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Repetitive transcranial magnetic stimulation (TMS), when applied to the dorsolateral prefrontal cortex (dlPFC), treats depression. Therapeutic effects are hypothesized to arise from propagation of local dlPFC stimulation effects across distributed networks; however, the mechanisms of this remain unresolved. dlPFC contains representations of different networks. As such, dlPFC TMS may exert different effects depending on the network being stimulated. Here, to test this, we applied high-frequency TMS to two nearby dlPFC targets functionally embedded in distinct anti-correlated networks—the default and salience networks— in the same individuals in separate sessions. Local and distributed TMS effects were measured with combined 18fluorodeoxyglucose positron emission tomography and functional magnetic resonance imaging. Identical TMS patterns caused opposing effects on local glucose metabolism: metabolism increased at the salience target following salience TMS but decreased at the default target following default TMS. At the distributed level, both conditions increased functional connectivity between the default and salience networks, with this effect being dramatically larger following default TMS. Metabolic and haemodynamic effects were also linked: across subjects, the magnitude of local metabolic changes correlated with the degree of functional connectivity changes. These results suggest that TMS effects upon dlPFC are network specific. They also invoke putative anti-depressant mechanisms of TMS: network de-coupling.

The identification of a neurodegenerative disorder’s distributed pattern of atrophy—or atrophy “signature”— can lend insights into the cortical networks that degenerate in individuals with specific constellations of symptoms. In addition, this signature can be used as a biomarker to support early diagnoses and to potentially reveal pathological changes associated with said disorder. Here, we characterized the cortical atrophy signature of Behavioral Variant Frontotemporal Dementia (bvFTD). We used a data-driven approach to estimate cortical thickness using surface-based analyses in two independent, sporadic bvFTD samples (n=30 and n=71, total n=101), using age- and gender-matched cognitively and behaviorally normal individuals. We found highly similar patterns of cortical atrophy across the two independent samples, supporting the reliability of our bvFTD signature. Next, we investigated whether our bvFTD signature targets specific large-scale cortical networks, as is the case for other neurodegenerative disorders. We specifically asked whether the bvFTD signature topographically overlaps with the salience network, as previous reports have suggested. We hypothesized that because phenotypic presentations of bvFTD are diverse, this would not be the case, and that the signature would cross canonical network boundaries. Consistent with our hypothesis, the bvFTD signature spanned rostral portions of multiple networks, including the default-mode, limbic, frontoparietal control, and salience networks. We then tested whether the signature comprised multiple anatomical subtypes which themselves overlapped with specific networks. To explore this, we performed a hierarchical clustering analysis. This yielded three clusters, only one of which extensively overlapped with a canonical network (the limbic network). Taken together, these findings argue against the hypothesis that the salience network is preferentially affected in bvFTD, but rather suggest that—at least in patients who meet diagnostic criteria for the full-blown syndrome—neurodegeneration in bvFTD encompasses a distributed set of prefrontal, insular, and anterior temporal nodes of multiple large-scale brain networks, in keeping with the phenotypic diversity of this disorder.

Background and ObjectivesPatients with primary progressive aphasia (PPA) have gradually progressive language deficits during the initial phase of the illness. As the underlying neurodegenerative disease progresses, patients with PPA start losing independent functioning due to the development of nonlanguage cognitive or behavioral symptoms. The timeline of this progression from the mild cognitive impairment stage to the dementia stage of PPA is variable across patients. In this study, in a sample of patients with PPA, we measured the magnitude of cortical atrophy within functional networks believed to subserve diverse cognitive and affective functions. The objective of the study was to evaluate the utility of this measure as a predictor of time to subsequent progression to dementia in PPA.MethodsPatients with PPA with largely independent daily function were recruited through the Massachusetts General Hospital Frontotemporal Disorders Unit. All patients underwent an MRI scan at baseline. Cortical atrophy was then estimated relative to a group of amyloid-negative cognitively normal control participants. For each patient, we measured the time between the baseline visit and the subsequent visit at which dementia progression was documented or last observation. Simple and multivariable Cox regression models were used to examine the relationship between cortical atrophy and the likelihood of progression to dementia.ResultsForty-nine patients with PPA (mean age = 66.39 ± 8.36 years, 59.2% females) and 25 controls (mean age = 67.43 ± 4.84 years, 48% females) were included in the data analysis. Greater baseline atrophy in not only the left language network (hazard ratio = 1.47, 95% CI = 1.17–1.84) but also in the frontoparietal control (1.75, 1.25–2.44), salience (1.63, 1.25–2.13), default mode (1.55, 1.19–2.01), and ventral frontotemporal (1.41, 1.16–1.71) networks was associated with a higher risk of progression to dementia. A multivariable model identified contributions of the left frontoparietal control (1.94, 1.09–3.48) and ventral frontotemporal (1.61, 1.09–2.39) networks in predicting dementia progression, with no additional variance explained by the language network (0.75, 0.43–1.31).DiscussionThese results suggest that baseline atrophy in cortical networks subserving nonlanguage cognitive and affective functions is an important predictor of progression to dementia in PPA. This measure should be included in precision medicine models of prognosis in PPA.

