Martha E. Shenton

Harvard Medical School | HMS · Department of Psychiatry and Radiology

Mild traumatic brain injury (mTBI), also referred to as concussion, remains a controversial diagnosis because the brain often appears quite normal on conventional computed tomography (CT) and magnetic resonance imaging (MRI) scans. Such conventional tools, however, do not adequately depict brain injury in mTBI because they are not sensitive to dete...

Data from postmortem, CT, and magnetic resonance imaging (MRI) studies indicate that patients with schizophrenia may have anatomical abnormalities of the left temporal lobe, but it is unclear whether these abnormalities are related to the thought disorder characteristic of schizophrenia. We used new MRI neuroimaging techniques to derive (without kn...

After more than 100 years of research, the neuropathology of schizophrenia remains unknown and this is despite the fact that both Kraepelin (1919/1971: Kraepelin, E., 1919/1971. Dementia praecox. Churchill Livingston Inc., New York) and Bleuler (1911/1950: Bleuler, E., 1911/1950. Dementia praecox or the group of schizophrenias. International Univer...

Both post-mortem and neuroimaging studies have contributed significantly to what we know about the brain and schizophrenia. MRI studies of volumetric reduction in several brain regions in schizophrenia have confirmed early speculations that the brain is disordered in schizophrenia. There is also a growing body of evidence suggesting that a disturba...

The Clinical High Risk (CHR) stage of psychosis is characterized by subthreshold symptoms of schizophrenia including negative symptoms, dysphoric mood, and functional deterioration. Hyperconnectivity of the default-mode network (DMN) has been observed in early schizophrenia, but the extent to which hyperconnectivity is present in CHR, and the exten...

INTRODUCTION Blood‐based biomarkers offer a promising approach for the detection of neuropathologies from repetitive head impacts (RHI). We evaluated plasma biomarkers of amyloid, tau, neurodegeneration, and inflammation in former football players. METHODS The sample included 180 former football players and 60 asymptomatic, unexposed male particip...

Objective Exposure to repetitive head impacts (RHI) has been linked to Chronic Traumatic Encephalopathy (CTE) and neuropathological alterations such as white matter shear injuries. In this study, we use diffusion-tensor imaging (DTI) to investigate in vivo white matter alterations among former American football players. We also investigate how age...

Characterizing cortical plasticity becomes increasingly important for identifying compensatory mechanisms and structural reserve in the ageing population. While cortical thickness (CT) largely contributed to systems neuroscience, it incompletely informs about the underlying neuroplastic pathophysiology. In turn, microstructural characteristics may...

Background and Objectives Exposure to repetitive head impacts (RHI) is linked to the development of chronic traumatic encephalopathy (CTE), which can only be diagnosed at post-mortem. The presence of a cavum septum pellucidum (CSP) is a common finding in post-mortem studies of confirmed CTE and in neuroimaging studies of individuals exposed to RHI....

Importance Exposure to repetitive head impacts (RHI) is associated with increased risk for neurodegeneration. Accumulation of toxic proteins due to impaired brain clearance is suspected to play a role. Objective To investigate whether perivascular space (PVS) volume is associated with lifetime exposure to RHI in individuals at risk for RHI-associa...

Objective: Neurobehavioral dysregulation (NBD), a core clinical feature of traumatic encephalopathy syndrome, encompasses neuropsychiatric symptoms reported among individuals with a history of repetitive head impact exposure, including contact sport athletes. The objective of this study was to examine the construct and subconstructs of NBD through...

Background The time following a recent onset of psychosis is a critical period during which intervention may be maximally effective. Studying individuals in this period also offers an opportunity to investigate putative brain biomarkers of illness prior to the long-term effects of chronicity and medication. The Human Connectome Project for Early Ps...

Recent studies show that accelerated cortical gray matter (GM) volume reduction seen in anatomical MRI can help distinguish between individuals at clinical high risk (CHR) for psychosis who will develop psychosis and those who will not. This reduction is suggested to represent atypical developmental or degenerative changes accompanying an accumulat...

