Mapping Essential Tremor to a Common Brain Network Using Functional Connectivity Analysis.

BACKGROUND AND OBJECTIVES: The cerebello-thalamo-cortical circuit plays a critical role in essential tremor (ET). However, abnormalities have been reported in multiple brain regions outside this circuit, leading to inconsistent characterization of ET pathophysiology. Here, we test whether these mixed findings in ET localize to a common functional network and whether this network has therapeutic relevance. METHODS: We conducted a systematic literature search to identify studies reporting structural or metabolic brain abnormalities in ET. We then used 'coordinate network mapping,' which leverages a normative connectome (n = 1,000) of resting-state fMRI data to identify regions commonly connected to findings across all studies. To assess whether these regions may be relevant for the treatment of ET, we compared our network with a therapeutic network derived from lesions that relieved ET. Finally, we investigated whether the functional connectivity of this ET symptom network is abnormal in an independent cohort of patients with ET as compared with healthy controls. RESULTS: Structural and metabolic brain abnormalities in ET were located in heterogeneous regions throughout the brain. However, these coordinates were connected to a common functional brain network, including the cerebellum, thalamus, motor cortex, precuneus, inferior parietal lobe, and insula. The cerebellum was identified as the hub of this network because it was the only brain region that was both functionally connected to the findings of over 90% of studies and significantly different in connectivity compared with a control data set of other movement disorders. This network was strikingly similar to the therapeutic network derived from lesions improving ET, with key regions aligning in the thalamus and cerebellum. Furthermore, positive functional connectivity between the cerebellar network hub and the sensorimotor cortices was significantly reduced in patients with ET compared with healthy controls, and connectivity within this network was correlated with tremor severity and cognitive functioning. DISCUSSION: These findings suggest that the cerebellum is the central hub of a network commonly connected to structural and metabolic abnormalities in ET. This network may have therapeutic utility in refining and informing new targets for neuromodulation of ET.

The functional anatomy of dystonia: Recent developments.

While dystonia has traditionally been viewed as a disorder of the basal ganglia, the involvement of other key brain structures is now accepted. However, just what these structures are remains to be defined. Neuroimaging has been an especially valuable tool in dystonia, yet traditional cross-sectional designs have not been able to separate causal from compensatory brain activity. Therefore, this chapter discusses recent studies using causal brain lesions, and animal models, to converge upon the brain regions responsible for dystonia with increasing precision. This evidence strongly implicates the basal ganglia, thalamus, brainstem, cerebellum, and somatosensory cortex, yet shows that different types of dystonia involve different nodes of this brain network. Nearly all of these nodes fall within the recently identified two-way networks connecting the basal ganglia and cerebellum, suggesting dysfunction of these specific pathways. Localisation of the functional anatomy of dystonia has strong implications for targeted treatment options, such as deep brain stimulation, and non-invasive brain stimulation.

Large-scale activation likelihood estimation meta-analysis of parkinsonian disorders.

Parkinsonism is a feature of several neurodegenerative disorders, including Parkinson's disease, progressive supranuclear palsy, corticobasal syndrome and multiple system atrophy. Neuroimaging studies have yielded insights into parkinsonian disorders; however, due to variability in results, the brain regions consistently implicated in these disorders remain to be characterized. The aim of this meta-analysis was to identify consistent brain abnormalities in individual parkinsonian disorders (Parkinson's disease, progressive supranuclear palsy, corticobasal syndrome and multiple system atrophy) and to investigate any shared abnormalities across disorders. A total of 44 591 studies were systematically screened following searches of two databases. A series of whole-brain activation likelihood estimation meta-analyses were performed on 132 neuroimaging studies (69 Parkinson's disease; 23 progressive supranuclear palsy; 17 corticobasal syndrome; and 23 multiple system atrophy) utilizing anatomical MRI, perfusion or metabolism PET and single-photon emission computed tomography. Meta-analyses were performed in each parkinsonian disorder within each imaging modality, as well as across all included disorders. Results in progressive supranuclear palsy and multiple system atrophy aligned with current imaging markers for diagnosis, encompassing the midbrain, and brainstem and putamen, respectively. PET imaging studies of patients with Parkinson's disease most consistently reported abnormality of the middle temporal gyrus. No significant clusters were identified in corticobasal syndrome. When examining abnormalities shared across all four disorders, the caudate was consistently reported in MRI studies, whilst the thalamus, inferior frontal gyrus and middle temporal gyri were commonly implicated by PET. To our knowledge, this is the largest meta-analysis of neuroimaging studies in parkinsonian disorders and the first to characterize brain regions implicated across parkinsonian disorders.

