Argye E Hillis

Johns Hopkins Medicine | JHUSOM · Department of Neurology

Primary progressive aphasia (PPA) is a neurodegenerative syndrome characterized by progressive language deficits. The main variants of PPA - semantic (svPPA), logopenic (lvPPA), and nonfluent (nfvPPA) - can be challenging to distinguish. Limb apraxia often co-occurs with PPA, but it is unclear whether PPA variants are associated with different apra...

Primary Progressive Aphasia (PPA) is a neurodegenerative disorder primarily affecting language functions. Neuromodulatory techniques (e.g., transcranial direct current stimulation, active-tDCS) and behavioral (speech-language) therapy have shown promising results in treating speech and language deficits in PPA patients. One mechanism of active-tDCS...

Unilateral spatial neglect (USN) is a common and disabling cognitive consequence of stroke wherein individuals demonstrate decreased response to contralesional information. Here, we provide an updated narrative review of studies that shed light on the neural mechanisms and predictors of recovery of USN. Additionally, we report a rapid review of ran...

The differences in mental health outcomes of right and left hemisphere strokes are well studied; however, there is a long-standing controversy surrounding whether depression is associated with lateralization of stroke or not. In this investigation, we examined the effect of lesion location on post-stroke depression controlling for lesion size and h...

Background Recent work has highlighted the utility of the Boston Naming Test and Hopkins Action Naming Assessment (HANA) for distinguishing between semantic (svPPA), logopenic (lvPPA) and non-fluent agrammatic (nfavPPA) variants of primary progressive aphasia (PPA). Aims To determine whether item level differences between variants on when naming v...

Purpose We present a 20-item naming test, the Severity-Calibrated Aphasia Naming Test (SCANT), that can serve as a proxy measure for an aphasia severity scale that is derived from a thorough test battery of connected speech production, single-word production, speech repetition, and auditory verbal comprehension. Method We use lasso regression and...

Aphasia, the loss of language ability following damage to the brain, is among the most disabling and common consequences of stroke. Subcortical stroke, occurring in the basal ganglia, thalamus, and/or deep white matter can result in aphasia, often characterized by word fluency, motor speech output, or sentence generation impairments. The link betwe...

The association between age and language recovery in stroke remains unclear. Here, we used neuroimaging data to estimate brain age, a measure of structural integrity, and examined the extent to which brain age at stroke onset is associated with (1) cross-sectional language performance, and (2) longitudinal recovery of language function, beyond chro...

Background General consensus exists between clinicians as to the incorporation of discourse outcome measures into language assessment for persons with aphasia (PWA). The development of core lexicon measures (CoreLex) has enabled clinicians to reduce time and labor intensive preparatory work for discourse analysis, which has been considered as an al...

Purpose of Review Stroke is a common cause of disability in aging adults. A given individual’s needs after stroke vary as a function of the stroke extent and location. The purpose of this review was to discuss recent clinical investigations addressing rehabilitation of an array of overlapping functional domains. Recent Findings Research is ongoing...

Objectives Generalization (or near-transfer) effects of an intervention to tasks not explicitly trained are the most desirable intervention outcomes. However, they are rarely reported and even more rarely explained. One hypothesis for generalization effects is that the tasks improved share the same brain function/computation with the intervention t...

Cerebrovascular Reactivity (CVR) provides an assessment of the brain’s vascular reserve and has been postulated to be a sensitive marker in cerebrovascular diseases. MRI-based CVR measurement typically employs alterations in arterial carbon dioxide (CO2) level while continuously acquiring Blood-Oxygenation-Level-Dependent (BOLD) images. CO2-inhalat...

Purpose Adults with right hemisphere damage demonstrate differences in connected speech compared to controls, but systematic, quantitative methods to capture these differences are lacking. The current study aimed to (a) investigate if measures using the Modern Cookie Theft picture description would identify discourse differences in acute right hemi...

Background Lesion-related factors are associated with severity of language impairment in persons with aphasia. The extent to which demographic and health factors predict language impairment beyond traditional cortical measures remains unknown. Identifying and understanding the contributions of factors to predictive models of severity constitutes cr...

