intervention is supported, it would add critically important insights into the potential of exercise to improve brain health in aging and could inform exercise prescription for older adults at risk for neurodegenerative disease brought on by cerebrovascular dysfunction., Trial Registration: ClinicalTrials.gov NCT05932069; https://clinicaltrials.gov/study/NCT05932069., International Registered Report Identifier (irrid): DERR1-10.2196/58316., (©Medina Oneyi Bello, Kevin Michael Mammino, Mark Anthony Vernon, Daniel G Wakeman, Chanse Aerius Denmon, Lisa Crystal Krishnamurthy, Venkatagiri Krishnamurthy, Keith Matthew McGregor, Thomas Samuel Novak, Joe Robert Nocera. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 26.09.2024.)

The global growth of an aging population is expected to coincide with an increase in aging-related pathologies, including those related to brain health. Thus, the potential for accelerated cognitive health declines due to adverse aging is expected to have profound social and economic implications. However, the progression to pathological conditions is not an inevitable part of aging. In fact, engaging in activities that improve cardiovascular fitness appears to be a means that offers the benefits of maintaining and/or improving cognitive health in older age. However, to date, the underlying mechanisms responsible for improved central nervous system health and function with exercise are not yet fully elucidated. Consequently, there is considerable interest in studies aimed at understanding the neurophysiological benefits of exercise on aging. One such area of study suggests that the improvements in brain health via exercise are, in part, driven by the recovery of inhibitory processes related to the neurotransmitter gamma-aminobutyric acid (GABA). In the present review, we highlight the opposing effects of aging and exercise on cortical inhibition and the GABAergic system's functional integrity. We highlight these changes in GABA function by reviewing work with in vivo measurements: transcranial magnetic stimulation (TMS) and magnetic resonance spectroscopy (MRS). We also highlight recent and significant technological and methodological advances in assessing the GABAergic system's integrity with TMS and MRS. We then discuss potential future research directions to inform mechanistic GABA study targeted to improve health and function in aging. We conclude by highlighting the significance of understanding the effects of exercise and aging, its influence on GABA levels, and why a better understanding is crucial to allow for more targeted and effective interventions aimed to ultimately improve age-related decline in aging., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Changes in regional levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) may indicate the potential for favorable responses to the treatment of stroke affecting the upper extremity. By selectively altering GABA levels during training, we may induce long-term potentiation and adjust excitatory/inhibitory balance (E/I balance). However, the impact of this alteration may be limited by neural damage or aging. Aerobic exercise has been shown to increase GABA levels in the sensorimotor cortex and improve motor learning by widening the dynamic range of E/I balance. The cross-sectional project, Effects of Acute Exercise on Functional Magnetic Resonance Spectroscopy Measures of GABA in Aging and Chronic Stroke (EASE), is designed to assess the functional relevance of changes in GABA concentration within the sensorimotor cortex before and after an acute aerobic exercise session., Methods/design: EASE will enroll 30 participants comprised of healthy younger adults (18-35 years; n = 10), older adults (60+ years; n = 10), and persons with chronic stroke (n = 10) affecting distal upper extremity function. We will use resting magnetic resonance spectroscopy to measure all participants' GABA levels at rest before and after aerobic exercise. In addition, we will employ functional magnetic resonance spectroscopy using motor skill acquisition and recall tasks in healthy adults. We hypothesize that acute aerobic exercise will increase resting sensorimotor GABA concentration and that higher GABA resting levels will predict better motor learning performance on measures taken both inside and outside the magnet. We also hypothesize that a higher dynamic range of GABA during task-based spectroscopy in healthy adults will predict better motor skill acquisition and recall., Discussion: The EASE project will evaluate the effect of acute exercise on GABA levels as a biomarker of upper extremity motor skill learning with two populations (aging adults and those with chronic stroke). We predict that acute exercise, higher sensorimotor GABA levels, and broader dynamic range will be related to better motor skill acquisition., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Subthreshold depressive symptoms are highly prevalent among older adults and are associated with numerous health risks including cognitive decline and decreased physical health. One brain region central to neuroanatomical models of depressive disorders is the anterior cingulate cortex (ACC). The rostral portion of the ACC-comprised of the pregenual ACC and subgenual ACC-is implicated in emotion control and reward processing. The goal of the current study was to examine how functional connectivity in subregions of the rostral ACC relate to depressive symptoms, measured by the Beck Depression Inventory-Second Edition, in an ethnically diverse sample of 28 community-dwelling older adults. Based on meta -analyses of previous studies in primarily young adults with clinical depression, we hypothesized that greater depressive symptoms would be associated with primarily increased resting-state functional connectivity from both the subgenual ACC and pregenual ACC to default mode network regions and the dorsolateral PFC. We instead found that higher depressive symptoms were associated with lower functional connectivity of the ACC to the dorsolateral PFC and regions within the default mode network, including from the subgenual ACC to the dorsolateral PFC and anterior cingulate and from the pregenual ACC to the middle cingulate gyrus. This preliminary study highlights brain alterations at subthreshold levels of depressive symptoms in older adults, which could serve as targets for interventions., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Cardiovascular disease (CVD) in the United States disproportionally affects people who are homeless. This disparity is a critical concern that needs to be addressed to improve the health of individuals who are homeless. The connections between a history of homelessness, i.e., its duration and frequency, and CVD risk are not well understood. The present study sought to investigate how a history of homelessness is correlated with CVD risk factors in a sample of homeless persons in the Deep South. This study recruited participants who were homeless from two local adult homeless shelters in Birmingham, AL. Participants ( n = 61) underwent interviews, physical measurements, and a capillary blood draw. Their mean age was 47 years, and 82% were men. Results showed the duration of homelessness was positively associated with several CVD risk factors (diabetes mellitus, total cholesterol, and low-density lipoprotein). However, there was no significant association between frequency of homelessness and any CVD risk factors. To get the more accurate estimate of CVD risk in this population, future research should incorporate additional risk factors related to homelessness and seek to develop a robust strategy to collect an accurate history of homelessness.