Mapping a network for tics in Tourette syndrome using causal lesions and structural alterations.

Tics are sudden stereotyped movements or vocalizations. Cases of lesion-induced tics are invaluable, allowing for causal links between symptoms and brain structures. While a lesion network for tics has recently been identified, the degree to which this network translates to Tourette syndrome has not been fully elucidated. This is important given that patients with Tourette syndrome make up a large portion of tic cases; therefore, existing and future treatments should apply to these patients. The aim of this study was to first localize a causal network for tics from lesion-induced cases and then refine and validate this network in patients with Tourette syndrome. We independently performed 'lesion network mapping' using a large normative functional connectome (n = 1000) to isolate a brain network commonly connected to lesions causing tics (n = 19) identified through a systematic search. The specificity of this network to tics was assessed through comparison to lesions causing other movement disorders. Using structural brain coordinates from prior neuroimaging studies (n = 7), we then derived a neural network for Tourette syndrome. This was done using standard anatomical likelihood estimation meta-analysis and a novel method termed 'coordinate network mapping', which uses the same coordinates, yet maps their connectivity using the aforementioned functional connectome. Conjunction analysis was used to refine the network for lesion-induced tics to Tourette syndrome by identifying regions common to both lesion and structural networks. We then tested whether connectivity from this common network is abnormal in a separate resting-state functional connectivity MRI data set from idiopathic Tourette syndrome patients (n = 21) and healthy controls (n = 25). Results showed that lesions causing tics were distributed throughout the brain; however, consistent with a recent study, these were part of a common network with predominant basal ganglia connectivity. Using conjunction analysis, coordinate network mapping findings refined the lesion network to the posterior putamen, caudate nucleus, globus pallidus externus (positive connectivity) and precuneus (negative connectivity). Functional connectivity from this positive network to frontal and cingulate regions was abnormal in patients with idiopathic Tourette syndrome. These findings identify a network derived from lesion-induced and idiopathic data, providing insight into the pathophysiology of tics in Tourette syndrome. Connectivity to our cortical cluster in the precuneus offers an exciting opportunity for non-invasive brain stimulation protocols.

Effects of non-invasive brain stimulation in dystonia: a systematic review and meta-analysis.

Background: Deep brain stimulation is a highly effective treatment of dystonia but is invasive and associated with risks, such as intraoperative bleeding and infections. Previous research has used non-invasive brain stimulation (NIBS) in an attempt to alleviate symptoms of dystonia. The results of these studies, however, have been variable, leaving efficacy unclear. Objectives: This study aimed to evaluate the effects of NIBS on symptoms of dystonia and determine whether methodological characteristics are associated with variability in effect size. Methods: Web of Science, Embase, and MEDLINE Complete databases were searched for articles using any type of NIBS as an intervention in dystonia patients, with changes in dystonia symptoms the primary outcome of interest. Results: Meta-analysis of 27 studies demonstrated a small effect size for NIBS in reducing symptoms of dystonia (random-effects Hedges' g = 0.21, p = .002). Differences in the type of NIBS, type of dystonia, and brain region stimulated had a significant effect on dystonia symptoms. Meta-regression revealed that 10 sessions of active stimulation and the application of concurrent motor training programs resulted in significantly larger mean effect sizes. Conclusion: NIBS has yielded small improvements to dystonic symptoms, but effect sizes depended on methodological characteristics, with more sessions of stimulation producing a larger response. Future research should further investigate the application of NIBS parallel to motor training, in addition to providing a greater quantity of sessions, to help define optimal parameters for NIBS protocols in dystonia. Registration: PROSPERO 2020, CRD42020175944.

Clinical and Structural Findings in Patients With Lesion-Induced Dystonia: Descriptive and Quantitative Analysis of Published Cases.