A number of pharmaceuticals have been identified as potential adjuvants to speech language therapy following stroke, but it is also important to consider which pharmaceuticals may result in a less robust recovery. Here we examine whether post-stroke language recovery was meaningfully impeded by cholinergic, GABAergic, or dopaminergic medications pa...

Wernicke’s area has been assumed since the 1800s to be the primary region supporting word and sentence comprehension. However, in 2015 and 2019, Mesulam and colleagues raised what they termed the ‘Wernicke conundrum’, noting widespread variability in the anatomical definition of this area and presenting data from primary progressive aphasia that ch...

Brain lesions can have many causes including injury, disease, and infections. Lesion-symptom mapping is a tool used by investigators to understand the relationship between brain structure and function. There are many different types of brain lesions with varying characteristics that researchers must consider when deciding which participants to incl...

Background The majority of patients with primary progressive aphasia (PPA) can be distinguished into one of three variants: semantic, non-fluent/agrammatic, or logopenic. However, many do not meet criteria for any one variant. Aim To identify aspects of cognitive-linguistic performance that yield an early unclassifiable PPA designation that predic...

NIHSS score is higher for left vs. right hemisphere strokes of equal volumes. However, differences in each vascular territory have not been evaluated yet. We hypothesized that left vs. right differences are driven by the middle cerebral artery (MCA) territory, and there is no difference between hemispheres for other vascular territories. This study...

To extract meaningful and reproducible models of brain function from stroke images, for both clinical and research proposes, is a daunting task severely hindered by the great variability of lesion frequency and patterns. Large datasets are therefore imperative, as well as fully automated image post-processing tools to analyze them. The development...

The Alberta Stroke Program Early CT Score (ASPECTS) is a simple visual system to assess the extent and location of ischemic stroke core. The capability of ASPECTS for selecting patients’ treatment, however, is affected by the variability in human evaluation. In this study, we developed a fully automatic system to calculate ASPECTS comparable with c...

Background: Although artificial intelligence systems that diagnosis among different conditions from medical images are long term aims, specific goals for automation of human-labor, time-consuming tasks are not only feasible but equally important. Acute conditions that require quantitative metrics, such as acute ischemic strokes, can greatly benefit...

The Alberta Stroke Program Early CT Score (ASPECTS) is a simple visual system to assess the extent and location of ischemic stroke core. The capability of ASPECTS for selecting patients’ treatment, however, is affected by the variability in human evaluation. In this study, we developed a fully automatic system to calculate ASPECTS comparable with c...

Purpose There are few evidence-based treatments for language deficits in primary progressive aphasia (PPA). PPA treatments are often adopted from the poststroke aphasia literature. The poststroke aphasia literature has shown promising results using Verb Network Strengthening Treatment (VNeST), a behavioral therapy that focuses on improving naming b...

A growing body of evidence indicates many, but not all, individuals with post-stroke aphasia experience executive dysfunction. Relationships between language and executive function skills are often reported in the literature, but the degree of interdependence between these abilities remains largely unanswered. Therefore, in this study, we investiga...

Cerebrovascular disease is a leading cause of death globally. Prevention and early intervention are known to be the most effective forms of its management. Non-invasive imaging methods hold great promises for early stratification, but at present lack the sensitivity for personalized prognosis. Resting-state functional magnetic resonance imaging (rs...

In contrast to the traditional definition of the disorder, many individuals with aphasia exhibit non-linguistic cognitive impairments, including executive control deficits. Classic lesion studies cite frontal lobe damage in executive dysfunction, but more recent lesion symptom-mapping studies in chronic aphasia present mixed results. In this study,...

Hemispatial neglect is among the most disabling consequences of right hemisphere stroke. However, there is no concensus on the optimal assessments to identify neglect. We hypothesized that different tests for neglect given the same day (1) detect distinct aspects and types of neglect, and (2) are sensitive to different cognitive functions (beyond s...

Background Perfusion and structural imaging play an important role in ischemic stroke. Magnetic resonance fingerprinting (MRF) arterial spin labeling (ASL) is a novel noninvasive method of ASL perfusion that allows simultaneous estimation of cerebral blood flow (CBF), bolus arrival time (BAT), and tissue T 1 map in a single scan of <4 minutes. Here...