Having a healthy sleep pattern plays a vital role in one's overall health. Sleep in the elderly is characterized by decreased slow-wave sleep and an increase of REM sleep. Furthermore, quantitative electroencephalographic (qEEG) studies have shown an age-related attenuation of total EEG power in sleep. However, exercise has been shown to improve sleep across all age groups. In this study, we used the Sleep Profiler™ EEG Sleep Monitor to observe EEG changes occurring during sleep following an aerobic exercise intervention. This study was done on older adults ( N = 18, with only five subjects containing both pre- and post-data of sufficient quality for analysis) with an age range 60-85 years. The aerobics regimen was performed three times weekly for 12-weeks commencing with 20-min sessions. The time of each session progressed by 1-2 min/session as needed to a maximum time of 45 min per session. The macro-architecture (sleep stages) and microarchitecture (EEG) results were analyzed using MATLAB. For the microarchitecture, our results showed more deep sleep following the aerobic exercise regimen. Furthermore, for the microarchitecture, out results shows an increase in total EEG power post-exercise in both light (N1 and L1) and deep sleep (N2 and N3). These preliminary changes in sleep the microarchitecture suggest that non-pharmacologic methods might mitigate age-related EEG changes with potential implications for neurocognitive health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cassim, McGregor, Nocera, García, Sinon, Kreuzer and García.)

Older adults typically experience a decline in cognitive function, but improvements in physical health and lifestyle can be neuroprotective across the human lifespan. The primary objective of this study is to advance our basic understanding of how cardiorespiratory fitness and neurophysiological attributes relate to cognitive decline. While cerebral blood flow (CBF) is critical for the supply of nutrients to the tissue, the brain's major neurotransmitters (i.e., gamma-aminobutyric acid, GABA, and glutamate-glutamine complex, Glx) are closely linked to oxidative metabolism. Within the context of flow-metabolism coupling, the critical question is how these neurophysiological parameters interplay, resulting in cognitive decline. Further, how cardiorespiratory fitness may impact aging neurophysiology and cognition is not well understood. To address these questions, we recruited 10 younger and 12 older cognitively intact participants to collect GABA and Glx using magnetic resonance spectroscopy (MRS), CBF using pseudo-continuous arterial spin labeling Magnetic Resonance Imaging (MRI), VO2max as a measure of cardiorespiratory fitness using the YMCA submax test, and cognitive and motor-cognitive measures using a battery of behavioral assessments. We observed expected differences in GABA+, Glx, and CBF between younger and older participants in pre-SMA, a frontal domain-general region. When GABA+ and Glx were related to CBF via multiple linear regression, Glx was identified as the main contributor to the model. For higher-order executive function (i.e., inhibition versus color naming), GABA*Glx*CBF interaction was critical in younger, while only Glx was involved in older participants. For unimanual motor dexterity, GABA*Glx interaction was the common denominator across both groups, but younger participants' brain also engages CBF. In terms of selective motor inhibition, CBF from younger participants was the only major neurophysiological factor. In terms of fitness, cardiorespiratory fitness was significantly related to GABA, Glx, and motor performance when combining cohorts, but no group-specific relationships were observed. Taken together, our results indicate that Glx and CBF coupling decreases with aging, perhaps due to altered glial oxidative metabolism. Our data suggest that GABA, Glx, and CBF are engaged and weighted differently for different cognitive measures sensitized to aging, and higher fitness allows for a more efficient metabolic shift that facilitates improved performance on cognitive-motor tasks., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Krishnamurthy, Paredes Spir, Mammino, Nocera, McGregor, Crosson and Krishnamurthy.)

1 Hz repetitive transcranial magnetic stimulation (rTMS) was used to decrease excitability of right pars triangularis (R PTr) to determine whether increased R PTr activity during picture naming in older adults hampers word finding. We hypothesized that decreasing R PTr excitability would reduce interference with word finding, facilitating faster picture naming. 15 older and 16 younger adults received two rTMS sessions. In one, speech onset latencies for picture naming were measured after both sham and active R PTr stimulation. In the other session, sham and active stimulation of a control region, right pars opercularis (R POp), were administered before picture naming. Order of active vs. sham stimulation within session was counterbalanced. Younger adults showed no significant effects of stimulation. In older adults, a trend indicated that participants named pictures more quickly after active than sham R PTr stimulation. However, older adults also showed longer responses during R PTr than R POp sham stimulation. When order of active vs. sham stimulation was modeled, older adults receiving active stimulation first had significantly faster responding after active than sham R PTr stimulation and significantly faster responding after R PTr than R POp stimulation, consistent with experimental hypotheses. However, older adults receiving sham stimulation first showed no significant differences between conditions. Findings are best understood, based on previous studies, when the interaction between the excitatory effects of picture naming and the inhibitory effects of 1 Hz rTMS on R PTr is considered. Implications regarding right frontal activity in older adults and for design of future experiments are discussed., Competing Interests: Competing Interests: The authors have declared that competing interests exist. Charles M. Epstein received royalties from Neuronetics, Inc., which manufactures transcranial magnetic stimulators. No Neuronetics equipment was used in this study., (© 2021 Massachusetts Institute of Technology.)