Background Intimate partner violence (IPV) perpetration is highly prevalent among veterans. Suggested risk factors of IPV perpetration include combat exposure, post-traumatic stress disorder (PTSD), depression, alcohol use, and mild traumatic brain injury (mTBI). While the underlying brain pathophysiological characteristics associated with IPV perp...

Cortical thickness analyses have provided valuable insights into changes in cortical brain structure after stroke and their association with recovery. Across studies though, relationships between cortical structure and function show inconsistent results. Recent developments in diffusion-weighted imaging of the cortex have paved the way to uncover h...

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC ab...

Exposure to repetitive head impacts (RHIs) in contact sports is associated with neurodegenerative disorders including chronic traumatic encephalopathy (CTE) which currently can be diagnosed only at postmortem. American football players are at higher risk of developing CTE given their exposure to RHIs. One promising approach for diagnosing CTE in vi...

Decades of psychosis research highlight the prevalence and the clinical significance of negative emotions, such as fear and anxiety. Translational evidence demonstrates the pivotal role of the amygdala in fear and anxiety. However, most of these approaches have used hypothesis-driven analyses with predefined regions of interest. A data-driven analy...

Background Mild traumatic brain injury (mTBI) is common in children. Long-term cognitive and behavioral outcomes as well as underlying structural brain alterations following pediatric mTBI have yet to be determined. In addition, the effect of age-at-injury on long-term outcomes is largely unknown. Methods Children with a history of mTBI ( n = 406;...

Background Traumatic encephalopathy syndrome (TES) is defined as the clinical manifestation of the neuropathological entity chronic traumatic encephalopathy (CTE). A core feature of TES is neurobehavioral dysregulation (NBD), a neuropsychiatric syndrome in repetitive head impact (RHI)-exposed individuals, characterized by a poor regulation of emoti...

Objective Impaired visuospatial memory is a clinical feature in individuals with neuropathologically confirmed chronic traumatic encephalopathy (CTE) post-mortem. Altered white matter microstructure in the cingulum bundle (CB) has previously been associated with impaired visuospatial memory in other neurodegenerative disorders. The aim of this stud...

On average, healthy older adults prefer positive over neutral or negative stimuli. This positivity bias is related to memory and attention processes and is linked to the function and structure of several interconnected brain areas. However, the relationship between the positivity bias and white matter integrity remains elusive. The present study ex...

Background Repetitive head impacts (RHI) from American football can lead to tau and non‐tau pathologies that might present as white matter hyperintensities (WMH) on FLAIR MRI. In 2022, we published a study in Alzheimer’s & Dementia that examined WMH and their association with risk factors and clinical function in former elite football players. That...

Background Repetitive head impact (RHI) exposure from the routine play of American football increases the risk of later‐life cognitive impairment and dementia from the neurodegenerative disease, chronic traumatic encephalopathy (CTE). Although neuropathological studies of CTE have found comorbid neurodegenerative and other pathologies, neuritic Aβ...

Background Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease thought to be caused, in part, by repetitive head impact (RHI) exposure and characterized by phosphorylated tau deposition with varying patterns in the cerebral cortex. Flortaucipir tau PET data from the DIAGNOSE CTE Research Project was examined to investigate tau PET...

Background The NINDS criteria define Traumatic Encephalopathy Syndrome (TES) as the clinical manifestation of the neuropathologically diagnosed chronic traumatic encephalopathy (CTE). The core clinical features of TES include both cognitive and neuropsychiatric symptoms, the latter termed neurobehavioral dysregulation (NBD) . We explored potential...

INTRODUCTION Tau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project. METHOD We compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same‐age...

Objective White matter hyperintensity (WMH) burden is greater, has a frontal-temporal distribution, and is associated with proxies of exposure to repetitive head impacts (RHI) in former American football players. These findings suggest that in the context of RHI, WMH might have unique etiologies that extend beyond those of vascular risk factors and...

