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Introduction This study aims to measure frequency and correlates of initial idiopathic psychiatric diagnosis in a cohort of 147 patients with Frontotemporal Dementia (FTD)-spectrum disorders. Methods Participants were evaluated at the National Institutes of Health in Bethesda, Maryland. Initial participant diagnoses were determined by chart review and patient and informant interviews. Logistic regression was used to assess the relationships between diagnosis and age of symptom onset, gender, education, family history of psychiatric illness, and family history of dementia. Additional exploratory analyses investigated patients’ first symptom type. Results 25% (n=43) of all the patients reviewed were initially misdiagnosed with an idiopathic psychiatric illness, which is less than half the commonly cited 50% rate.3 Depression was the most common misdiagnosis (46.5%). Family history of dementia, family history of mental illness and an exploratory analysis of behavioral first symptoms suggested significant association with a greater likelihood of initial idiopathic psychiatric diagnosis in FTD patients. Discussion This data confirms patterns of initial idiopathic psychiatric diagnosis in FTD and elucidates potential factors underlying misdiagnosis. Potential implications for patient outcomes, caregiver burden and healthcare costs are discussed.

Military and law enforcement breachers are exposed to many low-level blasts during their training and occupational experiences in which they detonate explosives to force entry into secured structures. There is a concern that exposure to these repetitive blast events in career breachers could result in cumulative neurological effects. This study aimed to determine concentrations of neurofilament light (NF-L), tau, and amyloid-beta 42 (Aβ42) in serum and in neuronal-derived extracellular vesicles (EVs) in an experienced breacher population, and to examine biomarker associations with neurobehavioral symptoms. Thirty-four participants enrolled in the study: 20 experienced breachers and 14 matched military or civilian law enforcement controls. EV tau concentrations were significantly elevated in experienced breachers (0.3301 ± 0.5225) compared to controls (−0.4279 ± 0.7557; F = 10.43, p = 0.003). No statistically significant changes were observed in EV levels of NF-L or Aβ42 or in serum levels of NF-L, tau, or Aβ42 (p’s > 0.05). Elevated EV tau concentrations correlated with increased Neurobehavioral Symptom Inventory (NSI) score in experienced breachers (r = 0.596, p = 0.015) and predicted higher NSI score (F(1,14) = 7.702, p = 0.015, R2 = 0.355). These findings show that neuronal-derived EV concentrations of tau are significantly elevated and associated with neurobehavioral symptoms in this sample of experienced breachers who have a history of many low-level blast exposures.

Combat military and civilian law enforcement personnel may be exposed to repetitive low-intensity blast events during training and operations. Persons who use explosives to gain entry (i.e., breach) into buildings are known as “breachers” or dynamic entry personnel. Breachers operate under the guidance of established safety protocols, but despite these precautions, breachers who are exposed to low-level blast throughout their careers frequently report performance deficits and symptoms to healthcare providers. Although little is known about the etiology linking blast exposure to clinical symptoms in humans, animal studies demonstrate network-level changes in brain function, alterations in brain morphology, vascular and inflammatory changes, hearing loss, and even alterations in gene expression after repeated blast exposure. To explore whether similar effects occur in humans, we collected a comprehensive data battery from 20 experienced breachers exposed to blast throughout their careers and 14 military and law enforcement controls. This battery included neuropsychological assessments, blood biomarkers, and magnetic resonance imaging measures, including cortical thickness, diffusion tensor imaging of white matter, functional connectivity, and perfusion. To better understand the relationship between repetitive low-level blast exposure and behavioral and imaging differences in humans, we analyzed the data using similarity-driven multi-view linear reconstruction (SiMLR). SiMLR is specifically designed for multiple modality statistical integration using dimensionality-reduction techniques for studies with high-dimensional, yet sparse, data (i.e., low number of subjects and many data per subject). We identify significant group effects in these data spanning brain structure, function, and blood biomarkers.

Background: Changes in sexual behaviors in frontotemporal dementia (FTD) are common and multifaceted, but not well characterized. Objective: To characterize changes in sexual behaviors and intimacy in FTD compared to corticobasal syndrome (CBS) and normal controls (NC), and to evaluate the neuroanatomical associations of these changes. Methods: Spouses of 30 FTD patients, 20 CBS patients, and 35 NC completed the Sexual Symptoms in Neurological Illness and Injury Questionnaire (SNIQ), which captures changes in sexual interest, inappropriate sexual behaviors, and prosocial sexual behaviors. 25 patients with FTD and 14 patients with CBS also received 18-flouorodeoxyglucose positron-emission topography (18FDG-PET) scans to determine the metabolic changes associated with these symptoms. Results: FTD patients showed a greater increase in inappropriate sexual behaviors than CBS patients [p = 0.009] and NC [p

Prism adaptation (PA) alters spatial cognition according to the direction of visual displacement by temporarily modifying sensorimotor mapping. Right-shifting prisms (right PA) improve neglect of left space in patients, possibly by decreasing activity in the left hemisphere and increasing it in the right. Left PA shifts attention to the right in healthy individuals by an opposite mechanism. However, functional imaging studies of PA are inconsistent, perhaps because of differing activation tasks. We measured resting-state functional connectivity (RSFC) in healthy individuals before and after PA. Right, vs. left, PA decreased RSFC in the navigation network defined by the right posterior parietal cortices (PPCs), hippocampus, and cerebellum. Right PA, relative to baseline, increased RSFC between regions within both PPCs and between the PPCs and the right middle frontal gyrus, whereas left PA decreased RSFC between these regions. These results show that right PA modulates connectivity within the right-hemisphere navigation network and shifts attention leftward by increasing connectivity in the right frontoparietal network and left PA produces essentially opposite effects, consistent with the interhemispheric competition model. These finding explain the action of PA on intact cognition and will help optimize interventions in neglect patients.