Stroke-related tissue damage within lesioned brain areas is topologically non-uniform and has underlying tissue composition changes that may have important implications for rehabilitation. However, we know of no uniformly accepted, objective non-invasive methodology to identify pericavitational areas within the chronic stroke lesion. To fill this gap, we propose a novel magnetic resonance imaging (MRI) methodology to objectively quantify the lesion core and surrounding pericavitational perimeter, which we call tissue integrity gradation via T2w T1w ratio (TIGR). TIGR uses standard T1-weighted (T1w) and T2-weighted (T2w) anatomical images routinely collected in the clinical setting. TIGR maps are analyzed with relation to subject-specific gray matter and cerebrospinal fluid thresholds and binned to create a false colormap of tissue damage within the stroke lesion, and these are further categorized into low-, medium-, and high-damage areas. We validate TIGR by showing that the cerebral blood flow within the lesion reduces with greater tissue damage ( p = 0.005). We further show that a significant task activity can be detected in pericavitational areas and that medium-damage areas contain a significantly lower magnitude of hemodynamic response function than the adjacent damaged areas ( p < 0.0001). We also demonstrate the feasibility of using TIGR maps to extract multivariate brain-behavior relationships ( p < 0.05) and show general agreement in location compared to binary lesion, T1w-only, and T2w-only maps but that the extent of brain behavior maps may depend on signal sensitivity as denoted by the sparseness coefficient ( p < 0.0001). Finally, we show the feasibility of quantifying TIGR in early and late subacute stroke phases, where higher-damage areas were smaller in size ( p = 0.002) and that lesioned voxels transition from lower to higher damage with increasing time post-stroke ( p = 0.004). We conclude that TIGR is able to (1) identify tissue damage gradient within the stroke lesion across different post-stroke timepoints and (2) more objectively delineate lesion core from pericavitational areas wherein such areas demonstrate reasonable and expected physiological and functional impairments. Importantly, because T1w and T2w scans are routinely collected in the clinic, TIGR maps can be readily incorporated in clinical settings without additional imaging costs or patient burden to facilitate decision processes related to rehabilitation planning., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Krishnamurthy, Krishnamurthy, Rodriguez, McGregor, Glassman, Champion, Rocha, Harnish, Belagaje, Kundu and Crosson.)

Although there is a rapidly growing literature on dynamic connectivity methods, the primary focus has been on separate network estimation for each individual, which fails to leverage common patterns of information. We propose novel graph-theoretic approaches for estimating a population of dynamic networks that are able to borrow information across multiple heterogeneous samples in an unsupervised manner and guided by covariate information. Specifically, we develop a Bayesian product mixture model that imposes independent mixture priors at each time scan and uses covariates to model the mixture weights, which results in time-varying clusters of samples designed to pool information. The computation is carried out using an efficient Expectation-Maximization algorithm. Extensive simulation studies illustrate sharp gains in recovering the true dynamic network over existing dynamic connectivity methods. An analysis of fMRI block task data with behavioral interventions reveal sub-groups of individuals having similar dynamic connectivity, and identifies intervention-related dynamic network changes that are concentrated in biologically interpretable brain regions. In contrast, existing dynamic connectivity approaches are able to detect minimal or no changes in connectivity over time, which seems biologically unrealistic and highlights the challenges resulting from the inability to systematically borrow information across samples., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Recent stroke studies have shown that the ipsi-lesional thalamus longitudinally and significantly decreases after stroke in the acute and subacute stages. However, additional considerations in the chronic stages of stroke require exploration including time since stroke, gender, intracortical volume, aging, and lesion volume to better characterize thalamic differences after cortical infarct. This cross-sectional retrospective study quantified the ipsilesional and contralesional thalamus volume from 69 chronic stroke subjects' anatomical MRI data (age 35-92) and related the thalamus volume to time since stroke, gender, intracortical volume, age, and lesion volume. The ipsi-lesional thalamus volume was significantly smaller than the contra-lesional thalamus volume (t(68) = 13.89, p < 0.0001). In the ipsilesional thalamus, significant effect for intracortical volume (t(68) = 2.76, p = 0.008), age (t(68) = 2.47, p = 0.02), lesion volume (t(68) = - 3.54, p = 0.0008), and age*time since stroke (t(68) = 2.46, p = 0.02) were identified. In the contralesional thalamus, significant effect for intracortical volume (t(68) = 3.2, p = 0.002) and age (t = - 3.17, p = 0.002) were identified. Clinical factors age and intracortical volume influence both ipsi- and contralesional thalamus volume and lesion volume influences the ipsilesional thalamus. Due to the cross-sectional nature of this study, additional research is warranted to understand differences in the neural circuitry and subsequent influence on volumetrics after stroke.

Blood Oxygen Level Dependent (BOLD) functional MRI is a complex neurovascular signal whose magnitude depends on baseline physiological factors such as cerebral blood flow (CBF). Because baseline CBF varies across the brain and is altered with aging, the interpretation of stand-alone aging-related BOLD changes can be misleading. The primary objective of this study was to develop a methodology that combines task fMRI and arterial spin labeling (ASL) techniques to sensitize task-induced BOLD activity by covarying out the baseline physiology (i.e., CBF) in an aging model. We recruited 11 younger and 13 older healthy participants who underwent ASL and an overt language fMRI task (semantic category member generation). We measured in-scanner language performance to investigate the effect of BOLD sensitization on BOLD-behavior relationships. The results demonstrate that our correction approach is effective at enhancing the specificity and sensitivity of the BOLD signal in both groups. In addition, the correction strengthens the statistical association between task BOLD activity and behavioral performance. Although CBF has inherent age dependence, our results show that retaining the age factor within CBF aides in greater sensitization of task fMRI signals. From a cognitive standpoint, compared to young adults, the older participants showed a delayed domain-general language-related task activity possibly due to compromised vessel compliance. Further, assessment of functional evolution of corrected BOLD activity revealed biphasic BOLD dynamics in both groups where BOLD deactivation may reflect greater semantic demand or increased premium on domain general executive functioning in response to task difficulty. Although it was promising to note that the predictability of behavior using the proposed methodology outperforms other methodologies (i.e., no correction and normalization by division), and provides moderate stability and adequate power, further work with a larger cohort and other task designs is necessary to improve the stability of predicting associated behavior. In summary, we recommend correction of task fMRI signals by covarying out baseline CBF especially when comparing groups with different neurovascular properties. Given that ASL and BOLD fMRI are well established and widely employed techniques, our proposed multi-modal methodology can be readily implemented into data processing pipelines to obtain more accurate BOLD activation maps., (Copyright © 2020 Krishnamurthy, Krishnamurthy, Drucker, Kundu, Ji, Hortman, Roberts, Mammino, Tran, Gopinath, McGregor, Rodriguez, Qiu, Crosson and Nocera.)