Background and Objectives Recent data link exposure to repetitive head impacts (RHIs) from American football with increased white matter hyperintensity (WMH) burden. WMH might have unique characteristics in the context of RHI beyond vascular risk and normal aging processes. We evaluated biological correlates of WMH in former American football playe...

Characterizing cortical plasticity becomes increasingly important for identifying compensatory mechanisms and structural reserve in the aging population. While cortical thickness (CT) largely contributed to systems neuroscience, it incompletely informs about the underlying neuroplastic pathophysiology. In turn, microstructural characteristics may c...

The temporal pole (TP) is considered one of the major paralimbic cortical regions, and is involved in a variety of functions such as sensory perception, emotion, semantic processing, and social cognition. Based on differences in cytoarchitecture, the TP can be further subdivided into smaller regions (dorsal, ventrolateral and ventromedial), each fo...

Background: Exposure to repetitive head impacts (RHI) in American football players can lead to cognitive impairment and dementia due to neurodegenerative disease, particularly chronic traumatic encephalopathy (CTE). The pathognomonic lesion of CTE consists of perivascular aggregates of hyper-phosphorylated tau in neurons at the depths of cortical...

Background Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generaliz...

Aim: To harmonize two ascertainment and severity rating instruments commonly used for the clinical high risk syndrome for psychosis (CHR-P): the Structured Interview for Psychosis-risk Syndromes (SIPS) and the Comprehensive Assessment of At-Risk Mental States (CAARMS). Methods: The initial workshop is described in the companion report from Addin...

Background Anorexia nervosa (AN) is a potentially fatal psychiatric condition, associated with structural brain changes such as gray matter volume loss. The pathophysiological mechanisms for these changes are not yet fully understood. Iron is a crucial element in the development and function of the brain. Considering the systemic alterations in iro...

The gray matter/white matter (GM/WM) boundary of the brain is vulnerable to shear strain associated with mild traumatic brain injury (mTBI). It is, however, unknown whether GM/WM microstructure is associated with long-term outcomes following mTBI. The diffusion and structural MRI data of 278 participants between 18 and 65 years of age with and with...

Objective To investigate how the presence/side of hippocampal sclerosis (HS) are related to the white matter structure of cingulum bundle (CB), arcuate fasciculus (AF), and inferior longitudinal fasciculus (ILF) in mesial temporal lobe epilepsy (MTLE). Methods We acquired diffusion‐weighted magnetic resonance imaging (MRI) from 86 healthy and 71 i...

Recent studies show that accelerated cortical gray matter (GM) volume reduction seen in anatomical MRI can help distinguish between individuals at clinical high risk (CHR) for psychosis who will develop psychosis and those who will not. This reduction is thought to result from an accumulation of microstructural changes, such as decreased spine dens...

Background and purpose: While brain iron dysregulation has been observed in several neurodegenerative disorders, its association with the progressive neurodegeneration in Niemann-Pick type C is unknown. Systemic iron abnormalities have been reported in patients with Niemann-Pick type C and in animal models of Niemann-Pick type C. In this study, we...

Background We previously found greater spatial extent of flortaucipir (tau) PET elevations in Arizona‐Boston (DETECT) Study of 26 former National Football League (NFL) players than in 31 normal controls—using a voxel‐based Majority Count Statistics (MCS) algorithm which enabled us to detect tau PET abnormalities in the player group free from the in...

Cortical thickness (CT) analyses have provided valuable insights into changes in cortical brain structure after stroke and their association with recovery. Across studies though, relationships between cortical structure and function show inconsistent results. Recent developments in diffusion-weighted imaging of the cortex have paved the way to unco...

Background Alterations in brain connectivity may underlie neuropsychiatric conditions such as schizophrenia. We here assessed the degree of convergence of frontostriatal fiber projections in 56 young adult healthy controls (HCs) and 108 matched Early Psychosis-Non-Affective patients (EP-NAs) using our novel fiber cluster analysis of whole brain dif...