Non-invasive brain stimulation has been increasingly recognized for its potential as an investigational, diagnostic and therapeutic tool across the clinical neurosciences. Transcranial magnetic stimulation (TMS) is a non-invasive method of focal neuromodulation. Diagnostically, TMS can be used to probe cortical excitability and plasticity, as well as for functional mapping. Therapeutically, depending on the pattern employed, TMS can either facilitate or inhibit stimulated cortex potentially modulating maladaptive physiology through its effects on neuroplasticity. Despite this potential, applications of TMS in neurology have only been approved for diagnostic clinical neurophysiology, pre-surgical mapping of motor and language cortex, and the treatment of migraines. In this article, we discuss the principles of TMS and its clinical applications in neurology, including experimental applications in stroke rehabilitation, seizures, autism spectrum disorder, neurodegenerative disorders, movement disorders, tinnitus, chronic pain and functional neurological disorder. To promote increased cross-talk across neurology and psychiatry, we also succinctly review the TMS literature for the treatment of major depression and obsessive compulsive disorder. Overall, we argue that larger clinical trials that are better informed by circuit-level biomarkers and pathophysiological models will lead to an expansion of the application of TMS for patients cared for by neurologists.

While cognitive assessment by videoconference has become possible over the past decade, the COVID-19 pandemic underscores the critical need for expansion and examination of these methods, their appropriateness for various patient populations, and their benefits and limitations. Validity and reliability studies of tele-neuropsychological testing have been conducted in MCI or mild AD dementia patients (e.g., MMSE=25+); few studies have assessed the feasibility of neurologic examination by video, and none in atypical dementias, assuming that patients with some types (e.g., language, comportment) or greater severity of cognitive-behavioral impairment would be unable to participate. Here we report the feasibility of telehealth services for a multi-disciplinary dementia subspecialty clinic that include cognitive-behavioral and neurologic assessment with patients with atypical neurodegenerative syndromes.104 patient-carepartner (P-C) dyads met with providers in the MGH FTD Unit by videoconference (March-December, 2020) for routine clinical care. P-Cs completed validated questionnaires assessing cognition-mood/behavior/function on REDCap prior to video clinical interview and cognitive assessment, including the MoCA and Boston Cognitive Exam (BCE2.0), a newly revised brief cognitive assessment battery adapted for telehealth. P-Cs met with a neurologist for a basic neurologic examination (including eye-movement examination), review of assessment results, and discussion of care plan. P-Cs completed a satisfaction survey.The 104 P-Cs included a range of atypical neurodegenerative disorders (bvFTD, PCA, PPA, CBS, PSP, eoAD, Multidomain syndrome) mild-to-severe impairment (CDR range: 0-3). 76% completed the MoCA (25% had CDR=2). 36% also completed the BCEv2. Comparison of remote assessment data to previous in-person testing is ongoing. Of P-Cs who completed a satisfaction survey, all reported being "very satisfied" with the appointment, with 93% open to participating in a remote visit again. 87% found the telehealth visit comparable to an in-person visit. 66% preferred a future combination of remote and in-person visits.Multi-disciplinary telehealth visits appear to be feasible with patients with atypical cognitive-behavioral syndromes of across the severity spectrum. P-Cs report a high degree of satisfaction with the telehealth visit and an openness to ongoing telehealth visits. Results have implications for increasing accessibility of multidisciplinary medical services for patients and families living with complex forms of dementia.