Objective Repetitive transcranial magnetic stimulation (rTMS) can cause potentially useful changes in brain functional connectivity (FC), but the number of treatment sessions required is unknown. We applied the continual reassessment method (CRM), a Bayesian, adaptive, dose-finding procedure to a rTMS paradigm in an attempt to answer this question. Materials and methods The sample size was predetermined at 15 subjects and the cohort size was set with three individuals (i.e., five total cohorts). In a series of consecutive daily sessions, we delivered rTMS to the left posterior parietal cortex and measured resting-state FC with fMRI in a predefined hippocampal network in the left hemisphere. The session number for each successive cohort was determined by the CRM algorithm. We set a response criterion of a 0.028 change in FC between the hippocampus and the parietal cortex, which was equal to the increase seen in 87.5% of participants in a previous study using five sessions. Results A ≥criterion change was observed in 9 of 15 participants. The CRM indicated that greater than four sessions are required to produce the criterion change reliably in future studies. Conclusions The CRM can be adapted for rTMS dose finding when a reliable outcome measure, such as FC, is available. The minimum effective dose needed to produce a criterion increase in FC in our hippocampal network of interest at 87.5% efficacy was estimated to be greater than four sessions. This study is the first demonstration of a Bayesian, adaptive method to explore a rTMS parameter.

Repetitive transcranial magnetic stimulation (rTMS) targeted to the hippocampal network via the inferior parietal cortex (HN-Stim) can strengthen hippocampal-cortical connectivity and improve episodic memory, offering a potential clinical intervention. However, acceptance of this technique has been tempered by the infrequent reproduction of findings in rTMS research on cognitive processes. We tested the reproducibility of the HN-Stim effect on episodic memory in our laboratory using different procedures from those previously published. We tested episodic memory in 29 participants before, one day, and one week after, three consecutive days of 20 Hz HN-Stim. Participants received stimulation targeted either to the area of inferior parietal cortex maximally connected to the left anterior hippocampus (HN-Stim; N = 14) or the vertex (control; N = 15), where we expected no effect. HN-Stim increased episodic memory performance one day, but not one week, after the last stimulation session. While failing to reproduce the lasting beneficial effect on memory found by others after five days of treatment, we found robust effects on behavior 24 hours after treatment. HN-Stim is a safe and reliable means of enhancing episodic memory and may have potential for boosting learning and treating memory deficits.

Nondeclarative learning and memory involve acquiring and retaining skills or habits and include subtypes, such as procedural learning, priming, and classical conditioning. Animal studies, lesion, and functional imaging studies in humans have implicated a range of brain areas, including frontal and parietal cortical regions, basal ganglia, cerebellum in these functions. Repetitive transcranial magnetic stimulation (rTMS) can modulate functional connectivity in brain networks and provide causal evidence for their involvement in behavior. In this chapter, we review the use of rTMS to investigate the brain networks underlying nondeclarative learning by stimulating their cortical nodes and examining the effects of these interventions on behavior and imaging measures of brain activity and connectivity, with emphasis on how the timing of stimulation (before, during, or after learning) affects these measures.

Objective The goal of this effort to investigate if experienced breachers, professionals with a career history of exposure to repeated low-level blasts, exhibited postural instability. Methods Postural data were examined using traditional tests of means and compared to normative data. Results Breachers had significantly lower NeuroCom Sensory Organization Test (SOT) visual scores (within normative limits), prolonged Limits of Stability (LOS) test reaction time (30% of breachers and 7% of controls testing abnormal), and slower LOS movement velocity (21% of breachers and 0% of controls testing abnormal) compared to controls. Conclusion Our LOS test findings are like those previously reported for students in the military breacher training course and seem to indicate that while acute effects of blasts on sensory control of balance fade away, effects on postural LOS persist over time.

Recent studies used fMRI population receptive field (pRF) mapping to demonstrate that retinotopic organization extends from primary visual cortex to ventral and dorsal visual pathways by quantifying visual field maps, receptive field size, and laterality throughout multiple areas. Visuospatial representation in the posterior parietal cortex (PPC) is modulated by attentional deployment, raising the question of whether spatial representation in the PPC is dynamic and flexible and that this flexibility contributes to visuospatial learning. To answer this question, changes in spatial representation within PPC, as measured with pRF mapping, were recorded before and after visuomotor adaptation. Visuospatial input was laterally manipulated, rightward or leftward, via prism adaptation, a well-established visuomotor technique that modulates visuospatial performance. Based on existing models of prism adaptation mechanism of action, we predicted left prism adaptation to produce a right visuospatial bias via an increasing pRF size in the left parietal cortex. However, our hypothesis was agnostic as to whether right PPC will show an opposite effect given the bilateral bias to right visual field. Findings show that adaptation to left-shifting prisms increases pRF size in both PPCs, while leaving space representation in early visual cortex unchanged. This is the first evidence that prism adaptation drives a dynamic reorganization of response profiles in the PPC. Our results show that spatial representation in the PPC not only reflects changes driven by attentional deployment but dynamically changes in response to visuomotor adaptation. Furthermore, our results provide support for using prism adaptation as a tool to rehabilitate visuospatial deficits.SIGNIFICANCE STATEMENTRepresentation of space in the posterior parietal cortex (PPC) is reflective of attentional selection. Deploying attention to a certain spatial location modulates response profiles of a corresponding set of neurons with receptive fields in the corresponding spatial location. Here, we show that visuomotor adaptation accomplished through left-shifting prism adaptation dynamically changes the representation of space in the PPC while preserving early visual representations. This is the first evidence that visuomotor adaptation drives an instant reorganization of spatial representation in PPC. This result has implications for understanding the dynamic organization of spatial representation in the PPC and for the rehabilitation of patients with neglect syndrome, whose spatial attention is compromised.