BACKGROUND AND OBJECTIVES: Brain lesions are a well-recognized etiology of dystonia. These cases are especially valuable because they offer causal insight into the neuroanatomical substrates of dystonia. To date, knowledge of lesion-induced dystonia comes mainly from isolated case reports or small case series, restricting broader description and analysis. METHODS: Cases of lesion-induced dystonia were first identified from a systematic review of published literature. Latent class analysis then investigated whether patients could be classified into subgroups based on lesion location and body regions affected by dystonia. Regression analyses subsequently investigated whether subgroup membership predicted clinical characteristics of dystonia. RESULTS: Three hundred fifty-nine published cases were included. Lesions causing dystonia occurred in heterogeneous locations, most commonly in the basal ganglia (46.2%), followed by the thalamus (28.1%), brainstem (22.6%), and white matter (21.2%). The most common form of lesion-induced dystonia was focal dystonia (53.2%), with the hand (49.9%) and arm (44.3%) most commonly affected. Of all cases, 86.6% reported co-occurring neurologic manifestations and 26.1% reported other movement disorders. Latent class analysis identified 3 distinct subgroups of patients: those with predominantly limb dystonias, which were associated with basal ganglia lesions; those with hand dystonia, associated with thalamic lesions; and those with predominantly cervical dystonia, associated with brainstem and cerebellar lesions. Regression demonstrated significant differences between these subgroups on a range of dystonia symptoms, including dystonic tremor, symptom latency, other movement disorders, and dystonia variability. DISCUSSION: Although dystonia can be induced by lesions to numerous brain regions, there are distinct relationships between lesion locations and dystonic body parts. This suggests that the affected brain networks are different between types of dystonia.

Lesion network mapping for symptom localization: recent developments and future directions.

PURPOSE OF REVIEW: Focal lesions causing specific neurological or psychiatric symptoms can occur in multiple different brain locations, complicating symptom localization. Here, we review lesion network mapping, a technique used to aid localization by mapping lesion-induced symptoms to brain circuits rather than individual brain regions. We highlight recent examples of how this technique is being used to investigate clinical entities and identify therapeutic targets. RECENT FINDINGS: To date, lesion network mapping has successfully been applied to more than 40 different symptoms or symptom complexes. In each case, lesion locations were combined with an atlas of human brain connections (the human connectome) to map heterogeneous lesion locations causing the same symptom to a common brain circuit. This approach has lent insight into symptoms that have been difficult to localize using other techniques, such as hallucinations, tics, blindsight, and pathological laughter and crying. Further, lesion network mapping has recently been applied to lesions that improve symptoms, such as tremor and addiction, which may translate into new therapeutic targets. SUMMARY: Lesion network mapping can be used to map lesion-induced symptoms to brain circuits rather than single brain regions. Recent findings have provided insight into long-standing clinical mysteries and identified testable treatment targets for circuit-based and symptom-based neuromodulation.

Neurobiological effects of deep brain stimulation: A systematic review of molecular brain imaging studies.

Deep brain stimulation (DBS) is an established treatment for several brain disorders, including Parkinson's disease, essential tremor, dystonia and epilepsy, and an emerging therapeutic tool in many other neurological and psychiatric disorders. The therapeutic efficacy of DBS is dependent on the stimulation target, but its mechanisms of action are still relatively poorly understood. Investigating these mechanisms is challenging, partly because the stimulation devices and electrodes have limited the use of functional MRI in these patients. Molecular brain imaging techniques, such as positron emission tomography (PET) and single photon emission tomography (SPET), offer a unique opportunity to characterize the whole brain effects of DBS. Here, we investigated the direct effects of DBS by systematically reviewing studies performing an `on' vs `off' contrast during PET or SPET imaging. We identified 62 studies (56 PET and 6 SPET studies; 531 subjects). Approximately half of the studies focused on cerebral blood flow or glucose metabolism in patients Parkinson's disease undergoing subthalamic DBS (25 studies, n = 289), therefore Activation Likelihood Estimation analysis was performed on these studies. Across disorders and stimulation targets, DBS was associated with a robust local increase in ligand uptake at the stimulation site and target-specific remote network effects. Subthalamic nucleus stimulation in Parkinson's disease showed a specific pattern of changes in the motor circuit, including increased ligand uptake in the basal ganglia, and decreased ligand uptake in the primary motor cortex, supplementary motor area and cerebellum. However, there was only a handful of studies investigating other brain disorder and stimulation site combinations (1-3 studies each), or specific neurotransmitter systems, preventing definitive conclusions of the detailed molecular effects of the stimulation in these cases.