We have previously shown that aerobic exercise improves measures of verbal fluency in older adults, and such an improvement is correlated with improved cardiovascular reserve (i.e., estimates of VO 2 ). Due to increasing popularity in computer-based cognitive training, we explored whether the addition of cognitive training to aerobic exercise would further enhance the beneficial cognitive impact of exercise. Therefore, this study sought to test the hypothesis that a cognitive training regimen alone would directly improve executive function and that this effect would be potentiated with the addition of aerobic exercise. The interventions lasted 12 weeks, and cognitive assessments were taken immediately prior to and after the interventions. We found that only the groups employing aerobic exercise showed improvements in verbal fluency (semantic and letter) and cardiovascular fitness with no other executive functions being significantly impacted. Cognitive training alone was associated with decreased verbal fluency. These data replicate previous findings which indicate that aerobic exercise may have a remedial or mitigating effect of cognitive decline. In addition, they provide evidence that the addition of concurrent cognitive training to an aerobic exercise program does not provide synergistic improvement in executive functions., Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background: Externally guided (EG) and internally guided (IG) movements are postulated to recruit two parallel neural circuits, in which motor cortical neurons interact with either the cerebellum or striatum via distinct thalamic nuclei. Research suggests EG movements rely more heavily on the cerebello-thalamo-cortical circuit, whereas IG movements rely more on the striato-pallido-thalamo-cortical circuit (1). Because Parkinson's (PD) involves striatal dysfunction, individuals with PD have difficulty generating IG movements (2). Objectives: Determine whether individuals with PD would employ a compensatory mechanism favoring the cerebellum over the striatum during IG lower limb movements. Methods: 22 older adults with mild-moderate PD, who had abstained at least 12 h from anti-PD medications, and 19 age-matched controls performed EG and IG rhythmic foot-tapping during functional magnetic resonance imaging. Participants with PD tapped with their right (more affected) foot. External guidance was paced by a researcher tapping participants' ipsilateral 3rd metacarpal in a pattern with 0.5 to 1 s intervals, while internal guidance was based on pre-scan training in the same pattern. BOLD activation was compared between tasks (EG vs. IG) and groups (PD vs. control). Results: Both groups recruited the putamen and cerebellar regions. The PD group demonstrated less activation in the striatum and motor cortex than controls. A task (EG vs. IG) by group (PD vs. control) interaction was observed in the cerebellum with increased activation for the IG condition in the PD group. Conclusions: These findings support the hypothesized compensatory shift in which the dysfunctional striatum is assisted by the less affected cerebellum to accomplish IG lower limb movement in individuals with mild-moderate PD. These findings are of relevance for temporal gait dysfunction and freezing of gait problems frequently noted in many people with PD and may have implications for future therapeutic application.

Background: Little is known about the dietary intake of these nutrients in stroke survivors, who often experience greater difficulties with physical functioning due to cognitive impairment., Objectives: To explore whether dietary intake and physical function differ between those with and without self-report cognitive impairment., Methods: The present study analyzes data from the 2011-2012 and 2013-2014 National Health and Nutrition Examination Survey. Individuals were included if they self-reported a stroke and had data regarding cognitive impairment (self-reported "periods of confusion or memory problems") and dietary intake from 24-hr recalls (N = 360). A subset had handgrip strength (N = 330) and questionnaire data regarding the presence of 19 different functional limitations (N = 187)., Results: Of the 360 stroke survivor participants (66 ± 1 years, 53% female, mean±SEM), 48% reported cognitive impairment. Dietary intake of polyunsaturated fatty acids was 19% lower (p = 0.01), with a trend for 13% lower vitamin B6 intake (p = 0.07) in those with cognitive impairment compared to those who did not. Those with cognitive impairment had lower handgrip strength and reported twice as many functional limitations (p's<0.01)., Conclusion: A lower intake of polyunsaturated fat and vitamin B6 may be associated with cognitive function, ultimately affecting physical functioning, post-stroke. It is possible that differing stroke severity and difficulty recalling dietary habits could have affected the present findings. Therefore, further research is needed to determine if interventions designed to modify polyunsaturated fat and vitamin B6 intakes are able to influence cognitive and physical function in stroke survivors with varying degrees of functional and cognitive deficits.

Objective: We have previously demonstrated that aerobic exercise improves upper extremity motor function concurrent with changes in motor cortical activity using task-based functional magnetic resonance imaging (fMRI). However, it is currently unknown how a 12-week aerobic exercise intervention affects resting-state functional connectivity (rsFC) in motor networks. Previous work has shown that over a 6-month or 1-year exercise intervention, older individuals show increased resting state connectivity of the default mode network and the sensorimotor network (Voss et al., 2010b; Flodin et al., 2017). However, the effects of shorter-term 12-week exercise interventions on functional connectivity have received less attention. Method: Thirty-seven sedentary right-handed older adults were randomized to either a 12-week aerobic, spin cycling exercise group or a 12-week balance-toning exercise group. Resting state functional magnetic resonance images were acquired in sessions PRE/POST interventions. We applied seed-based correlation analysis to left and right primary motor cortices (L-M1 and R-M1) and anterior default mode network (aDMN) to test changes in rsFC between groups after the intervention. In addition, we performed a regression analysis predicting connectivity changes PRE/POST intervention across all participants as a function of time spent in aerobic training zone regardless of group assignment. Results: Seeding from L-M1, we found that participants in the cycling group had a greater PRE/POST change in rsFC in aDMN as compared to the balance group. When accounting for time in aerobic HR zone, we found increased heart rate workload was positively associated with increased change of rsFC between motor networks and aDMN. Interestingly, L-M1 to aDMN connectivity changes were also related to motor behavior changes in both groups. Respective of M1 laterality, comparisons of all participants from PRE to POST showed a reduction in the extent of bilateral M1 connectivity after the interventions with increased connectivity in dominant M1. Conclusion: A 12-week physical activity intervention can change rsFC between primary motor regions and default mode network areas, which may be associated with improved motor performance. The decrease in connectivity between L-M1 and R-M1 post-intervention may represent a functional consolidation to the dominant M1. Topic Areas: Neuroimaging, Aging.