Aim: To harmonize two ascertainment and severity rating instruments commonly used for the clinical high risk syndrome for psychosis (CHR-P): the Structured Interview for Psychosis-risk Syndromes (SIPS) and the Comprehensive Assessment of At-Risk Mental States (CAARMS). Methods: The initial workshop is described in the companion report from Addingto...

Studies applying Free Water Imaging have consistently reported significant global increases in extracellular free water (FW) in populations of individuals with early psychosis. However, these published studies focused on homogenous clinical participant groups (e.g., only first episode or chronic), thereby limiting our understanding of the time cour...

Sport-related concussion (SRC) affects an estimated 1.6 to 3.8 million Americans each year. Sport-related concussion results from biomechanical forces to the head or neck that lead to a broad range of neurologic symptoms and impaired cognitive function. Although most individuals recover within weeks, some develop chronic symptoms. The heterogeneity...

Sleep disturbances are strongly associated with mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD). PTSD and mTBI have been linked to alterations in white matter (WM) microstructure, but whether poor sleep quality has a compounding effect on WM remains largely unknown. We evaluated sleep and diffusion magnetic resonance im...

The choroid plexus (ChP) is part of the blood‐cerebrospinal fluid barrier, regulating brain homeostasis and the brain's response to peripheral events. Its upregulation and enlargement are considered essential in psychosis. However, the timing of the ChP enlargement has not been established. This study introduces a novel magnetic resonance imaging‐b...

Background Patterns of cognitive impairment in former American football players are uncertain because objective neuropsychological data are lacking. This study characterized the neuropsychological test performance of former college and professional football players. Methods One hundred seventy male former football players ( n =111 professional, n...

Childhood sexual abuse (CSA) is a potentially unique risk factor for auditory hallucinations (AH), but few studies have examined the moderating effects of sex or the association of CSA with limbic gray matter volume (GMV) in transdiagnostic samples of people with psychotic disorders. Here we found that people with psychotic disorders reported highe...

Traumatic brain injury (TBI) in military populations can cause disruptions in brain structure and function, along with cognitive and psychological dysfunction. Diffusion magnetic resonance imaging (dMRI) can detect alterations in white matter (WM) microstructure, but few studies have examined brain asymmetry. Examining asymmetry in large samples ma...

Background: Current clinical assessments of Posttraumatic stress disorder (PTSD) rely solely on subjective symptoms and experiences reported by the patient, rather than objective biomarkers of the illness. Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. Here...

Repetitive head impacts (RHI) are commonly observed in athletes participating in contact sports such as American football, ice hockey, and soccer. RHI usually do not result in acute symptoms and are therefore often referred to as subclinical or “subconcussive” head impacts. Epidemiological studies report an association between exposure to RHI and a...

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is characterized by perivascular foci of phosphorylated tau (p‐tau) notably in the depths of sulci, with varying patterns in the cerebral cortex. Prior studies show elevated flortaucipir (FTP) PET binding in former American professional football players(PRO). However, the as...

Neurological soft signs (NSS) are minor deviations in motor performance. During childhood and adolescence, NSS are examined for functional motor phenotyping to describe development, to screen for comorbidities, and to identify developmental vulnerabilities. Here, we investigate underlying brain structure alterations in association with NSS in physi...

Background: Military service members are at increased risk for mental health issues and comorbidity with mild traumatic brain injury (mTBI) is common. Largely overlapping symptoms between conditions suggest a shared pathophysiology. The present work investigates the associations between white matter microstructure, psychological functioning, and s...

Brain iron is central to dopaminergic neurotransmission, a key component in schizophrenia pathology. Iron can also generate oxidative stress, which is one proposed mechanism for gray matter volume reduction in schizophrenia. The role of brain iron in schizophrenia and its potential link to oxidative stress has not been previously examined. In this...

Purpose: Flourine-18-flortaucipir tau positron emission tomography (PET) was developed for the detection for Alzheimer's disease. Human imaging studies have begun to investigate its use in chronic traumatic encephalopathy (CTE). Flortaucipir-PET to autopsy correlation studies in CTE are needed for diagnostic validation. We examined the association...