Background Developing, monitoring, and reporting of fidelity are essential and integral components to the design of randomised controlled trials (RCTs) in stroke and aphasia. Treatment fidelity refers to the degree to which an intervention is delivered as intended and is directly related to the quality of the evidence generated by RCTs. Clear docum...

Background and Purpose Hydration at the time of stroke may impact functional outcomes. We sought to investigate the relationship between blood pressure, hydration status, and stroke severity in patients with acute ischemic stroke (AIS). Methods We evaluated hydration status, determined by blood urea nitrogen (BUN)/creatinine ratio, in consecutive...

In acute ischemic stroke, reported relationships between lesion metrics and behavior have largely focused on lesion volume and location. However, hypoperfusion has been shown to correlate with deficits in the acute stage. Hypoperfusion is typically identified using perfusion imaging in clinical settings, which requires contrast. Unfortunately, cont...

Background Treatment success is the desired outcome in aphasia rehabilitation. However, to date, there is a lack of consensus on what defines a 'successful' result on a given aphasia outcome measurement instrument (OMI). Aim In this methodological paper, we present strategies for how to define and measure treatment success on a given OMI at the gr...

We present a 20-item naming test, the Severity-Calibrated Aphasia Naming Test (SCANT), that can serve as a proxy measure for an aphasia severity scale that is derived from a thorough test battery of connected speech production, single word production, speech repetition, and auditory verbal comprehension. We use feature selection techniques from mac...

Broca’s area is frequently implicated in sentence comprehension but its specific role is debated. Most lesion studies have investigated deficits at the chronic stage. We aimed (1) to use acute imaging to predict which left hemisphere stroke patients will recover sentence comprehension; and (2) to better understand the role of Broca’s area in senten...

Testing Procedures Influence Allocentric and Egocentric Neglect Associations Hemispatial visual neglect is common after right hemisphere (RH) stroke and can impact attention to the left side of view (egocentric) or the left side of objects irrespective of location (allocentric). Allocentric and egocentric neglect correlations have been reported as...

This chapter explores the involvement of the temporal lobes in distinct language functions. The examination of cases of localized damage to the temporal lobes and the resulting pattern of impairment across language tasks and types of errors made can reveal clear neural regions and associated networks essential for word comprehension, semantics, nam...

In this forthcoming multicenter, prospective, randomized, double-blind placebo-controlled trial, we will investigate the augmentative effects of a selective serotonin reuptake inhibitor, escitalopram, on language therapy in individuals with post-stroke aphasia. We hypothesize that, when combined with language therapy, daily escitalopram will result...

Verbal fluency (VF) is an informative cognitive task. Lesion and functional imaging studies implicate distinct cerebral areas that support letter versus semantic fluency and the understanding of neural and cognitive mechanisms underlying task performance. Most lesion studies include chronic stroke patients. People with primary progressive aphasia (...

Background and Aim: Anatomical features of Middle Cerebral Artery (MCA) bifurcation favors larger emboli entering the inferior rather than superior division. As cardiac source emboli are on average larger than arterial source emboli, we hypothesize that patients with atrial fibrillation have infarcts that involve more temporal and parietal lobes th...

Background Accessible tools to efficiently detect and segment diffusion abnormalities in acute strokes are highly anticipated by the clinical and research communities. Methods We developed a tool with deep learning networks trained and tested on a large dataset of 2,348 clinical diffusion weighted MRIs of patients with acute and sub-acute ischemic...

Background and Aim: NIHSS score is higher for left versus right hemisphere strokes of equal volumes. However, differences in each vascular territory have not been evaluated yet. We hypothesized that left versus right differences are driven by the middle cerebral artery (MCA) territory, and there is no difference between hemispheres for other vascul...

Background and Aim: Anatomical features of Middle Cerebral Artery (MCA) bifurcation favors larger emboli entering the inferior rather than superior division. As cardiac source emboli are on average larger than arterial source emboli, we hypothesize that patients with atrial fibrillation have infarcts that involve more temporal and parietal lobes th...