Functional connectivity using task-residual data capitalizes on remaining variance after mean task-related signal is removed from a time series. The degree of network specificity in language and attention domains featured by task-residual and resting-state data types were compared. Functional connectivity based on task-residual data evidenced stronger laterality of the language and attention connections and thus greater network specificity compared to resting-state functional connectivity of the same connections. Covariance between network nodes of task-residuals may thus reflect the degree to which two regions are coordinated in their specific activity, rather than a general shared co-activation. Task-residual functional connectivity provides complementary data to that of resting-state, emphasizing network relationships during task engagement., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Data from previous cross-sectional studies have shown that an increased level of physical fitness is associated with improved motor dexterity across the lifespan. In addition, physical fitness is positively associated with increased laterality of cortical function during unimanual tasks; indicating that sedentary aging is associated with a loss of interhemispheric inhibition affecting motor performance. The present study employed exercise interventions in previously sedentary older adults to compare motor dexterity and measure of interhemispheric inhibition using transcranial magnetic stimulation (TMS) after the interventions. Methods: Twenty-one community-dwelling, reportedly sedentary older adults were recruited, randomized and enrolled to a 12-week aerobic exercise group or a 12-week non-aerobic exercise balance condition. The aerobic condition was comprised of an interval-based cycling "spin" activity, while the non-aerobic "balance" exercise condition involved balance and stretching activities. Participants completed upper extremity dexterity batteries and estimates of VO 2 max in addition to undergoing single (ipsilateral silent period-iSP) and paired-pulse interhemispheric inhibition (ppIHI) in separate assessment sessions before and after study interventions. After each intervention during which heart rate was continuously recorded to measure exertion level (load), participants crossed over into the alternate arm of the study for an additional 12-week intervention period in an AB/BA design with no washout period. Results: After the interventions, regardless of intervention order, participants in the aerobic spin condition showed higher estimated VO 2 max levels after the 12-week intervention as compared to estimated VO 2 max in the non-aerobic balance intervention. After controlling for carryover effects due to the study design, participants in the spin condition showed longer iSP duration than the balance condition. Heart rate load was more strongly correlated with silent period duration after the Spin condition than estimated VO 2 . Conclusions: Aging-related changes in cortical inhibition may be influenced by 12-week physical activity interventions when assessed with the iSP. Although inhibitory signaling is mediates both ppIHI and iSP measures each TMS modality likely employs distinct inhibitory networks, potentially differentially affected by aging. Changes in inhibitory function after physical activity interventions may be associated with improved dexterity and motor control at least as evidence from this feasibility study show.

Objective: The last 25 years have seen profound changes in neurocognitive rehabilitation that continue to motivate its evolution. Although the concept of nervous system plasticity was discussed by William James (1890), the foundation for experience-based plasticity had not reached the critical empirical mass to seriously impact rehabilitation research until after 1992. The objective of this review is to describe how the emergence of neural plasticity has changed neurocognitive rehabilitation research., Method: The important developments included (a) introduction of a widely available tool that could measure brain plasticity (i.e., functional MRI); (b) development of new structural imaging techniques that could define limits of and opportunities for neural plasticity; (c) deployment of noninvasive brain stimulation to leverage neural plasticity for rehabilitation; (d) growth of a literature indicating that exercise has positively impacts neural plasticity, especially for older persons; and (e) enhancement of neural plasticity by creating interventions that generalize beyond the boundaries of treatment activities. Given the massive literature, each of these areas is developed by example., Results: The expanding influence of neural plasticity has provided new models and tools for neurocognitive rehabilitation in neural injuries and disorders, as well as methods for measuring neural plasticity and predicting its limits and opportunities. Early clinical trials have provided very encouraging results., Conclusion: Now that neural plasticity has gained a firm foothold, it will continue to influence the evolution of neurocognitive rehabilitation research for the next 25 years and advance rehabilitation for neural injuries and disease. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Previous work has shown that older adults who evidence increased right inferior frontal gyrus (IFG) activity during language tasks show decreased sematic verbal fluency performance. The current study sought to evaluate if an aerobic exercise intervention can alter patterns of brain activity during a semantic verbal fluency task assessed by functional magnetic resonance imaging (fMRI). Thirty-two community-dwelling, sedentary older adults were enrolled to a 12-week aerobic "Spin" exercise group or a 12-week nonaerobic exercise control condition (Balance). Thirty participants completed their assigned intervention (16 Spin; 14 Balance) with pre- and postintervention assessments of a semantic verbal fluency task during fMRI and estimated VO 2 max testing. There was a significant increase in the change scores for estimated VO 2 max of the Spin group when compared to the Balance group. Semantic verbal fluency output within the scanner was also improved in the Spin group as compared to controls at postassessment. Group fMRI comparisons of IFG activity showed lower activity in the right IFG following the intervention in the aerobic Spin group when compared to the Balance group. Regression analysis of imaging data with change in both estimated VO 2 max and semantic verbal fluency was negatively correlated with activity in right IFG. The current work is registered as clinical trial with NCT01787292 and NCT02787655., Competing Interests: The authors report no financial conflict of interests.

Our understanding of G protein-coupled receptors (GPCRs) in the central nervous system (CNS) has been hampered by the limited availability of tools allowing for the study of their signaling with precise temporal control. To overcome this, we tested the utility of the bistable mammalian opsin melanopsin to examine G protein signaling in CNS neurons. Specifically, we used biolistic (gene gun) approaches to transfect melanopsin into cortical pyramidal cells maintained in organotypic slice culture. Whole cell recordings from transfected neurons indicated that application of blue light effectively activated the transfected melanopsin to elicit the canonical biphasic modulation of membrane excitability previously associated with the activation of GPCRs coupling to Gαq-11 Remarkably, full mimicry of exogenous agonist concentration could be obtained with pulses as short as a few milliseconds, suggesting that their triggering required a single melanopsin activation-deactivation cycle. The resulting temporal control over melanopsin activation allowed us to compare the activation kinetics of different components of the electrophysiological response. We also replaced the intracellular loops of melanopsin with those of the 5-HT2A receptor to create a light-activated GPCR capable of interacting with the 5-HT2A receptor interacting proteins. The resulting chimera expressed weak activity but validated the potential usefulness of melanopsin as a tool for the study of G protein signaling in CNS neurons., (Copyright © 2016 the American Physiological Society.)