Assessment of cortical inhibition depends on inter individual differences in the excitatory neural populations activated by transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is used to probe inhibitory intracortical neurotransmission and has been used to infer the neurobiological dysfunction that may underly several neurological disorders. One technique, short-interval intracortical inhibition (SICI), indexes gamma-aminobutyric acid (GABA) mediated inhibitory activity and is a promising biomarker. However emerging evidence suggests SICI does not exclusively represent GABAergic activity because it may be influenced by inter-individual differences in the specific excitatory neural populations activated by TMS. Here we used the latency of TMS motor evoked potentials (MEPs) to index these inter-individual differences, and found that a significant proportion of the observed variability in SICI magnitude was accounted for by MEP latency, r = - 0.57, r2 = 0.33, p = .014. We conclude that SICI is influenced by inter-individual differences in the excitatory neural populations activated by TMS, reducing the precision of this GABAergic probe. Interpreting SICI measures in the context of MEP latency may facilitate a more precise assessment of GABAergic intracortical inhibition. The reduced cortical inhibition observed in some neuropathologies could be influenced by reduced activity in specific excitatory neural populations. Including MEP latency assessment in research investigating SICI in clinical groups could assist in differentiating the cortical circuits impacted by neurological disorders.

The role of the primary motor cortex in motor imagery: A theta burst stimulation study.

While mentally simulated actions activate similar neural structures to overt movement, the role of the primary motor cortex (PMC) in motor imagery remains disputed. The aim of the study was to use continuous theta burst stimulation (cTBS) to modulate corticospinal activity to investigate the putative role of the PMC in implicit motor imagery in young adults with typical and atypical motor ability. A randomized, double blind, sham-controlled, crossover, offline cTBS protocol was applied to 35 young adults. During three separate sessions, adults with typical and low motor ability (developmental coordination disorder [DCD]), received active cTBS to the PMC and supplementary motor area (SMA), and sham stimulation to either the PMC or SMA. Following stimulation, participants completed measures of motor imagery (i.e., hand rotation task) and visual imagery (i.e., letter number rotation task). Although active cTBS significantly reduced corticospinal excitability in adults with typical motor ability, neither task performance was altered following active cTBS to the PMC or SMA, compared to performance after sham cTBS. These results did not differ across motor status (i.e., typical motor ability and DCD). These findings are not consistent with our hypothesis that the PMC (and SMA) is directly involved in motor imagery. Instead, previous motor cortical activation observed during motor imagery may be an epiphenomenon of other neurophysiological processes and/or activity within brain regions involved in motor imagery. This study highlights the need to consider multi-session theta burst stimulation application and its neural effects when probing the putative role of motor cortices in motor imagery.

Greater Cognitive-Motor Interference in Individuals Post-Stroke During More Complex Motor Tasks.

BACKGROUND AND PURPOSE: Dual-task (DT) walking assessments allow for the simultaneous evaluation of cognitive and motor performance. During DT walking, individuals may experience interference in one or both tasks, known as cognitive-motor interference (CMI). The primary purpose of this study was to compare CMI between individuals post-stroke and healthy persons group during single- and dual-motor and cognitive tasks, using 2 distinct walking tasks. METHODS: Motor performance was quantified as the total time for the Timed Up and Go (TUG) and gait speed for the 90-second walk (90W). Cognitive performance was measured as the correct response rate (CRR) during serial 7 subtractions. Participants performed the motor and cognitive tasks in isolation for the single-task (ST) and simultaneously for DT conditions, TUG-DT and 90W-DT. A repeated-measures analysis of variance assessed group (poststroke and healthy) by condition (ST and DT) interactions for the TUG, 90W, and CRR. RESULTS: There were significant main effects of group and condition for both the TUG and the 90W (P < 0.05). There was also an interaction effect for the TUG, with individuals post-stroke demonstrating a larger decrement in TUG-DT performance compared with healthy persons (P < 0.05). Furthermore, a significant interaction effect was observed for the CRR, in which healthy individuals exhibited a greater decrement in performance from the ST to the 90W-DT (P < 0.05). DISCUSSION AND CONCLUSIONS: Individuals post-stroke were susceptible to greater motor interference during the more complex motor task, the TUG-DT. However, the only decrements observed in cognitive performance from the ST to DT occurred in healthy individuals during the 90W-DT.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A367).

Large-scale analysis of interindividual variability in single and paired-pulse TMS data.