Classical lesion studies led to a consensus that episodic and procedural memory arises from segregated networks identified with the hippocampus and the caudate nucleus, respectively. Neuroimaging studies, however, show that competitive and cooperative interactions occur between networks during memory tasks. Furthermore, causal experiments to manipulate connectivity between these networks have not been performed in humans. Although nodes common to both networks, such as the precuneus and ventrolateral thalamus, may mediate their interaction, there is no experimental evidence for this. We tested how network-targeted noninvasive brain stimulation affects episodic–procedural network interactions and how these network manipulations affect episodic and procedural memory in healthy young adults. Compared to control (vertex) stimulation, hippocampal network-targeted stimulation increased within-network functional connectivity and hippocampal connectivity with the caudate. It also increased episodic, relative to procedural, memory, and this persisted one week later. The differential effect on episodic versus procedural memory was associated with increased functional connectivity between the caudate, precuneus, and ventrolateral thalamus. These findings provide direct evidence of episodic–procedural network competition, mediated by regions common to both networks. Enhanced hippocampal network connectivity may boost episodic, but decrease procedural, memory by co-opting resources shared between networks.

Persistent fatigue is common among military servicemembers returning from deployment, especially those with a history of mild traumatic brain injury (mTBI). The purpose of this study was to characterize fatigue following deployment using the Multidimensional Fatigue Inventory (MFI), a multidimensional self-report instrument. The study was developed to test the hypothesis that if fatigue involves disrupted effort/reward processing, this should manifest as altered basal ganglia functional connectivity as observed in other amotivational states.Twenty-eight current and former servicemembers were recruited and completed the MFI. All 28 participants had a history of at least one mTBI during deployment. Twenty-six participants underwent resting-state functional MRI. To test the hypothesis that fatigue was associated with basal ganglia functional connectivity, the investigators measured correlations between MFI subscale scores and the functional connectivity of the left and right caudate, the putamen, and the globus pallidus with the rest of the brain, adjusting for the presence of depression.The investigators found a significant correlation between functional connectivity of the left putamen and bilateral superior frontal gyri and mental fatigue scores. No correlations with the other MFI subscales survived multiple comparisons correction.This exploratory study suggests that mental fatigue in military servicemembers with a history of deployment with at least one mTBI may be related to increased striatal-prefrontal functional connectivity, independent of depression. A finding of effort/reward mismatch may guide future treatment approaches.

Objective Transcranial magnetic stimulation (TMS) can cause seizures in healthy individuals and patients. However, the rate at which this occurs is unknown. We estimated the risk of seizure and other adverse events with TMS. Methods We surveyed laboratories and clinics about seizures and other events observed between 2012 and 2016 (inclusive). Respondents (N = 174) reported an estimated 318,560 TMS sessions. Results Twenty-four seizures were reported (.08/1000 sessions). TMS delivered within published guidelines to subjects without recognized risk factors caused 4 seizures ( 1 Hz) rTMS delivered within published guidelines to individuals without known risk factors was no more likely to cause seizures than low-frequency and single/paired-pulse TMS. Subject risk factors (e.g., brain lesions and epilepsy) increased seizure risk substantially. Seizures appeared more common when safety guidelines were exceeded. Seizures were most likely to occur within the first few exposures to TMS. Conclusions TMS delivered within published guidelines to individuals without risk factors appears to cause fewer than 1 seizure per 60,000 sessions. The assumption that repetitive TMS is riskier than single and paired pulses under these conditions should be reevaluated. Significance This information should help laboratories, clinics, and regulatory authorities form updated safety policies for TMS.

Attention-deficit/hyperactivity disorder, the most prevalent developmental disorder in childhood, is a biologically heterogenous condition characterized by impaired attention and impulse control as well as motoric hyperactivity and anomalous motor skill development. Neuropsychological testing often demonstrates impairments in motivation and reward-related decision making in attention-deficit/hyperactivity disorder, believed to indicate dysfunction of the dopamine reward pathway. Development of reliable, non-invasive, easily obtained and quantitative biomarkers correlating with the presence and severity of clinical symptoms and impaired domains of function could aid in identifying meaningful attention-deficit/hyperactivity disorder subgroups and targeting appropriate treatments. To this end, 55 (37 male) 8–12-year-old children with attention-deficit/hyperactivity disorder and 50 (32 male) age-matched, typically-developing controls were enrolled in a transcranial magnetic stimulation protocol—used previously to quantify cortical disinhibition in both attention-deficit/hyperactivity disorder and Parkinson’s Disease—with a child-friendly reward motivation task. The primary outcomes were reward task-induced changes in short interval cortical inhibition and up-modulation of motor evoked potential amplitudes, evaluated using mixed model, repeated measure regression. Our results show that both reward cues and reward receipt reduce short-interval cortical inhibition, and that baseline differences by diagnosis (less inhibition in attention-deficit/hyperactivity disorder) were no longer present when reward was cued or received. Similarly, both reward cues and reward receipt up-modulated motor evoked potential amplitudes, but, differentiating the two groups, this Task-Related-Up-Modulation was decreased in children with attention-deficit/hyperactivity disorder. Furthermore, more severe hyperactive/impulsive symptoms correlated significantly with less up-modulation with success in obtaining reward. These results suggest that in children with attention-deficit/hyperactivity disorder, short interval cortical inhibition may reflect baseline deficiencies as well as processes that normalize performance under rewarded conditions. Task-Related-Up-Modulation may reflect general hypo-responsiveness in attention-deficit/hyperactivity disorder to both reward cue and, especially in more hyperactive/impulsive children, to successful reward receipt. These findings support transcranial magnetic stimulation evoked cortical inhibition and task-induced excitability as biomarkers of clinically relevant domains of dysfunction in childhood attention-deficit/hyperactivity disorder., Graphical Abstract Graphical Abstract, In this study of reward effects in motor cortex in children with attention-deficit/hyperactivity disorder (ADHD) compared to their typically developing peers, Detrick et al. report that transcranial magnetic stimulation-evoked short-interval cortical inhibition and task-related up-modulation significantly differed between groups and may therefore represent measurable biomarkers in ADHD.