Background: Although traditionally conceptualized as a language disorder, semantic variant primary progressive aphasia (svPPA) is often accompanied by significant behavioral and affective symptoms which considerably increase disease morbidity. Specifically, these neuropsychiatric symptoms are characterized by breaches in normative socioaffective function, for example, an inability to read social cues, excessive trusting of others, and decreased empathy. Our prior neuroimaging work identified 3 corticolimbic networks anchored in the amygdala, temporal pole, and frontoinsular cortex: an affiliation network, theorized to mediate social approach behavior; an aversion network, theorized to subserve the appraisal of social threat; and a perception network, theorized to mediate the detection of social cues. We hy­pothesized that degeneration of these networks could provide neuroanatomical substrates for socioaffective deficits in svPPA. Methods: We examined hypothesized relationships between subscores on the Social Impairment Rating Scale (SIRS) and atrophy in each of these 3 networks in a group of 16 svPPA patients (using matched cognitively normal controls as a reference). Results: Consistent with our predictions, the magnitude of atrophy in the affiliation network in svPPA patients correlated with the SIRS subscore of socioemotional detachment, while the magnitude of atrophy in the aversion network in svPPA patients correlated with the SIRS subscore of inappropriate trusting. We did not find the predicted association between perception network atrophy and the SIRS subscore of lack of attention to social cues. Conclusion: These findings highlight specific socioaffective deficits in svPPA and provide a neuroanatomical basis for these impairments by linking them to networks commonly targeted in this disorder.

Distinct regions of the cerebellum connect to separate regions of the cerebral cortex forming a complex topography. Although cerebellar organization has been examined in group-averaged data, study of individuals provides an opportunity to discover features that emerge at a higher spatial resolution. Here, functional connectivity MRI was used to examine the cerebellum of two intensively sampled individuals (each scanned 31 times). Connectivity to somatomotor cortex showed the expected crossed laterality and topography of the body maps. A surprising discovery was connectivity to the primary visual cortex along the vermis with evidence for representation of the central field. Within the hemispheres, each individual displayed a hierarchical progression from the inverted anterior lobe somatomotor map through to higher-order association zones. The hierarchy ended at Crus I/II and then progressed in reverse order through to the upright somatomotor map in the posterior lobe. Evidence for a third set of networks was found in the most posterior extent of the cerebellum. Detailed analysis of the higher-order association networks revealed robust representations of two distinct networks linked to the default network, multiple networks linked to cognitive control, as well as a separate representation of a language network. Although idiosyncratic spatial details emerged between subjects, each network could be detected in both individuals, and seed regions placed within the cerebellum recapitulated the full extent of the spatially specific cerebral networks. The observation of multiple networks in juxtaposed regions at the Crus I/II apex confirms the importance of this zone to higher-order cognitive function and reveals new organizational details. NEW & NOTEWORTHY Stable, within-individual maps of cerebellar organization reveal orderly macroscale representations of the cerebral cortex with local juxtaposed zones representing distinct networks. In addition, individuals reveal idiosyncratic organizational features.

Distinct regions of the cerebellum connect to separate regions of the cerebral cortex forming a complex topography. While key properties of cerebellar organization have been revealed in group-averaged data, in-depth study of individuals provides an opportunity to discover functional-anatomical features that emerge at a higher spatial resolution. Here functional connectivity MRI was used to examine the cerebellum of two intensively-sampled individuals (each scanned across 31 MRI sessions). Connectivity to somatomotor cortex showed the expected crossed laterality and inversion of the body maps between the anterior and posterior lobes. A surprising discovery was connectivity to the primary visual cortex along the vermis with evidence for representation of the central field. Within the hemispheres, each individual displayed a hierarchical progression from the inverted anterior lobe somatomotor map through to higher-order association zones. The hierarchy ended near Crus I/II and then progressed in reverse order through to the upright somatomotor map in the posterior lobe. Evidence for a third set of networks was found in the most posterior extent of the cerebellum. Detailed analysis of the higher-order association networks around the Crus I/II apex revealed robust representations of two distinct networks linked to the default network, multiple networks linked to cognitive control, as well as a separate representation of a language network. While idiosyncratic spatial details emerged between subjects, each of these networks could be detected in both individuals, and small seed regions placed within the cerebellum recapitulated the full extent of the spatially-specific cerebral networks. The observation of multiple networks in juxtaposed regions at the Crus I/II apex confirms the importance of this zone to higher-order cognitive function and reveals new organizational details.