Parkinson's disease is a neurodegenerative disorder that has received considerable attention in allopathic medicine over the past decades. However, it is clear that, to date, pharmacological and surgical interventions do not fully address symptoms of PD and patients' quality of life. As both an alternative therapy and as an adjuvant to conventional approaches, several types of rhythmic movement (e.g., movement strategies, dance, tandem biking, and Tai Chi) have shown improvements to motor symptoms, lower limb control, and postural stability in people with PD (1-6). However, while these programs are increasing in number, still little is known about the neural mechanisms underlying motor improvements attained with such interventions. Studying limb motor control under task-specific contexts can help determine the mechanisms of rehabilitation effectiveness. Both internally guided (IG) and externally guided (EG) movement strategies have evidence to support their use in rehabilitative programs. However, there appears to be a degree of differentiation in the neural substrates involved in IG vs. EG designs. Because of the potential task-specific benefits of rhythmic training within a rehabilitative context, this report will consider the use of IG and EG movement strategies, and observations produced by functional magnetic resonance imaging and other imaging techniques. This review will present findings from lower limb imaging studies, under IG and EG conditions for populations with and without movement disorders. We will discuss how these studies might inform movement disorders rehabilitation (in the form of rhythmic, music-based movement training) and highlight research gaps. We believe better understanding of lower limb neural activity with respect to PD impairment during rhythmic IG and EG movement will facilitate the development of novel and effective therapeutic approaches to mobility limitations and postural instability.

The idea that serotonergic synaptic transmission plays an essential role in the control of mood and the pharmacotherapy of anxiety and depression is one of the cornerstones of modern biological psychiatry. As a result, there is intense interest in understanding the mechanisms controlling the activity of serotonin-synthesizing (serotonergic) neurons. One of the oldest and most durable ideas emerging from this work is that serotonergic neurons are capable of autonomously regulating their own basal firing rate. Serotonergic neurons express on their surface 5-HT1A receptors (autoreceptors) that, when activated, induce the opening of potassium channels that hyperpolarize and thereby inhibit cell firing. Activity-dependent release of serotonin within serotonergic nuclei is thought to activate these autoreceptors, thus completing an autoinhibitory feedback loop. This concept, which was originally proposed in the 1970s, has proven to be enormously fruitful and has guided the interpretation of a broad range of clinical and preclinical work. Yet, remarkably, electrophysiological studies seeking to directly demonstrate this phenomenon, especially in in vitro brain slices, have produced mixed results. Here, we critically review this work with a focus on electrophysiological studies, which directly assess neuronal activity. We also highlight recent work suggesting that 5-HT1A receptor-mediated autoinhibition may play other roles in the control of firing besides acting as a feedback regulator for the pacemaker-like firing rate of serotonergic neurons.

Research using functional magnetic resonance imaging has for numerous years now reported the existence of a negative blood oxygenation level dependent (BOLD) response. Based on accumulating evidence, this negative BOLD signal appears to represent an active inhibition of cortical areas in which it is found during task activity. This particularly important with respect to motor function given that it is fairly well-established that, in younger adults, the ipsilateral sensorimotor cortex exhibits negative BOLD during unimanual movements in fMRI. This interhemispheric suppression of cortical activity may have useful implications for our understanding of both basic motor function and rehabilitation of injury or disease. However, to date, we are aware of no study that has tested the reliability of evoked negative BOLD in ipsilateral sensorimotor cortex in individuals across sessions. The current study employs a unimanual finger opposition task previously shown to evoke negative BOLD in ipsilateral sensorimotor cortex across three sessions. Reliability metrics across sessions indicates that both the magnitude and location of ipsilateral sensorimotor negative BOLD response is relatively stable over each of the three sessions. Moreover, the volume of negative BOLD in ipsilateral cortex was highly correlated with volume of positive BOLD activity in the contralateral primary motor cortex. These findings show that the negative BOLD signal can be reliably evoked in unimanual task paradigms, and that the signal dynamic could represent an active suppression of the ipsilateral sensorimotor cortex originating from the contralateral motor areas.

The effects of aging on rehabilitation of aging-related diseases are rarely a design consideration in rehabilitation research. In this brief review we present strong coincidental evidence from these two fields suggesting that deficits in aging-related disease or injury are compounded by the interaction between aging-related brain changes and disease-related brain changes. Specifically, we hypothesize that some aphasia, motor, and neglect treatments using repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) in stroke patients may address the aging side of this interaction. The importance of testing this hypothesis and addressing the larger aging by aging-related disease interaction is discussed. Underlying mechanisms in aging that most likely are relevant to rehabilitation of aging-related diseases also are covered.

Aerobic fitness (AF) and self-reported physical activity (srPA) do not represent the same construct. However, many exercise and brain aging studies interchangeably use AF and srPA measures, which may be problematic with regards to how these metrics are associated with brain outcomes, such as morphology. If AF and PA measures captured the same phenomena, regional brain volumes associated with these measures should directly overlap. This study employed the general linear model to examine the differential association between objectively-measured AF (treadmill assessment) and srPA (questionnaire) with gray matter density (GMd) in 29 cognitively unimpaired community-dwelling older adults using voxel based morphometry. The results show significant regional variance in terms of GMd when comparing AF and srPA as predictors. Higher AF was associated with greater GMd in the cerebellum only, while srPA displayed positive associations with GMd in occipito-temporal, left perisylvian, and frontal regions after correcting for age. Importantly, only AF level, and not srPA, modified the relationship between age and GMd, such that higher levels of AF were associated with increased GMd in older age, while decreased GMd was seen in those with lower AF as a function of age. These results support existing literature suggesting that both AF and PA exert beneficial effects on GMd, but only AF served as a buffer against age-related GMd loss. Furthermore, these results highlight the need for use of objective PA measurement and comparability of tools across studies, since results vary dependent upon the measures used and whether these are objective or subjective in nature.

Studies suggest improvements of neurocognitive function among older adults who undergo aerobic exercise training. This study sought to examine the impact of an aerobic exercise intervention on verbal fluency in sedentary older adults. Twenty community-dwelling older adults were recruited and enrolled in either a spin exercise group or a control condition. Participants were evaluated with an estimated V02max test and on measures of letter, category, and switching verbal fluency both before and after a 12-week intervention period. Spin exercise resulted in a significant improvement in category (semantic) verbal fluency when compared with the control group (15% vs. 2% increase, respectively; P = .001). Spin exercise also resulted in a significant improvement in estimated V02max (P = .005). Also important, the spin exercise group demonstrated a high level of adherence (mean adherence = 82.5%). Spin exercise can be an effective mode of aerobic exercise to improve semantic fluency in previously sedentary older adults.