This article is based on a consensus conference, promoted and supported by the International Federation of Clinical Neurophysiology (IFCN), which took place in Siena (Italy) in October 2018. The meeting intended to update the ten-year-old safety guidelines for the application of transcranial magnetic stimulation (TMS) in research and clinical settings (Rossi et al., 2009). Therefore, only emerging and new issues are covered in detail, leaving still valid the 2009 recommendations regarding the description of conventional or patterned TMS protocols, the screening of subjects/patients, the need of neurophysiological monitoring for new protocols, the utilization of reference thresholds of stimulation, the managing of seizures and the list of minor side effects. New issues discussed in detail from the meeting up to April 2020 are safety issues of recently developed stimulation devices and pulse configurations; duties and responsibility of device makers; novel scenarios of TMS applications such as in the neuroimaging context or imaging-guided and robot-guided TMS; TMS interleaved with transcranial electrical stimulation; safety during paired associative stimulation interventions; and risks of using TMS to induce therapeutic seizures (magnetic seizure therapy). An update on the possible induction of seizures, theoretically the most serious risk of TMS, is provided. It has become apparent that such a risk is low, even in patients taking drugs acting on the central nervous system, at least with the use of traditional stimulation parameters and focal coils for which large data sets are available. Finally, new operational guidelines are provided for safety in planning future trials based on traditional and patterned TMS protocols, as well as a summary of the minimal training requirements for operators, and a note on ethics of neuroenhancement.

Background: The etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach. Methods: FUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold. Results: We identified 73 significant gene–tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed. Conclusions: We identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.

Introduction The purpose of this study was to explore the effect of low testosterone level on whole-brain resting state (RS) connectivity in male veterans with symptoms such as sleep disturbance, fatiguability, pain, anxiety, irritability, or aggressiveness persisting after mild traumatic brain injury (mTBI). Follow-up analyses were performed to determine if sleep scores affected the results. Materials and Methods In our cross-sectional design study, RS magnetic resonance imaging scans on 28 veterans were performed, and testosterone, sleep quality, mood, and post-traumatic stress symptoms were measured. For each participant, we computed the average correlation of each voxel’s time-series with the rest of the voxels in the brain, then used AFNI’s 3dttest++ on the group data to determine whether the effects of testosterone level on whole-brain connectivity were significant. We then performed follow-up region of interest-based RS analyses of testosterone, with and without sleep quality as a covariate. The study protocol was approved by the National Institute of Health’s Combined Neuroscience Institutional Review Board. Results Sixteen participants reported repeated blast exposure in theater, leading to symptoms; the rest reported exposure to a single blast or a nonblast TBI. Thirty-three percent had testosterone levels Conclusion Lower testosterone levels were correlated with lower connectivity of the LPhG. Weaknesses of this study include a retrospective design based on self-report of mTBI and the lack of a control group without TBI. Without a control group or pre-injury testosterone measures, we were not able to attribute the rate of low testosterone in our participants to TBI per se. Also testosterone levels were checked only once. The high rate of low testosterone level that we found suggests there may be an association between low testosterone level and greater post-traumatic stress disorder symptoms following deployment, but the causality of the relationships between TBI and deployment stress, testosterone level, behavioral symptomatology, and LPhG connectivity remains to be determined. Our study on men with persistent symptoms postdeployment and post-mTBI may help us understand the role of low testosterone and sleep quality in persistent symptoms and may be important in developing therapeutic interventions. Our results highlight the role of the LPhG, as we found that whole-brain connectivity in that region was positively associated with testosterone level, with only a limited portion of that effect attributable to sleep quality.

Background: Blast exposure is a potential hazard in modern military operations and training, especially for some military occupations. Helmets, peripheral armor, hearing protection, and eye protection worn by military personnel provide some acute protection from blast effects but may not fully protect personnel against cumulative effects of repeated blast overpressure waves experienced over a career. The current study aimed to characterize the long-term outcomes of repeated exposure to primary blast overpressure in experienced career operators with an emphasis on the assessment of hearing and vestibular outcomes.Methods: Participants included experienced “breachers” (military and law enforcement explosives professionals who gain entry into structures through controlled detonation of charges) and similarly aged and experienced “non-breachers” (non-breaching military and law enforcement personnel). Responses to a clinical interview and performance on audiological and vestibular testing were compared.Results: Hearing loss, ringing in the ears, irritability, and sensitivity to light or noise were more common among breachers than non-breachers. Breachers reported more combat exposure than non-breachers, and subsequently, memory loss and difficulty concentrating were associated with both breaching and combat exposure. Vestibular and ocular motor outcomes were not different between breachers and non-breachers.Conclusion: Hearing-related, irritability, and sensitivity outcomes are associated with a career in breaching. Future studies examining long-term effects of blast exposure should take measures to control for combat exposure.

Funder: QingLan Research Project of Jiangsu for Outstanding Young Teachers, Funder: Project funded by Postdoctoral Science Foundation of Xuzhou Medical University, Funder: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical University, We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.

Repetitive transcranial magnetic stimulation (rTMS) of the inferior parietal cortex (IPC) increases resting-state functional connectivity (rsFC) of the hippocampus with the precuneus and other posterior cortical areas and causes proportional improvement of episodic memory. The anatomical pathway responsible for the propagation of these effects from the IPC is unknown and may not be direct. Using diffusion tensor imaging, we examined whether individual differences in fractional anisotropy (FA), a tensor-derived quantity related to white matter properties, in pathways between the IPC and medial temporal lobe (MTL), via the parahippocampal cortex and the precuneus, accounted for individual differences in hippocampal rsFC and memory change after rTMS. FA in the IPC-parahippocampal pathway was associated with rsFC change in a few small cortical clusters, while FA in the IPC-precuneus pathway was strongly linked to widespread changes in rsFC. FA in both pathways was related to episodic memory, but not to procedural memory. These results implicate pathways to the MTL and to the precuneus in the enhancing effect of parietal rTMS on hippocampal rsFC and memory.