Recently, an exhaustive examination of 11 state-of-the-art MR-based attenuation correction (AC) concluded that there are currently a few methods showing similar results compared to the gold-standard, CT-based AC. While the study presented a thorough portfolio of metrics to quantify accuracy (bias) and quality, it lacked one of the most important metrics to quantify robustness that is critical for its clinical applicability: intrascanner reproducibility (repeatability). In this paper, we provide for the first time a study of the repeatability of one of the outperforming brain MR-based AC methods: the statistical parametric mapping (SPM)-based pseudo-CT approach. Twenty two subjects undergoing 3 18F-FDG PET/MRI visits within two months were retrospectively analyzed in this paper. Pseudo-CT mu-maps were obtained from the coregistered MR images for all three visits and the PET data from visit 1 was reconstructed using all three mu-maps. Relative changes (RC), intraclass correlation coefficient, reproducibility coefficient (RDC95%) and Bland-Altman limits of agreement were used to measure repeatability. Voxel-based and regions of interest-based results showed that absolute RC for the reconstructed PET images are within ~2%. The brain cortex and the cerebellum were the regions with the largest variability (~3%). The differences across visits were not statistically significant ( ${p=0.90}$ ). In conclusion, this paper shows for the first time the repeatability of the SPM-based pseudo-CT approach for brain MR-based AC. These results, in addition to the ease of implementation and the quality and robustness previously demonstrated, confer this SPM-based method an ideal candidate for routine brain PET/MRI research and clinical studies.

Purpose The cerebellum is an intricate neural structure that orchestrates various cognitive and behavioral functions. In recent years, there has been an increasing interest in neuromodulation of the cerebellum with transcranial magnetic stimulation (TMS) for therapeutic and basic science applications. Theta burst stimulation (TBS) is an efficient and powerful TMS protocol that is able to induce longer-lasting effects with shorter stimulation times compared with traditional TMS. Parameters for cerebellar TBS are traditionally framed in the bounds of TBS to the cerebral cortex, even when the 2 have distinct histologic, anatomical, and functional characteristics. Tolerability limits have not been systematically explored in the literature for this specific application. Therefore, we aimed to determine the stimulation parameters that have been used for cerebellar. TBS to date and evaluate adverse events and adverse effects related to stimulation parameters. Methods We used PubMed to perform a critical review of the literature based on a systematic review of original research studies published between September 2008 and November 2019 that reported on cerebellar TBS. We recovered information from these publications and communication with authors about the stimulation parameters used and the occurrence of adverse events. Findings We identified 61 research articles on interventions of TBS to the cerebellum. These articles described 3176 active sessions of cerebellar TBS in 1203 individuals, including healthy participants and patients with various neurologic conditions, including brain injuries. Some studies used substantial doses (eg, pulse intensity and number of pulses) in short periods. No serious adverse events were reported. The specific number of patients who experienced adverse events was established for 48 studies. The risk of an adverse event in this population (n = 885) was 4.1%. Adverse events consisted mostly of discomfort attributable to involuntary muscle contractions. Authors used a variety of methods for calculating stimulation dosages, ranging from the long-established reference of electromyography of a hand muscle to techniques that atone for some of the differences between cerebrum and cerebellum. Implications No serious adverse events have been reported for cerebellar TBS. There is no substantial evidence of a tolerable maximal-efficacy stimulation dose in humans. There is no assurance of equivalence in the translation of cortical excitability and stimulation intensities from the cerebral cortex to cerebellar regions. Further research for the stimulation dose in cerebellar TBS is warranted, along with consistent report of adverse events. © 2020 Elsevier HS Journals, Inc.

Examination of large-scale distributed networks within the individual reveals details of cortical network organization that are absent in group-averaged studies. One recent discovery is that a distributed transmodal network, often referred to as the “default network,” comprises two closely interdigitated networks, only one of which is coupled to posterior parahippocampal cortex. Not all studies of individuals have identified the same networks, and questions remain about the degree to which the two networks are separate, particularly within regions hypothesized to be interconnected hubs. In this study we replicate the observation of network separation across analytical (seed-based connectivity and parcellation) and data projection (volume and surface) methods in two individuals each scanned 31 times. Additionally, three individuals were examined with high-resolution (7T; 1.35 mm) functional magnetic resonance imaging to gain further insight into the anatomical details. The two networks were identified with separate regions localized to adjacent portions of the cortical ribbon, sometimes inside the same sulcus. Midline regions previously implicated as hubs revealed near complete spatial separation of the two networks, displaying a complex spatial topography in the posterior cingulate and precuneus. The network coupled to parahippocampal cortex also revealed a separate region directly within the hippocampus, at or near the subiculum. These collective results support that the default network is composed of at least two spatially juxtaposed networks. Fine spatial details and juxtapositions of the two networks can be identified within individuals at high resolution, providing insight into the network organization of association cortex and placing further constraints on interpretation of group-averaged neuroimaging data. NEW & NOTEWORTHY Recent evidence has emerged that canonical large-scale networks such as the “default network” fractionate into parallel distributed networks when defined within individuals. This research uses high-resolution imaging to show that the networks possess juxtapositions sometimes evident inside the same sulcus and within regions that have been previously hypothesized to be network hubs. Distinct circumscribed regions of one network were also resolved in the hippocampal formation, at or near the parahippocampal cortex and subiculum.