OBJECTIVE: This study brought together over 60 transcranial magnetic stimulation (TMS) researchers to create the largest known sample of individual participant single and paired-pulse TMS data to date, enabling a more comprehensive evaluation of factors driving response variability. METHODS: Authors of previously published studies were contacted and asked to share deidentified individual TMS data. Mixed-effects regression investigated a range of individual and study level variables for their contribution to variability in response to single and paired-pulse TMS data. RESULTS: 687 healthy participant's data were pooled across 35 studies. Target muscle, pulse waveform, neuronavigation use, and TMS machine significantly predicted an individual's single-pulse TMS amplitude. Baseline motor evoked potential amplitude, motor cortex hemisphere, and motor threshold (MT) significantly predicted short-interval intracortical inhibition response. Baseline motor evoked potential amplitude, test stimulus intensity, interstimulus interval, and MT significantly predicted intracortical facilitation response. Age, hemisphere, and TMS machine significantly predicted MT. CONCLUSIONS: This large-scale analysis has identified a number of factors influencing participants' responses to single and paired-pulse TMS. We provide specific recommendations to minimise interindividual variability in single and paired-pulse TMS data. SIGNIFICANCE: This study has used large-scale analyses to give clarity to factors driving variance in TMS data. We hope that this ongoing collaborative approach will increase standardisation of methods and thus the utility of single and paired-pulse TMS.

'Expedited Interhemispheric Inhibition': A Simple Method to Collect Additional IHI Data in the Same Amount of Time.

Interhemispheric inhibition (IHI) is a dual-site TMS protocol measuring inhibitory interactions between the primary motor cortices (M1). IHI is performed by applying an initial conditioning stimulus followed by a test stimulus to the contralateral M1. Conventionally, the response in the contralateral hand to the conditioning TMS pulse is either not measured, or discarded. The aim of this experiment was to investigate whether MEPs evoked from these conditioning stimuli can be utilised as non-conditioned, or 'baseline', responses, and therefore expedite IHI data collection. We evaluated short-latency (10 ms) and long-latency (40 ms) IHI bidirectionally in 14 healthy participants. There was no difference in MEP amplitudes evoked by conventional single TMS pulses randomly inserted into IHI blocks, and those evoked by the conditioning stimulus. Nor was there any significant difference in IHI magnitude when using single pulse MEPs or conditioning stimulus MEPs as baseline responses. The utilisation of conditioning stimuli dispenses with the need to insert dedicated single TMS pulses into IHI blocks, allowing for additional IHI data to be collected in the same amount of time.

Large-scale analysis of interindividual variability in theta-burst stimulation data: Results from the 'Big TMS Data Collaboration'.

BACKGROUND: Many studies have attempted to identify the sources of interindividual variability in response to theta-burst stimulation (TBS). However, these studies have been limited by small sample sizes, leading to conflicting results. OBJECTIVE/HYPOTHESIS: This study brought together over 60 TMS researchers to form the 'Big TMS Data Collaboration', and create the largest known sample of individual participant TBS data to date. The goal was to enable a more comprehensive evaluation of factors driving TBS response variability. METHODS: 118 corresponding authors of TMS studies were emailed and asked to provide deidentified individual TMS data. Mixed-effects regression investigated a range of individual and study level variables for their contribution to iTBS and cTBS response variability. RESULTS: 430 healthy participants' TBS data was pooled across 22 studies (mean age = 41.9; range = 17-82; females = 217). Baseline MEP amplitude, age, target muscle, and time of day significantly predicted iTBS-induced plasticity. Baseline MEP amplitude and timepoint after TBS significantly predicted cTBS-induced plasticity. CONCLUSIONS: This is the largest known study of interindividual variability in TBS. Our findings indicate that a significant portion of variability can be attributed to the methods used to measure the modulatory effects of TBS. We provide specific methodological recommendations in order to control and mitigate these sources of variability.

Network localization of cervical dystonia based on causal brain lesions.

Cervical dystonia is a neurological disorder characterized by sustained, involuntary movements of the head and neck. Most cases of cervical dystonia are idiopathic, with no obvious cause, yet some cases are acquired, secondary to focal brain lesions. These latter cases are valuable as they establish a causal link between neuroanatomy and resultant symptoms, lending insight into the brain regions causing cervical dystonia and possible treatment targets. However, lesions causing cervical dystonia can occur in multiple different brain locations, leaving localization unclear. Here, we use a technique termed 'lesion network mapping', which uses connectome data from a large cohort of healthy subjects (resting state functional MRI, n = 1000) to test whether lesion locations causing cervical dystonia map to a common brain network. We then test whether this network, derived from brain lesions, is abnormal in patients with idiopathic cervical dystonia (n = 39) versus matched controls (n = 37). A systematic literature search identified 25 cases of lesion-induced cervical dystonia. Lesion locations were heterogeneous, with lesions scattered throughout the cerebellum, brainstem, and basal ganglia. However, these heterogeneous lesion locations were all part of a single functionally connected brain network. Positive connectivity to the cerebellum and negative connectivity to the somatosensory cortex were specific markers for cervical dystonia compared to lesions causing other neurological symptoms. Connectivity with these two regions defined a single brain network that encompassed the heterogeneous lesion locations causing cervical dystonia. These cerebellar and somatosensory regions also showed abnormal connectivity in patients with idiopathic cervical dystonia. Finally, the most effective deep brain stimulation sites for treating dystonia were connected to these same cerebellar and somatosensory regions identified using lesion network mapping. These results lend insight into the causal neuroanatomical substrate of cervical dystonia, demonstrate convergence across idiopathic and acquired dystonia, and identify a network target for dystonia treatment.