Hemispatial neglect is thought to result from disruption of interhemispheric equilibrium. Right hemisphere lesions deactivate the right frontoparietal network and hyperactivate the left via release from interhemispheric inhibition. Support for this putative mechanism comes from neuropsychological evidence as well as transcranial magnetic stimulation (TMS) studies in healthy subjects, in whom right posterior parietal cortex (PPC) inhibition causes neglect-like, rightward, visuospatial bias. Concurrent TMS and fMRI after right PPC TMS show task-dependent changes but may fail to identify effects of stimulation in areas not directly activated by the specific task, complicating interpretations. We used resting-state functional connectivity (RSFC) after inhibitory TMS over the right PPC to examine changes in the networks underlying visuospatial attention and used diffusion-weighted imaging to measure the structural properties of relevant white matter pathways. In a crossover experiment in healthy individuals, we delivered continuous theta burst TMS to the right PPC and vertex as control condition. We hypothesized that PPC inhibitory stimulation would result in a rightward visuospatial bias, decrease frontoparietal RSFC, and increase the PPC RSFC with the attentional network in the left hemisphere. We also expected that individual differences in fractional anisotropy (FA) of the frontoparietal network and the callosal pathway between the PPCs would account for variability of the TMS-induced RSFC changes. As hypothesized, TMS over the right PPC caused a rightward shift in line bisection judgment and increased RSFC between the right PPC and the left superior temporal gyrus. This effect was inversely related to FA in the posterior corpus callosum. Local inhibition of the right PPC reshapes connectivity in the attentional network and depends significantly on interhemispheric connections.

BACKGROUND: There are currently no disease-targeted treatments for cognitive or behavioral symptoms in patients with behavioral variant frontotemporal dementia (bvFTD). OBJECTIVE: To determine the effect of tolcapone, a specific inhibitor of Catechol-O-Methyltransferase (COMT), in patients with bvFTD. METHODS: In this randomized, double-blind, placebo-controlled, cross-over study at two study sites, we examined the effect of tolcapone on 28 adult outpatients with bvFTD. The primary outcome was reaction time on the N-back cognitive test. As an imaging outcome, we examined differences in the resting blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal intensity between subjects on placebo versus tolcapone performing the N-back test. Secondary outcomes included measures of cognitive performance and behavioral disturbance using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Neuropsychiatric Inventory-Questionnaire (NPI-Q), and Clinical Global Impressions scale (CGI). RESULTS: Tolcapone was well tolerated and no patients dropped out. The most frequent treatment-related adverse event during tolcapone treatment was elevated liver enzymes (21%). There were no significant differences between tolcapone treatment and placebo in the primary or imaging outcomes. However, there were significant differences between RBANS total scores (p < 0.01), NPI-Q total scores (p = 0.04), and CGI total scores (p = 0.035) between treatment conditions which were driven by differences between baseline and tolcapone conditions. Further, there was a trend toward significance between tolcapone and placebo on the CGI (p = 0.078). CONCLUSIONS: Further study of COMT inhibition and related approaches with longer duration of treatment and larger sample sizes in frontotemporal lobar degeneration-spectrum disorders may be warranted.

OBJECTIVE: To assess the effects of the common functional polymorphisms Brain-Derived Neurotrophic Factor (BDNF) val66met and Catechol O-methyltransferase (COMT) val158met on the cognitive, neuropsychiatric, motor symptoms, and MRI findings in participants with Frontotemporal Lobar Degeneration (FTLD) syndromes. METHODS: The Brain-Derived Neurotrophic Factor (BDNF) val66met and the Catechol O-methyltransferase (COMT) val158met polymorphisms were genotyped in 174 participants with FTLD syndromes including frontotemporal dementia (FTD), primary progressive aphasia (PPA) and corticobasal syndrome (CBS). Grey matter volumes, the Delis-Kaplan Executive Function System, Mattis Dementia Rating Scale, Wechsler Memory Scale, and the Neuropsychiatric Inventory were compared between allele groups. RESULTS: The BDNF met allele at position 66 was associated with a decrease in depressive symptoms [F(1, 136)=9.50, p=0.002]. The COMT val allele at position 158 was associated with impairment of executive function [F(1, 76)=6.14, p=0.015] and decreased bilateral volume of the head of the caudate among FTLD patients (uncorrected voxel-level threshold of p < 0.001). Neither polymorphism had a significant effect on motor function. CONCLUSIONS: These findings suggest that common functional polymorphisms likely contribute to the phenotypic variability seen in patients with FTLD syndromes. To our knowledge, this is the first study to implicate BDNF polymorphisms in depressive symptoms in FTLD. Our results also support an association between COMT polymorphisms and degeneration patterns and cognition in FTLD.

The ability to interpret transcranial magnetic stimulation (TMS)-evoked electroencephalography (EEG) potentials (TEPs) is limited by artifacts, such as auditory evoked responses produced by discharge of the TMS coil. TEPs generated from direct cortical stimulation should vary in their topographical activity pattern according to stimulation site and differ from responses to sham stimulation. Responses that do not show these effects are likely to be artifactual. In 20 healthy volunteers, we delivered active and sham TMS to the right prefrontal, left primary motor, and left posterior parietal cortex and compared the waveform similarity of TEPs between stimulation sites and active and sham TMS using a cosine similarity-based analysis method. We identified epochs after the stimulus when the spatial pattern of TMS-evoked activation showed greater than random similarity between stimulation sites and sham vs. active TMS, indicating the presence of a dominant artifact. To do this, we binarized the derivatives of the TEPs recorded from 30 EEG channels and calculated cosine similarity between conditions at each time point with millisecond resolution. Only TEP components occurring before approximately 80 ms differed across stimulation sites and between active and sham, indicating site and condition-specific responses. We therefore conclude that, in the absence of noise masking or other measures to decrease neural artifact, TEP components before about 80 ms can be safely interpreted as stimulation location-specific responses to TMS, but components beyond this latency should be interpreted with caution due to high similarity in their topographical activity pattern.