Examination of large-scale distributed networks within the individual reveals details of cortical network organization that are absent in group-averaged studies. One recent discovery is that a distributed transmodal network, often referred to as the ‘default network’, is comprised of two separate but closely interdigitated networks, only one of which is coupled to posterior parahippocampal cortex. Not all studies of individuals have identified the same networks and questions remain about the degree to which the two networks are separate, particularly within regions hypothesized to be interconnected hubs. Here we replicate the observation of network separation across analytical (seed-based connectivity and parcellation) and data projection (volume and surface) methods in 2 individuals each scanned 31 times. Additionally, 3 individuals were examined with high-resolution fMRI to gain further insight into the anatomical details. The two networks were identified with separate regions localized to adjacent portions of the cortical ribbon, sometimes inside the same sulcus. Midline regions previously implicated as hubs revealed near complete spatial separation of the two networks, displaying a complex spatial topography in the posterior cingulate and precuneus. The network coupled to parahippocampal cortex also revealed a separate region directly within the hippocampus at or near the subiculum. These collective results support that the default network is composed of at least two spatially juxtaposed networks. Fine spatial details and juxta-positions of the two networks can be identified within individuals at high resolution, providing insight into the network organization of association cortex and placing further constraints on interpretation of group-averaged neuroimaging data.

BackgroundAlthough neurobiological models of obsessive–compulsive disorder (OCD) traditionally emphasise the central role of corticostriatal brain regions, studies of default mode network integrity have garnered increasing interest, but have produced conflicting results.AimsTo resolve these discrepant findings by examining the integrity of default mode network subsystems in OCD.MethodComparison of seed-based resting-state functional connectivity of 11 default mode network components between 46 patients with OCD and 46 controls using functional magnetic resonance imaging.ResultsSignificantly reduced connectivity within the dorsal medial prefrontal cortex self subsystem was identified in the OCD group, and remained significant after controlling for medication status and life-time history of affective disorders. Further, greater connectivity between the self subsystem and salience and attention networks was observed.ConclusionsResults indicate that people with OCD show abnormalities in a neural system previously associated with self-referential processing in healthy individuals, and suggest the need for examination of dynamic interactions between this default mode network subsystem and other large-scale networks in this disorder.

Cerebral cortical intrinsic connectivity networks share topographically arranged functional connectivity with the cerebellum. However, the contribution of cerebellar nodes to distributed network organization and function remains poorly understood. In humans, we applied theta-burst transcranial magnetic stimulation, guided by subject-specific connectivity, to regions of the cerebellum to evaluate the functional relevance of connections between cerebellar and cerebral cortical nodes in different networks. We demonstrate that changing activity in the human lateral cerebellar Crus I/II modulates the cerebral default mode network, whereas vermal lobule VII stimulation influences the cerebral dorsal attention system. These results provide novel insights into the distributed, but anatomically specific, modulatory impact of cerebellar effects on large-scale neural network function.

Transcranial magnetic stimulation (TMS) is a neurophysiologic technique to noninvasively induce a controlled current pulse in a prespecified cortical target. This can be used to transiently disrupt the function of the targeted cortical region and explore causal relations to behavior, assess cortical reactivity, and map out functionally relevant brain regions, for example during presurgical assessments. Particularly when applied repetitively, TMS can modify cortical excitability and the effects can propagate trans-synaptically to interconnected cortical, subcortical, and spinal cord regions. As such, TMS can be used to assess the functional integrity of neural circuits and to modulate brain activity with potential therapeutic intent.