The classical assumption that word and sentence comprehension deficits in stroke aphasia follow from damage to Wernicke's area has been questioned following discrepant results in primary progressive aphasia. We tested the hypothesis of Mesulam et al. (2015; 2019) that word and sentence comprehension deficits in stroke aphasia result from 'double di...

Background: Accessible tools to efficiently detect and segment diffusion abnormalities in acute strokes are highly anticipated by the clinical and research communities. Methods: We developed a tool with deep learning networks trained and tested on a large dataset of 2,348 clinical diffusion weighted MRIs of patients with acute and sub-acute ischemi...

Primary progressive aphasia can be distinguished into one of three variants: semantic, non-fluent/agrammatic, and logopenic. While a considerable body of work exists characterizing each variant, few prior studies have addressed the problem of optimizing behavioral assessment in a typical outpatient evaluation setting. Our aim is to examine the sens...

Most naming error lesion-symptom mapping (LSM) studies have focused on semantic and/or phonological errors. Anomic individuals also produce unrelated word errors, which may be linked to semantic or modality-independent lexical deficits. To investigate the neural underpinnings of rarely-studied unrelated errors, we conducted LSM analyses in 100 indi...

Aphasia is a neurogenic communication disorder characterized by deficits in processes underlying language comprehension and/or expression caused by acquired brain injury (typically stroke) to or progressive neurodegeneration in language cortex. The manner in which post-stroke aphasia and primary progressive aphasia (PPA) are classified—and to a cer...

Altered functional connectivity is related to severity of language impairment in poststroke aphasia. However, it is not clear whether this finding specifically reflects loss of functional coherence, or more generally, is related to decreased structural connectivity due to cortical necrosis. The aim of the current study was to investigate this issue...

Purpose Many factors influence poststroke language recovery, yet little is known about the influence of previous stroke(s) on language after left hemisphere stroke. In this prospective longitudinal study, we investigated the role of prior stroke on language abilities following an acute left hemisphere ischemic stroke, while controlling for demograp...

Affective prosody, or the changes in rate, rhythm, pitch, and loudness that convey emotion, has long been implicated as a function of the right hemisphere (RH), yet there is a dearth of literature identifying the specific neural regions associated with its processing. The current systematic review aimed to evaluate the evidence on affective prosody...

Difficulty recognizing affective prosody (receptive aprosodia) can occur following right hemisphere damage (RHD). Not all individuals spontaneously recover their ability to recognize affective prosody, warranting behavioral intervention. However, there is a dearth of evidence-based receptive aprosodia treatment research in this clinical population....

Background: Naming impairment is commonly noted in individuals with aphasia. However, object naming receives more attention than action naming. Furthermore, most studies include participants with aphasia due to only one aetiology, commonly stroke. We developed a new assessment, the Hopkins Action Naming Assessment (HANA), to evaluate action naming...

The locus and extent of brain damage in the event of vascular insult can be quantitatively established quickly and easily with vascular atlases. Although highly anticipated by clinicians and clinical researchers, no digital MRI arterial atlas is readily available for automated data analyses. We created a digital arterial territory atlas based on le...

Background A mobile platform for the self-administration of sensor-based cognitive and behavioral assessments was developed. In addition to measurements typical of legacy neuropsychological tests, Miro also quantifies functions that are currently left to subjective clinical impressions such as motor function, language, and speech. Objective Studie...

Background: Hemispatial neglect is a debilitating consequence of right hemispheric ischemic stroke (RIS), with evidence that patient-level factors influence neglect severity. Study objective: Determine if cardiac function is associated with presence and severity of neglect, independent of infarct size. Methods: Two hundred and eighteen non-demented...

Background A clinical diagnosis of primary progressive aphasia relies on behavioral characteristics and patterns of atrophy to determine a variant: logopenic; nonfluent/agrammatic; or semantic. The dual stream model is a contemporary paradigm that has been applied widely to understand brain-behavior relationships; however, applications to neurodege...

Background: Previous studies utilized lesion-centric approaches to study the role of the thalamus in language. In this study, we tested the hypotheses that non-lesioned dorsomedial and ventral anterior nuclei (DMVAC) and pulvinar lateral posterior nuclei complexes (PLC) of the thalamus and their projections to the left hemisphere show secondary eff...