Visuospatial cognition has an inherent lateralized bias. Individual differences in the direction and magnitude of this bias are associated with asymmetrical D2/3 dopamine binding and dopamine system genotypes. Dopamine level affects feedback-based learning and dopamine signaling asymmetry is related to differential learning from reward and punishment. High D2 binding in the left hemisphere is associated with preference for reward. Prism adaptation (PA) is a simple sensorimotor technique, which modulates visuospatial bias according to the direction of the deviation. Left-deviating prism adaptation (LPA) induces rightward bias in healthy subjects. It is therefore possible that the right side of space increases in saliency along with left hemisphere dopaminergic activity. Right-deviating prism adaptation (RPA) has been used mainly as a control condition because it does not modulate behavior in healthy individuals. Since LPA induces a rightward visuospatial bias as a result of left hemisphere modulation, and higher dopaminergic activity in the left hemisphere is associated with preference for rewarding events we hypothesized that LPA would increase the preference for learning with reward. Healthy volunteers performed a computer-based probabilistic classification task before and after LPA or RPA. Consistent with our predictions, PA altered the preference for rewarded versus punished learning, with the LPA group exhibiting increased learning from reward. These results suggest that PA modulates dopaminergic activity in a lateralized fashion.

Background Neuropsychiatric disorders are a leading source of disability and require novel treatments that target mechanisms of disease. As such disorders are thought to result from aberrant neuronal circuit activity, neuromodulation approaches are of increasing interest given their potential for manipulating circuits directly. Low intensity transcranial electrical stimulation (tES) with direct currents (transcranial direct current stimulation, tDCS) or alternating currents (transcranial alternating current stimulation, tACS) represent novel, safe, well-tolerated, and relatively inexpensive putative treatment modalities. Objective This report seeks to promote the science, technology and effective clinical applications of these modalities, identify research challenges, and suggest approaches for addressing these needs in order to achieve rigorous, reproducible findings that can advance clinical treatment. Methods The National Institute of Mental Health (NIMH) convened a workshop in September 2016 that brought together experts in basic and human neuroscience, electrical stimulation biophysics and devices, and clinical trial methods to examine the physiological mechanisms underlying tDCS/tACS, technologies and technical strategies for optimizing stimulation protocols, and the state of the science with respect to therapeutic applications and trial designs. Results Advances in understanding mechanisms, methodological and technological improvements (e.g., electronics, computational models to facilitate proper dosing), and improved clinical trial designs are poised to advance rigorous, reproducible therapeutic applications of these techniques. A number of challenges were identified and meeting participants made recommendations made to address them. Conclusions These recommendations align with requirements in NIMH funding opportunity announcements to, among other needs, define dosimetry, demonstrate dose/response relationships, implement rigorous blinded trial designs, employ computational modeling, and demonstrate target engagement when testing stimulation-based interventions for the treatment of mental disorders.

The main objectives of this study were to describe P50 and P300 cortical topography in patients with schizophrenia and to define a robust methodology of signal quantification using high density EEG. Within a clinical trial in which patients with schizophrenia and auditory verbal hallucinations were submitted to 10 days rTMS treatment, P50 and P300 were investigated as possible neurophysiological measurements to assess treatment effectiveness together with psychometric scales like Psychotic symptom rating scale (PSYRATS), depression, anxiety and stress scale (DASS) and Quality of Life scale (QoL). Here we describe the technique of collecting P50 and P300 using high-density EEG and we reproduce the preliminary data of P300 in one healthy subject and P50 in two patients and two healthy subjects.

The main purpose of this study was to investigate the relationship between resting state and auditory-motor task electroencephalogram beta and gamma distribution in healthy subjects and subjects with schizophrenia. First, we looked to changes in the resting state EEG distribution in three healthy subjects and in three patients with schizophrenia. We also analyzed high-beta and gamma cortical activity from high-density EEG during a cognitively-driven auditory-motor task in two participants, one normal subject and one diagnosed with schizophrenia. For the auditory-motor task, we asked the participants to press a button using the thumb of both hands independently, during two three-minute sessions. Resting state EEG showed more fragmentation in schizophrenia patients when compared with the healthy participants. During the auditory-motor task, we observed increased cortical fragmentation and clustering during the hand response in the patient and healthy control compared with a resting state EEG. The fragmentation remains stable during both hand response time and reference period located between the command “press” and “do not press” suggesting that this task activates a network which remains similar during the entire task.

Background While transcranial magnetic stimulation (TMS) has been studied for the treatment of psychiatric disorders, emerging evidence supports its use for pain and headache by stimulating either motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC). However, its clinical implementation is hindered due to a lack of consensus in the quality of clinical evidence and treatment recommendation/guideline(s). Thus, working collaboratively, this multinational multidisciplinary expert panel aims to: 1) assess and rate the existing outcome evidence of TMS in various pain/headache conditions; 2) provide TMS treatment recommendation/guidelines for the evaluated conditions and comorbid depression; and 3) assess the cost-effectiveness and technical issues relevant to the long-term clinical implementation of TMS for pain and headache. Methods Seven task groups were formed under the guidance of a 5-member steering committee with four task groups assessing the utilization of TMS in the treatment of Neuropathic Pain (NP), Acute Pain, Primary Headache Disorders, and Posttraumatic Brain Injury related Headaches (PTBI-HA), and remaining three assessing the treatment for both pain and comorbid depression, and the cost-effectiveness and technological issues relevant to the treatment. Results The panel rated the overall level of evidence and recommendability for clinical implementation of TMS as: 1) high and extremely/strongly for both NP and PTBI-HA respectively; 2) moderate for postoperative pain and migraine prevention, and recommendable for migraine prevention. While the use of TMS for treating both pain and depression in one setting is clinically and financially sound, more studies are required to fully assess the long-term benefit of the treatment for the two highly comorbid conditions, especially with neuronavigation. Conclusions After extensive literature review, the panel provided recommendations and treatment guidelines for TMS in managing neuropathic pain and headaches. In addition, the panel also recommended more outcome and cost-effectiveness studies to assess the feasibility of the long-term clinical implementation of the treatment.