Communication between cortical regions is necessary for optimal cognitive processing. Functional relationships between cortical regions can be inferred through measurements of temporal synchrony in spontaneous activity patterns. These relationships can be further elaborated by surveying effects of cortical lesions upon inter-regional connectivity. Lesions to cortical hubs and heteromodal association regions are expected to induce distributed connectivity changes and higher-order cognitive deficits, yet their functional consequences remain relatively unexplored. Here, we used resting-state fMRI to investigate intrinsic functional connectivity (FC) and graph theoretical metrics in 12 patients with circumscribed lesions of the medial prefrontal cortex (mPFC) portion of the Default Network (DN), and compared these metrics with those observed in healthy matched comparison participants and a sample of 1139 healthy individuals. Despite significant mPFC destruction, patients did not demonstrate weakened intrinsic FC among undamaged DN nodes. Instead, network-specific changes were manifested as weaker negative correlations between the DN and attentional and somatomotor networks. These findings conflict with the DN being a homogenous system functionally anchored at mPFC. Rather, they implicate a role for mPFC in mediating cross-network functional interactions. More broadly, our data suggest that lesions to association cortical hubs might induce clinical deficits by disrupting communication between interacting large-scale systems.

Most candidate genes and genetic abnormalities linked to autism spectrum disorders (ASD) are thought to play a role in developmental and experience-dependent plasticity. As a possible index of plasticity, we assessed the modulation of motor corticospinal excitability in individuals with Asperger’s syndrome (AS) using transcranial magnetic stimulation (TMS). We measured the modulatory effects of theta-burst stimulation (TBS) on motor evoked potentials (MEPs) induced by single-pulse TMS in individuals with AS as compared with age-, gender- and IQ-matched neurotypical controls. The effect of TBS lasted significantly longer in the AS group. The duration of the TBS-induced modulation alone enabled the reliable classification of a second study cohort of subjects as AS or neurotypical. The alteration in the modulation of corticospinal excitability in AS is thought to reflect aberrant mechanisms of plasticity, and might provide a valuable future diagnostic biomarker for the disease and ultimately offer a target for novel therapeutic interventions.

Intrinsic activity in the brain is organized into networks. Although constrained by their anatomical connections, functional correlations between nodes of these networks reorganize dynamically. Dynamic organization implies that couplings between network nodes can be reconfigured to support processing demands. To explore such reconfigurations, we combined repetitive transcranial magnetic stimulation (rTMS) and functional connectivity MRI (fcMRI) to modulate cortical activity in one node of the default network, and assessed the effect of this upon functional correlations throughout the network. Two different frequencies of rTMS to the same default network node (the left posterior inferior parietal lobule, lpIPL) induced two topographically distinct changes in functional connectivity. High-frequency rTMS to lpIPL decreased functional correlations between cortical default network nodes, but not between these nodes and the hippocampal formation. In contrast, low frequency rTMS to lpIPL did not alter connectivity between cortical default network nodes, but increased functional correlations between lpIPL and the hippocampal formation. These results suggest that the default network is composed of (at least) two subsystems. More broadly, the finding that two rTMS stimulation regimens to the same default network node have distinct effects reveals that this node is embedded within a network that possesses multiple, functionally distinct relationships among its distributed partners.

The brain’s default network (DN) is comprised of several cortical regions demonstrating robust intrinsic connectivity at rest. The authors sought to examine the differential effects of emotional reasoning and reasoning under certainty upon the DN through the employment of an event-related fMRI design in healthy participants. Participants were presented with syllogistic arguments which were organized into a 2 × 2 factorial design in which the first factor was emotional salience and the second factor was certainty/uncertainty. We demonstrate that regions of the DN were activated both during reasoning that is emotionally salient and during reasoning which is more certain, suggesting that these processes are neurally instantiated on a network level. In addition, we present evidence that emotional reasoning preferentially activates the dorsomedial (dMPFC) subsystem of the DN, whereas reasoning in the context of certainty activates areas specific to the DN’s medial temporal (MTL) subsystem. We postulate that emotional reasoning mobilizes the dMPFC subsystem of the DN because this type of reasoning relies upon the recruitment of introspective and self-relevant data such as personal bias and temperament. In contrast, activation of the MTL subsystem during certainty argues that this form of reasoning involves the recruitment of mnemonic and semantic associations to derive conclusions.