Reduced motor cortex inhibition and a 'cognitive-first' prioritisation strategy for older adults during dual-tasking.

It is well established that older adults are less able to perform attentionally demanding motor tasks, placing them at greater risk of accident-related injury. The primary purpose of this study was to investigate whether the interplay between prefrontal and motor cortex activity could predict such age-related performance deficits. Using a dual-task (DT) paradigm, 15 younger and 15 older adults participated in experiment 1, where brain activity was simultaneously measured using functional near infrared spectroscopy (fNIRS) and transcranial magnetic stimulation (TMS). Experiment 1 demonstrated poorer performance for the older group across a range of DTs combining visuomotor arm tracking with a secondary cognitive or motor task. Interestingly however, older adults' DT performance error was isolated to the motor component of DTs. TMS data revealed reduced motor cortex (M1) inhibition during DTs for older adults, and a trend for this correlating with poorer performance. In contrast, poorer performing younger adults showed significantly higher M1 inhibition. Experiment 2 was conducted given a high amount of movement artifact in experiment 1 fNIRS data. Using fNIRS to measure prefrontal, premotor, and motor cortex activity in an additional 15 older adults, we found no evidence of an interplay between these regions predicting DT performance. Nevertheless, performance data replicated experiment 1 in showing that DT error was isolated to motor tasks in older adults, with no significant cognitive task error. Overall, this study shows that older adults seemed to adopt a 'cognitive-first' prioritisation strategy during the DTs involved in our study, and that deficits in DT performance may be related to the modulation of M1 inhibitory mechanisms. We propose that clinicians advise older adults to allocate greater attention to motor tasks during activities where they may be at risk of accident-related injury.

The effect of dual-task difficulty on the inhibition of the motor cortex.

Dual-tasking is intrinsic to many daily activities, including walking and driving. However, the activity of the primary motor cortex (M1) in response to dual-tasks (DT) is still not well characterised. A recent meta-analysis (Corp in Neurosci Biobehav Rev 43:74-87, 2014) demonstrated a reduction in M1 inhibition during dual-tasking, yet responses were not consistent between studies. It was suggested that DT difficulty might account for some of this between-study variability. The aim of this study was to investigate whether corticospinal excitability and M1 inhibition differed between an easier and more difficult dual-task. Transcranial magnetic stimulation (TMS) was applied to participants' abductor pollicis brevis muscle representation during a concurrent pincer grip task and stationary bike-riding. The margin of error in which to maintain pincer grip force was reduced to increase task difficulty. Compared to ST conditions, significantly increased M1 inhibition was demonstrated for the easier, but not more difficult, DT. However, there was no significant difference in M1 inhibition between easy and difficult DTs. The difference in difficulty between the two tasks may not have been wide enough to result in significant differences in M1 inhibition. Increased M1 inhibition for the easy DT condition was in opposition to the reduction in M1 inhibition found in our meta-analysis (Corp in Neurosci Biobehav Rev 43:74-87, 2014). We propose that this may be partially explained by differences in the timing of the TMS pulse between DT studies.

Chronic traumatic encephalopathy: historical origins and current perspective.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is most often identified in postmortem autopsies of individuals exposed to repetitive head impacts, such as boxers and football players. The neuropathology of CTE is characterized by the accumulation of hyperphosphorylated tau protein in a pattern that is unique from that of other neurodegenerative diseases, including Alzheimer's disease. The clinical features of CTE are often progressive, leading to dramatic changes in mood, behavior, and cognition, frequently resulting in debilitating dementia. In some cases, motor features, including parkinsonism, can also be present. In this review, the historical origins of CTE are revealed and an overview of the current state of knowledge of CTE is provided, including the neuropathology, clinical features, proposed clinical and pathological diagnostic criteria, potential in vivo biomarkers, known risk factors, and treatment options.