Background An aphasia treatment was designed to shift laterality from the left to right lateral frontal lobe during word production by initiating word-finding trials with complex left-hand movements. Previous findings indicated successful relateralization. Objective The current study was designed to ascertain whether the shift was attributable to the left-hand movement. Methods Using stratified random sampling, 14 subjects were equally divided between Intention (IT) and Control (CT) treatments. CT was identical to IT, except with no left-hand movements. Both treatments trained picture naming (phases 1 and 2) and category-member generation (phase 3), each phase lasting 10 sessions. Functional magnetic resonance imaging of category member generation occurred at pretreatment, posttreatment, and 3-month follow-up. Results IT shifted lateral frontal activity rightward compared with pretreatment both at posttreatment (t = -2.602, df = 6, P < .05) and 3-month follow-up (t = -2.332, df = 5, P < .05), but CT did not. IT and CT yielded similar changes for all picture-naming and category probes. However, IT patients showed gains for untrained category (t = 3.33, df = 6, P < .01) and picture-naming probes (t = 3.77, df = 5, P < .01), but CT patients did not. Conclusions The rightward shift in lateral frontal activity for IT was because of the left-hand movements. IT evoked greater generalization than CT., (© The Author(s) 2014.)

Background: The sale of women and children accounts for the greatest proportion of human trafficking globally, with Southeast Asia acting as the illegal industry's largest international hub. At least 225,000 women and children are trafficked from the region every year, accounting for approximately one-third of the global human trade. The health ramifications of trafficking are severe: many survivors contract infectious diseases including sexually transmitted infections and develop mental health conditions, including anxiety, panic disorder, and major depression. The complications associated with studying a highly secretive illegal trade have severely limited research on effective prevention measures. Because this presents a challenge for organizations that hope to develop prevention strategies, we asked the following question: How do social determinants facilitate or mitigate trafficking of women and children in Southeast Asia, and what recommendations does the literature provide for combating trafficking via these social determinants?, Methods: Using a Cochrane-based systematic search methodology, five independent researchers reviewed 1,148 articles from the past ten years (2001–2011). After three phases of independent review, they selected and analyzed 61 articles to identify the determinants that impact trafficking of women and children in Southeast Asia., Results: Key social determinants that facilitate trafficking include poverty, female gender, lack of policy and enforcement, age, migration, displacement and conflict, ethnicity, culture, ignorance of trafficking methods, and caste status. Conversely, protective determinants that mitigate trafficking include formal education, citizenship, maternal education, higher caste status, and birth order. Recommendations relating to a variety of the determinants are identified and discussed in detail., Conclusions: Social determinants are central to the processes that mitigate and facilitate the sale and exploitation of women and children in Southeast Asia. Specifically, the facilitation of education and empowerment, along with the creation and enforcement of effective policies, could lessen the vulnerability of women and children to modern-day slavery., (Copyright © 2013 Perry and McEwing. This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Physical fitness has been long associated with maintenance and improvement of motor performance as we age. In particular, measures of psychomotor speed and motor dexterity tend to be higher in physically fit aging adults as compared to their sedentary counterparts. Using functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS), we explored the patterns of neural activity that may, in part, account for differences between individuals of varying physical fitness levels. In this study, we enrolled both sedentary and physically fit middle age (40-60) and younger (18-30) adults and measured upper extremity motor performance during behavioral testing. In a follow-up session, we employed TMS and fMRI to assess levels of interhemispheric communication during unimanual tasks. Results show that increased physical fitness is associated with better upper extremity motor performance on distal dexterity assessments and increased levels of interhemispheric inhibition in middle age adults. Further, the functional correlates of changes of ipsilateral activity appears to be restricted to the aging process as younger adults of varying fitness levels do not differ in hemispheric patterns of activity or motor performance. We conclude that sedentary aging confers a loss of interhemispheric inhibition that is deleterious to some aspects of motor function, as early as midlife, but these changes can be mediated by chronic engagement in aerobic exercise.

Functional magnetic resonance imaging (fMRI) studies have identified consistent age-related changes during various cognitive tasks, such that older individuals display more positive and less negative task-related activity than young adults. Recently, evidence shows that chronic physical exercise may alter aging-related changes in brain activity; however, the effect of exercise has not been studied for the neural substrates of language function. Additionally, the potential mechanisms by which aging alters neural recruitment remain understudied. To address these points, the present study enrolled elderly adults who were either sedentary or physically active to characterize the neural correlates of language function during semantic fluency between these groups in comparison to a young adult sample. Participants underwent fMRI during semantic fluency and transcranial magnetic stimulation to collect the ipsilateral silent period, a measure of interhemispheric inhibition. Results indicated that sedentary older adults displayed reductions in negative task-related activity compared to the active old group in areas of the attention network. Longer interhemispheric inhibition was associated with more negative task-related activity in the right and left posterior perisylvian cortex, suggesting that sedentary aging may result in losses in task facilitatory cortical inhibition. However, these losses may be mitigated by regular engagement in physical exercise.

Recent studies have shown that during unimanual motor tasks, aging adults show bilateral recruitment of primary motor cortex (M1), while younger adults show a suppression of the ipsilateral motor cortex. Additional work has indicated that increased bilateral M1 recruitment in older adults may be deleterious when performing some motor tasks. However, higher levels of physical fitness are associated with improved dexterity and fitness may mitigate the loss of both inhibitory and excitatory communication in aging adults. The goal of this study was to assess dexterity and interhemispheric motor communication in physically fit and sedentary middle-age (40-60 years) right handed participants using tests of hand deftness and transcranial magnetic stimulation (TMS). To behaviorally assess the influence of interhemispheric communication on motor performance, participants also perform the coin rotation deftness task while maintaining pinch force with the opposite hand (bimanual condition). We correlated these behavioral measures with the ipsilateral silent period using TMS to assess interhemispheric inhibition. Our results show that the middle-aged adults who were physically fit had better dexterity of their right hand (finger tapping and peg-board). When performing the coin rotation task the fit group had no between hand differences, but the sedentary group's left hand performance was inferior to the their right hand. We found that better dexterity correlated with ipsilateral silent period duration (greater inhibition) thereby supporting the postulate that fitness improves interhemispheric motor communication.