ObjectiveCompared to typically developing (TD) peers, children with attention-deficit/hyperactivity disorder (ADHD) consistently demonstrate impaired transcranial magnetic stimulation (TMS)-evoked short interval cortical inhibition (SICI) of motor evoked potentials (MEPs) in resting motor cortex (M1). To determine whether perturbed M1 physiology also reflects clinically relevant behavioral dysfunction, we evaluated M1 physiology during a cognitive control task taxing motor response selection/inhibition.MethodsIn this case-control study, behavioral ratings, motor skill (assessed using standardized examination), and left M1 physiology were evaluated in 131 right-handed, 8- to 12-year-old children (66 ADHD: mean 10.5 years, 43 male; 65 TD: mean 10.6 years, 42 male). The primary outcomes were MEP amplitudes and SICI, evaluated during rest and during a modified “racecar” Slater-Hammel stop signal reaction task, with TMS pulses administered 150 ms prior to the target go action and after the dynamic stop cue.ResultsGo responses were significantly slower (p = 0.01) and more variable (p = 0.002) in ADHD. Children with ADHD showed less M1 SICI at rest (p = 0.02) and during go (p = 0.03) and stop trials (p = 0.02). Rest M1 excitability increased during response inhibition task engagement (p < 0.0001). This Task-Related Up-Modulation (TRUM) was less robust across and within groups, with diminished task upmodulation associated with significantly more severe ADHD behavioral ratings and slower stop signal reaction times.ConclusionChildren with ADHD show anomalous motor cortex physiology, with deficient SICI across behavioral states and less TRUM from rest to action selection. Associations of these physiologic measures with ADHD symptoms and cognitive control measures support further investigation into biological mechanisms.

Wang et al. (2014) found that that five daily sessions of repetitive transcranial magnetic stimulation (rTMS) of the posterior parietal cortex (PPC) significantly increased functional connectivity (FC) in a network centered on the hippocampus, and caused a correlated increase in memory performance. However, this finding has not been reproduced independently and the requirement for five sessions has not been validated. We aimed to reproduce the imaging results of this experiment, focusing on hippocampal FC changes and using fewer days of rTMS. We measured resting state FC before and after three (N= 9) or four (N= 6) consecutive daily PPC rTMS sessions, using similar delivery parameter settings as Wang et al. (2014). Eight subjects received 3 d of rTMS delivered to the vertex as a control. We employed whole-brain and hypothesis-based statistical approaches to test for hippocampal FC changes. Additionally, we calculated FC in 17 brain networks to determine whether the topographic pattern of FC change was similar between studies. We did not include behavioral testing in this study. PPC, but not vertex, rTMS caused significant changes in hippocampal FC to the same regions as in the previous study. Brain-wide changes in hippocampal FC significantly exceeded changes in global connectedness, indicating that the effect of PPC rTMS was specific to the hippocampal network. Baseline hippocampal FC, measured before receiving stimulation, predicted the degree of rTMS-induced hippocampal FC as in the previous study. These findings reproduce the imaging findings of Wang et al. (2014) and show that FC enhancement can occur after only three to four sessions of PPC rTMS.

OBJECTIVE To investigate the association between traumatic brain injury (TBI)-related brain lesions and long-term caregiver burden in relation to dysexecutive syndrome. SETTING National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. PARTICIPANTS A total of 256 participants: 105 combat veterans with TBI, 23 healthy control combat veterans (HCv), and 128 caregivers. OUTCOME MEASURE Caregiver burden assessed by the Zarit Burden Interview at 40 years postinjury. DESIGN Participants with penetrating TBI were compared with HCv on perceived caregiver burden and neuropsychological assessment measures. Data of computed tomographic scans (overlay lesion maps of participants with a penetrating TBI whose caregivers have a significantly high burden) and behavioral statistical analyses were combined to identify brain lesions associated with caregiver burden. RESULTS Burden was greater in caregivers of veterans with TBI than in caregivers of HCv. Caregivers of participants with lesions affecting cognitive and behavioral indicators of dysexecutive syndrome (ie, left dorsolateral prefrontal cortex and dorsal anterior cingulate cortex) showed greater long-term burden than caregivers of participants with lesions elsewhere in the brain. CONCLUSION AND IMPLICATION The TBI-related brain lesions have a lasting effect on long-term caregiver burden due to cognitive and behavioral factors associated with dysexecutive syndrome.

Inhibitory transcranial magnetic stimulation, of which continuous theta burst stimulation (cTBS) is a common form, has been used to inhibit cortical areas during investigations of their function. cTBS applied to the primary motor area (M1) depresses motor output excitability via a local effect and impairs procedural motor learning. This could be due to an effect on M1 itself and/or to changes in its connectivity with other nodes in the learning network. To investigate this issue, we used functional magnetic resonance imaging to measure changes in brain activation and connectivity during implicit procedural learning after real and sham cTBS of M1. Compared to sham, real cTBS impaired motor sequence learning, but caused no local or distant changes in brain activation. Rather, it reduced functional connectivity between motor (M1, dorsal premotor & supplementary motor areas) and visual (superior & inferior occipital gyri) areas. It also increased connectivity between frontal associative (superior & inferior frontal gyri), cingulate (dorsal & middle cingulate), and temporal areas. This potentially compensatory shift in coupling, from a motor-based learning network to an associative learning network accounts for the behavioral effects of cTBS of M1. The findings suggest that the inhibitory transcranial magnetic stimulation affects behavior via relatively subtle and distributed effects on connectivity within networks, rather than by taking the stimulated area “offline.”