Heterogeneity within the Alzheimer's disease (AD) syndromic spectrum is typically classified in a domain-specific manner (e.g., language vs. visual cognitive function). The central aim of this study was to investigate whether impairment in visual cognitive tasks thought to be subserved by posterior cortical dysfunction in non-amnestic AD presentations is associated with tau, amyloid, or neurodegeneration in those regions using 18F-AV-1451 and 11C-PiB positron emission tomography (PET) and magnetic resonance imaging (MRI). Sixteen amyloid-positive patients who met criteria for either Posterior Cortical Atrophy (PCA; n = 10) or logopenic variant Primary Progressive Aphasia (lvPPA; n = 6) were studied. All participants underwent a structured clinical assessment, neuropsychological battery, structural MRI, amyloid PET, and tau PET. The neuropsychological battery included two visual cognitive tests: VOSP Number Location and Benton Facial Recognition. Surface-based whole-cortical general linear models were used to first explore the similarities and differences between these biomarkers in the two patient groups, and then to assess their regional associations with visual cognitive test performance. The results show that these two variants of AD have both dissociable and overlapping areas of tau and atrophy, but amyloid is distributed with a stereotyped localization in both variants. Performance on both visual cognitive tests were associated with tau and atrophy in the right lateral and medial occipital association cortex, superior parietal cortex, and posterior ventral occipitotemporal cortex. No cortical associations were observed with amyloid PET. We further demonstrate that cortical atrophy has a partially mediating effect on the association between tau pathology and visual cognitive task performance. Our findings show that non-amnestic variants of AD have partially dissociable spatial patterns of tau and atrophy that localize as expected based on symptoms, but similar patterns of amyloid. Further, we demonstrate that impairments of visual cognitive dysfunction are strongly associated with tau in visual cortical regions and mediated in part by atrophy. Keywords: Alzheimer's disease, Amyloid imaging, Tau imaging, Brain atrophy, Visual function

There are currently two techniques to manipulate brain function non-invasively: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). These brain stimulation techniques work to cause long-term change within the brain. We have been combining noninvasive brain stimulation with functional magnetic resonance imaging (fMRI) to investigate the plasticity of brain networks. When fMRI is used as an outcome measure, it is possible to identify the specificity of tDCS-modulated plasticity in a visual rehabilitation protocol. Alternatively, fMRI can be used as a guide for stimulation. Brain stimulation with TMS affects neural networks, and fMRI guidance combined with an understanding of network effects of TMS may improve TMS therapy.

The authors evaluated the 60-Second Test (SST), a brief test of mental concentration, as a supplement to the Glasgow Coma Scale (GCS) for monitoring verbally responsive patients in the neuro-intensive care unit. The SST demonstrated excellent reliability and was abnormal in 79% of patients assigned a top GCS score of 15. However, both tests had poor responsiveness to clinically identified changes in level of consciousness (LOC). The SST is sensitive to subtle alterations in LOC but, like the GCS, may have limitations as a monitoring tool in the neurocritical care setting.

Brain plasticity can be conceptualized as nature’s invention to overcome limitations of the genome and adapt to a rapidly changing environment. As such, plasticity is an intrinsic property of the brain across the life-span. However, mechanisms of plasticity may vary with age. The combination of transcranial magnetic stimulation (TMS) with electroencephalography (EEG) or functional magnetic resonance imaging (fMRI) enables clinicians and researchers to directly study local and network cortical plasticity, in humans in vivo, and characterize their changes across the age-span. Parallel, translational studies in animals can provide mechanistic insights. Here, we argue that, for each individual, the efficiency of neuronal plasticity declines throughout the age-span and may do so more or less prominently depending on variable ‘starting-points’ and different ‘slopes of change’ defined by genetic, biological, and environmental factors. Furthermore, aberrant, excessive, insufficient, or mistimed plasticity may represent the proximal pathogenic cause of neurodevelopmental and neurodegenerative disorders such as autism spectrum disorders or Alzheimer’s disease.

Theta burst stimulation (TBS) protocols have recently emerged as a method to transiently alter cortical excitability in the human brain through repetitive transcranial magnetic stimulation. TBS involves applying short trains of stimuli at high frequency repeated at intervals of 200 milliseconds. Because repetitive transcranial magnetic stimulation is known to carry a risk of seizures, safety guidelines have been established. TBS has the theoretical potential of conferring an even higher risk of seizure than other repetitive transcranial magnetic stimulation protocols because it delivers high-frequency bursts. In light of the recent report of a seizure induced by TBS, the safety of this new protocol deserves consideration. We performed an English language literature search and reviewed all studies published from May 2004 to December 2009 in which TBS was applied. The adverse events were documented, and crude risk was calculated. The majority of adverse events attributed to TBS were mild and occurred in 5% of subjects. Based on this review, TBS seems to be a safe and efficacious technique. However, given its novelty, it should be applied with caution. Additionally, this review highlights the need for rigorous documentation of adverse events associated with TBS and intensity dosing studies to assess the seizure risk associated with various stimulation parameters (e.g., frequency, intensity, and location).