Background: Progressive neurodegenerative impairment with central language features, primary progressive aphasia (PPA), can be further distinguished for many individuals into one of three variants: semantic, non-fluent/agrammatic, and logopenic variant PPA. Variants differ in their relative preservation and deficits of language skills, particularly...

Background: White matter disconnection of language-specific brain regions associates with worse aphasia recovery. Despite a loss of direct connections, many stroke survivors may maintain indirect connections between brain regions. Objective:To determine (1) whether preserved direct connections between language-specific brain regions relate to bette...

Introduction: The vertical-occipital fasciculus (VOF), which was initially described by Wernicke more than a century ago but recently rediscovered, connects visual association cortices to the posterior language areas. We hypothesized that the vertical-occipital fasciculus plays a critical role in reading. Methods: Thirty-two participants with subac...

Introduction: The Frontotemporal Lobar Degeneration Module (FTLD-MOD) includes a neuropsychological battery designed to assess the clinical features of FTLD, although much is unknown about its utility. We investigated FTLD-MOD and Uniform Data Set 3.0 (UDS) language tests for differential diagnosis and disease monitoring. Methods: Linear regress...

Background: The classification of patients with primary progressive aphasia (PPA) into variants is time-consuming, costly, and requires combined expertise by clinical neurologists, neuropsychologists, speech pathologists, and radiologists. Objective: The aim of the present study is to determine whether acoustic and linguistic variables provide a...

Background Transcranial direct current stimulation (tDCS), in conjunction with language therapy, improves language therapy outcomes in primary progressive aphasia (PPA). However, no studies show whether white matter integrity predicts language therapy or tDCS effects in PPA. Objective We aimed to determine whether white matter integrity, measured...

Recent studies have combined multiple neuroimaging modalities to gain further understanding of the neurobiological substrates of aphasia. Following this line of work, the current study uses machine learning approaches to predict aphasia severity and specific language measures based on a multimodal neuroimaging dataset. A total of 116 individuals wi...

Transcranial direct current stimulation has been shown to increase the efficiency of language therapy in chronic aphasia; however, to date, an optimal stimulation site has not been identified. We investigated whether neuromodulation of the right cerebellum can improve naming skills in chronic aphasia. Using a randomized, double-blind, sham-controll...

Language recovery following acute left hemisphere (LH) stroke is notoriously difficult to predict. Global language measures (e.g., overall aphasia severity) and gross lesion metrics (e.g., size) provide incomplete recovery predictions. In this study, we test the hypothesis that the types of naming errors patients produce, combined with dysfunctiona...

People with aphasia demonstrate impaired production of bound inflectional morphemes, such as noun plurals and possession. They often show greater difficulty in marking possession versus plurality. Using a new tool for eliciting language, the Morphosyntactic Generation test, we assessed people with primary progressive aphasia and those in the acute...

Background and Purpose Left hemisphere stroke often results in a variety of language deficits due to varying patterns of damage to language networks. The Cookie Theft picture description task, a classic, quick bedside assessment, has been shown to quantify narrative speech reliably. In this study, we utilized diffusion tensor imaging (DTI) to asses...

Objective: To determine the contribution of white matter hyperintensities (WMH) to language deficits while accounting for cortical atrophy in individuals with primary progressive aphasia (PPA). Method: Forty-three individuals with PPA completed neuropsychological assessments of nonverbal semantics, naming, and sentence repetition plus T2-weighte...

Background: It is estimated that ∼30% of stroke survivors have aphasia, a language disorder resulting from damage to left-hemisphere language networks. In acute care settings, efficient identification of aphasia is critical, but there is a paucity of efficient bedside assessments. Objective: To determine whether objective measures on a picture d...

Lesion and imaging studies have shown that the left inferior frontal gyrus (IFG) is involved in selective semantic retrieval of information from the temporal lobes. However, causal, i.e., interventional, evidence is sparse. In the present study we addressed this question by testing whether transcranial direct current stimulation (tDCS) over the lef...