The striatum and medial temporal lobes (MTL) exhibit dissociable roles during learning. Whereas the striatum and its network of thalamic relays and cortical nodes are necessary for nondeclarative learning, the MTL and associated network are required for declarative learning. Several studies have suggested that these networks are functionally competitive during learning. Since these discoveries, however, evidence has accumulated that they can operate in a cooperative fashion. In this review, we discuss evidence for both competition and cooperation between these systems during learning, with the aim of reconciling these seemingly contradictory findings. Examples of cooperation between the striatum and MTL have been provided, especially during consolidation and generalization of knowledge, and do not appear to be precluded by differences in functional specialization. However, whether these systems cooperate or compete does seem to depend on the phase of learning and cognitive or motor aspects of the task. The involvement of other regions, such as midbrain dopaminergic nuclei and the prefrontal cortex, may promote and mediate cooperation between the striatum and the MTL during learning. Building on this body of research, we propose a model for striatum-MTL interactions in learning and memory and attempt to predict, in general terms, when cooperation or competition will occur.

Mutations in the microtubule-associated protein tau (MAPT) gene cause autosomal dominant frontotemporal lobar degeneration with tau inclusions (FTLD-tau). MAPT p.R406W carriers present clinically with progressive memory loss and neuropathologically with neuronal and glial tauopathy. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. To identify the genes and pathways that are dysregulated in FTLD-tau, we performed transcriptomic analyses in induced pluripotent stem cell (iPSC)–derived neurons carrying MAPT p.R406W and CRISPR/Cas9-corrected isogenic controls. We found that the expression of the MAPT p.R406W mutation was sufficient to create a significantly different transcriptomic profile compared with that of the isogeneic controls and to cause the differential expression of 328 genes. Sixty-one of these genes were also differentially expressed in the same direction between MAPT p.R406W carriers and pathology-free human control brains. We found that genes differentially expressed in the stem cell models and human brains were enriched for pathways involving gamma-aminobutyric acid (GABA) receptors and pre-synaptic function. The expression of GABA receptor genes, including GABRB2 and GABRG2, were consistently reduced in iPSC-derived neurons and brains from MAPT p.R406W carriers. Interestingly, we found that GABA receptor genes, including GABRB2 and GABRG2, are significantly lower in symptomatic mouse models of tauopathy, as well as in brains with progressive supranuclear palsy. Genome wide association analyses reveal that common variants within GABRB2 are associated with increased risk for frontotemporal dementia (P −3). Thus, our systems biology approach, which leverages molecular data from stem cells, animal models, and human brain tissue can reveal novel disease mechanisms. Here, we demonstrate that MAPT p.R406W is sufficient to induce changes in GABA-mediated signaling and synaptic function, which may contribute to the pathogenesis of FTLD-tau and other primary tauopathies.

ObjectiveTo evaluate brain 18Fluorodeoxyglucose PET (FDG-PET) differences among patients with a clinical diagnosis of corticobasal syndrome (CBS) and distinct underling primary pathologies.MethodsWe studied 29 patients with a diagnosis of CBS who underwent FDG-PET scan and postmortem neuropathologic examination. Patients were divided into subgroups on the basis of primary pathologic diagnosis: CBS-corticobasal degeneration (CBS-CBD) (14 patients), CBS-Alzheimer disease (CBS-AD) (10 patients), and CBS–progressive supranuclear palsy (CBS-PSP) (5 patients). Thirteen age-matched healthy patients who underwent FDG-PET were the control group (HC). FDG-PET scans were compared between the subgroups and the HC using SPM-12, with a threshold of pFWE < 0.05.ResultsThere were no differences in Mattis Dementia Rating Scale or finger tapping scores between CBS groups. Compared to HC, the patients with CBS presented significant hypometabolism in frontoparietal regions, including the perirolandic area, basal ganglia, and thalamus of the clinically more affected hemisphere. Patients with CBS-CBD showed a similar pattern with a more marked, bilateral involvement of the basal ganglia. Patients with CBS-AD presented with posterior, asymmetric hypometabolism, including the lateral parietal and temporal lobes and the posterior cingulate. Finally, patients with CBS-PSP disclosed a more anterior hypometabolic pattern, including the medial frontal regions and the anterior cingulate. A conjunction analysis revealed that the primary motor cortex was the only common area of hypometabolism in all groups, irrespective of pathologic diagnosis.Discussion and conclusionsIn patients with CBS, different underling pathologies are associated with different patterns of hypometabolism. Our data suggest that FDG-PET scans could help in the etiologic diagnosis of CBS.

Traumatic cerebrovascular injury (TCVI) is a common pathologic mechanism of traumatic brain injury (TBI) and presents an attractive target for intervention. The aims of this study were to assess cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) using magnetic resonance imaging (MRI) to assess their value as biomarkers of TCVI in chronic TBI, characterize the spatial distribution of TCVI, and assess the relationships between each biomarker and neuropsychological and clinical assessments. Forty-two subjects (27 chronic TBI, 15 age- and gender-matched healthy volunteers) were studied cross-sectionally. CBF was measured by arterial spin labeling and CVR by assessing the MRI-blood oxygen level-dependent signal with hypercapnia challenge. A focused neuropsychological battery adapted from the TBI Common Data Elements and neurobehavioral symptom questionnaires were administered at the time of the imaging session. Chronic TBI subjects showed a significant reduction in mean global, gray matter (GM), and white matter (WM) CVR, compared with healthy volunteers (p