Deterioration of motor and cognitive performance with advancing age is well documented, but its cause remains unknown. Animal studies dating back to the late 1970s reveal that age-associated neurocognitive changes are linked to age-dependent changes in synaptic plasticity, including alterations of long-term potentiation and depression (LTP and LTD). Non-invasive brain stimulation techniques enable measurement of LTP- and LTD-like mechanisms of plasticity, in vivo, in humans, and may thus provide valuable insights. We examined the effects of a 40-s train of continuous theta-burst stimulation (cTBS) to the motor cortex (600 stimuli, three pulses at 50 Hz applied at a frequency of 5 Hz) on cortico-spinal excitability as measured by the motor evoked potentials (MEPs) induced by single-pulse transcranial magnetic stimulation before and after cTBS in the contralateral first dorsal interosseus muscle. Thirty-six healthy individuals aged 19–81 years old were studied in two sites (Boston, USA and Barcelona, Spain). The findings did not differ across study sites. We found that advancing age is negatively correlated with the duration of the effect of cTBS (r = −0.367; p = 0.028) and the overall amount of corticomotor suppression induced by cTBS (r = −0.478; p = 0.003), and positively correlated with the maximal suppression of amplitude on motor evoked responses in the target muscle (r = 0.420; p = 0.011). We performed magnetic resonance imaging (MRI)-based individual morphometric analysis in a subset of subjects to demonstrate that these findings are not explained by age-related brain atrophy or differences in scalp-to-brain distance that could have affected the TBS effects. Our findings provide empirical evidence that the mechanisms of cortical plasticity area are altered with aging and their efficiency decreases across the human lifespan. This may critically contribute to motor and possibly cognitive decline.

The default mode network is a group of brain regions that are active when an individual is not focused on the outside world and the brain is at "wakeful rest."1,2,3 It is thought the default mode network corresponds to self-referential or "internal mentation".2,3 It has been hypothesized that, in humans, activity within the default mode network is correlated with certain pathologies (for instance, hyper-activation has been linked to schizophrenia 4,5,6 and autism spectrum disorders 7 whilst hypo-activation of the network has been linked to Alzheimer's and other neurodegenerative diseases 8). As such, noninvasive modulation of this network may represent a potential therapeutic intervention for a number of neurological and psychiatric pathologies linked to abnormal network activation. One possible tool to effect this modulation is Transcranial Magnetic Stimulation: a non-invasive neurostimulatory and neuromodulatory technique that can transiently or lastingly modulate cortical excitability (either increasing or decreasing it) via the application of localized magnetic field pulses.9 In order to explore the default mode network's propensity towards and tolerance of modulation, we will be combining TMS (to the left inferior parietal lobe) with functional magnetic resonance imaging (fMRI). Through this article, we will examine the protocol and considerations necessary to successfully combine these two neuroscientific tools.

Objective Previous work has demonstrated that corticospinal facilitation from 20 Hz repetitive transcranial magnetic stimulation (rTMS) was greater during a second rTMS session 24 h after the first. We sought to determine whether such metaplasticity is dependent on a particular phase of the normal sleep–wake/circadian cycle. Methods Twenty healthy participants received two sessions of 20 Hz rTMS over the hand motor cortex (M1) spaced 12 h apart, either over-day or overnight. Results Baseline corticospinal excitability did not differ by group or session. The time-of-day of Session 1 did not influence the relative increase in excitability following rTMS. However, the increase in excitability from the second rTMS session was 2-fold greater in the overnight group. Conclusions When a night with sleep follows rTMS to M1, the capacity to induce subsequent plasticity in M1 is enhanced, suggesting sleep–wake and/or circadian-dependent modulation of processes of metaplasticity. Significance TMS treatment of neuropsychiatric disorders entails repeated sessions of rTMS. Our findings suggest that the timing of sessions relative to the sleep–wake/circadian cycle may be a critical factor in the cumulative effect of treatment. Future studies using this paradigm may provide mechanistic insights into human metaplasticity, leading to refined strategies to enhance non-invasive stimulation therapies.