This study compared the reliability of motor maps over 3 sessions from both neuronavigated transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) data between younger and older adults. Seven younger (ages 19-31) and seven older (ages 64-76) adults participated in three joint TMS/fMRI assessment sessions separated by 7 or 14 days. Sessions involved mapping of the right first dorsal interosseous muscle using single-pulse TMS immediately followed by block-design fMRI scanning involving volitional right-hand index finger to thumb oppositional squeeze. Intersession reliability of map volume, evaluated by intraclass correlation and Jaccard Coefficient between testing sessions, was more consistent for younger adults in both fMRI and TMS. A positive correlation was evidenced between fMRI and TMS map volumes and Jaccard Coefficients indicating spatial consistency across sessions between the two measures. Comparisons of map reliability between age groups showed that younger adults have more stable motor maps in both fMRI and TMS. fMRI and TMS maps show consistency across modalities. Future interpretation of motor maps should attempt to account for potential increased variability of such mapping in older age groups. Despite these age group differences in reliability, fMRI and TMS appear to offer consistent and complementary information about cortical representation of the first dorsal interosseous muscle.

Deubiquitinating enzymes (DUBs) are proteases that control the post-translational modification of proteins by ubiquitin and in turn regulate diverse cellular pathways. Despite a growing understanding of DUB biology at the structural and molecular level, little is known about the physiological importance of most DUBs. Here, we systematically identify DUBs encoded by the genome of Drosophila melanogaster and examine their physiological importance in vivo. Through domain analyses we uncovered 41 Drosophila DUBs, most of which have human orthologues. Systematic knockdown of the vast majority of DUBs throughout the fly or in specific cell types had dramatic consequences for Drosophila development, adult motility or longevity. Specific DUB subclasses proved to be particularly necessary during development, while others were important in adults. Several DUBs were indispensable in neurons or glial cells during developmental stages; knockdown of others perturbed the homeostasis of ubiquitinated proteins in adult flies, or had adverse effects on wing positioning as a result of neuronal requirements. We demonstrate the physiological significance of the DUB family of enzymes in intact animals, find that there is little functional redundancy among members of this family of proteases, and provide insight for future investigations to understand DUB biology at the molecular, cellular and organismal levels.

Aerobic exercise has been suggested to ameliorate aging-related decline in humans. Recently, evidence has indicated chronological aging is associated with decreases in measures of interhemispheric inhibition during unimanual movements, but that such decreases may be mitigated by long-term physical fitness. The present study investigated measures of ipsilateral (right) primary motor cortex activity during right-hand movements using functional magnetic resonance imaging and transcranial magnetic stimulation (TMS). Healthy, right-handed participant groups were comprised of 12 sedentary older adults, 12 physically active older adults, and 12 young adults. Active older adults and younger adults evidenced longer ipsilateral silent periods (iSP) and less positive BOLD of ipsilateral motor cortex (iM1) as compared to sedentary older adults. Across groups, duration of iSP from TMS was inversely correlated with BOLD activity in iM1 during unimanual movement. These findings suggest that increased physical activity may have a role in decreasing aging-related losses of interhemispheric inhibition., (Published by Elsevier B.V.)

Despite over 140 years of research on Broca's area, the connections of this region to medial frontal cortex remain unclear. The current study investigates this structural connectivity using diffusion-weighted MRI tractography in living humans. Our results show connections between Broca's area and Brodmann's areas (BA) 9, 8, and 6 (both supplementary motor area (SMA) in caudal BA 6, and Pre-SMA in rostral BA 6). Trajectories follow an anterior-to-posterior gradient, wherein the most anterior portions of Broca's area connect to BA 9 and 8 while posterior Broca's area connects to Pre-SMA and SMA. This anterior-posterior connectivity gradient is also present when connectivity-based parcellation of Broca's area is performed. Previous studies of language organization suggest involvement of anterior Broca's area in semantics and posterior Broca's area in syntax/phonology. Given corresponding patterns of functional and structural organization of Broca's area, it seems well warranted to investigate carefully how anterior vs. posterior medial frontal cortex differentially affect semantics, syntax and phonology., (Copyright 2010 Elsevier Inc. All rights reserved.)

Five nonfluent aphasia patients participated in a picture-naming treatment that used an intention manipulation (opening a box and pressing a button on a device in the box with the left hand) to initiate naming trials and was designed to re-lateralize word production mechanisms from the left to the right frontal lobe. To test the underlying assumption regarding re-lateralization, patients participated in fMRI of category-member generation before and after treatment. Generally, the four patients who improved during treatment showed reduced frontal activity from pre- to post-treatment fMRI with increasing concentration of activity in the right posterior frontal lobe (motor/premotor cortex, pars opercularis), demonstrating a significant shift in lateraliity toward the right lateral frontal lobe, as predicted. Three of these four patients showed no left frontal activity by completion of treatment, indicating that right posterior lateral frontal activity supported category-member generation. Patients who improved in treatment showed no difference in lateralization of lateral frontal activity from normal controls pre-treatment, but post-treatment, their lateral frontal activity during category-member generation was significantly more right lateralized than that of controls. Patterns of activity pre- and post-treatment suggested increasing efficiency of cortical processing as a result of treatment in the four patients who improved. The one patient who did not improve during treatment showed a leftward shift in lateral frontal lateralization that was significantly different from the four patients who did improve. Neither medial frontal nor posterior perisylvian re-lateralization from immediately pre- to immediately post-treatment images was a necessary condition for significant treatment gains or shift in lateral frontal lateralization. Of the three patients who improved and in whom posterior perisylvian activity could be measured at post-treatment fMRI, all maintained equal or greater amounts of left-hemisphere perisylvian activity as compared to right. This finding is consistent with reviews suggesting both hemispheres are involved in recovery of language in aphasia patients.