Paul Fillmore

Left Hemisphere Plasticity and Aphasia Recovery

A recent study by our group revealed a strong relationship between functional brain changes in the left hemisphere and anomia treatment outcome in chronic stroke patients (N=26) with aphasia (Fridriksson, 2010). The current research represents a continuation of this work in which we have refined our methods and added data from four more patients (for a total sample size of 30) to assess where in the left hemisphere treatment-related brain changes occur. Unlike Fridriksson (2010) which only focused on changes in correct naming as a marker of treatment outcome, the current study examined the relationship between changes in left hemisphere activity and changes in correct naming, semantic paraphasias, and phonemic paraphasias following treatment. We also expanded on the work by Fridriksson by examining whether neurophysiological measures taken at baseline (defined henceforth as the time-point before the start of anomia treatment) predict treatment outcome. Our analyses revealed that changes in activation in perilesional areas predicted treatment-related increases in correct naming in individuals with chronic aphasia. This relationship was most easily observed in the left frontal lobe. A decrease in the number of semantic and phonemic paraphasias was predicted by an activation change in the temporal lobe involving cortical areas that were shown to be active during picture naming in 14 normal subjects. In contrast, a far less certain relationship was found between baseline neurophysiological measures and anomia treatment outcome. Our findings suggest that improved naming associated with behavioral anomia treatment in aphasia is associated with modulation of the left frontal lobe whereas a reduction in naming errors is mediated by left posterior regions that classically are thought to be involved in language processing.

Damage to the anterior arcuate fasciculus predicts non-fluent speech production in aphasia

Non-fluent aphasia implies a relatively straightforward neurological condition characterized by limited speech output. However, it is an umbrella term for different underlying impairments affecting speech production. Several studies have sought the critical lesion location that gives rise to non-fluent aphasia. The results have been mixed but typically implicate anterior cortical regions such as Brocas area, the left anterior insula, and deep white matter regions. To provide a clearer picture of cortical damage in non-fluent aphasia, the current study examined brain damage that negatively influences speech fluency in patients with aphasia. It controlled for some basic speech and language comprehension factors in order to better isolate the contribution of different mechanisms to fluency, or its lack. Cortical damage was related to overall speech fluency, as estimated by clinical judgements using the Western Aphasia Battery speech fluency scale, diadochokinetic rate, rudimentary auditory language comprehension, and executive functioning (scores on a matrix reasoning test) in 64 patients with chronic left hemisphere stroke. A region of interest analysis that included brain regions typically implicated in speech and language processing revealed that non-fluency in aphasia is primarily predicted by damage to the anterior segment of the left arcuate fasciculus. An improved prediction model also included the left uncinate fasciculus, a white matter tract connecting the middle and anterior temporal lobe with frontal lobe regions, including the pars triangularis. Models that controlled for diadochokinetic rate, picture-word recognition, or executive functioning also revealed a strong relationship between anterior segment involvement and speech fluency. Whole brain analyses corroborated the findings from the region of interest analyses. An additional exploratory analysis revealed that involvement of the uncinate fasciculus adjudicated between Brocas and global aphasia, the two most common kinds of non-fluent aphasia. In summary, the current results suggest that the anterior segment of the left arcuate fasciculus, a white matter tract that lies deep to posterior portions of Brocas area and the sensory-motor cortex, is a robust predictor of impaired speech fluency in aphasic patients, even when motor speech, lexical processing, and executive functioning are included as co-factors. Simply put, damage to those regions results in non-fluent aphasic speech; when they are undamaged, fluent aphasias result.

Damage to Left Anterior Temporal Cortex Predicts Impairment of Complex Syntactic Processing: A Lesion-Symptom Mapping Study

Sentence processing problems form a common consequence of left‐hemisphere brain injury, in some patients to such an extent that their pattern of language performance is characterized as “agrammatic”. However, the location of left‐hemisphere damage that causes such problems remains controversial. It has been suggested that the critical site for syntactic processing is Brocas area of the frontal cortex or, alternatively, that a more widely distributed network is responsible for syntactic processing. The aim of this study was to identify brain regions that are required for successful sentence processing. Voxel‐based lesion‐symptom mapping (VLSM) was used to identify brain regions where injury predicted impaired sentence processing in 50 native speakers of Icelandic with left‐hemisphere stroke. Sentence processing was assessed by having individuals identify which picture corresponded to a verbally presented sentence. The VLSM analysis revealed that impaired sentence processing was best predicted by damage to a large left‐hemisphere temporo‐parieto‐occipital area. This is likely due to the multimodal nature of the sentence processing task, which involves auditory and visual analysis, as well as lexical and syntactic processing. Specifically impaired processing of noncanonical sentence types, when compared with canonical sentence processing, was associated with damage to the left‐hemisphere anterior superior and middle temporal gyri and the temporal pole. Anterior temporal cortex, therefore, appears to play a crucial role in syntactic processing, and patients with brain damage to this area are more likely to present with receptive agrammatism than patients in which anterior temporal cortex is spared. Hum Brain Mapp 34:2715–2723, 2013.

Re-Establishing Broca's Initial Findings.

The importance of the left inferior pre-frontal cortex (LIPC) for speech production was first popularized by Paul Broca, providing a cornerstone of behavioral neurology and laying the foundation for future research examining brain-behavior relationships. Although Brocas findings were rigorously challenged, comprehensive contradictory evidence was not published until 130years later. This evidence suggested that damage to left anterior insula was actually the best predictor of motor speech impairment. Using high-resolution structural magnetic resonance imaging (MRI) in patients with chronic stroke, we reveal that LIPC involvement more accurately predicts acquired motor speech impairment than insula damage. Perfusion-weighted MRI provides complementary evidence, highlighting how damage to left inferior pre-frontal gyrus often includes insula involvement, and vice versa. Our findings suggest that Brocas initial conclusions associating acquired motor speech impairment with LIPC damage remain valid nearly 150years after his initial report on this issue.

Regional white matter damage predicts speech fluency in chronic post-stroke aphasia.

Recently, two different white matter regions that support speech fluency have been identified: the aslant tract and the anterior segment of the arcuate fasciculus (ASAF). The role of the ASAF was demonstrated in patients with post-stroke aphasia, while the role of the aslant tract shown in primary progressive aphasia. Regional white matter integrity appears to be crucial for speech production; however, the degree that each region exerts an independent influence on speech fluency is unclear. Furthermore, it is not yet defined if damage to both white matter regions influences speech in the context of the same neural mechanism (stroke-induced aphasia). This study assessed the relationship between speech fluency and quantitative integrity of the aslant region and the ASAF. It also explored the relationship between speech fluency and other white matter regions underlying classic cortical language areas such as the uncinate fasciculus and the inferior longitudinal fasciculus (ILF). Damage to these regions, except the ILF, was associated with speech fluency, suggesting synergistic association of these regions with speech fluency in post-stroke aphasia. These observations support the theory that speech fluency requires the complex, orchestrated activity between a network of pre-motor, secondary, and tertiary associative cortices, supported in turn by regional white matter integrity.

Age-specific MRI brain and head templates for healthy adults from 20 through 89 years of age

This study created and tested a database of adult, age-specific MRI brain and head templates. The participants included healthy adults from 20 through 89 years of age. The templates were done in five-year, 10-year, and multi-year intervals from 20 through 89 years, and consist of average T1W for the head and brain, and segmenting priors for gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). It was found that age-appropriate templates provided less biased tissue classification estimates than age-inappropriate reference data and reference data based on young adult templates. This database is available for use by other investigators and clinicians for their MRI studies, as well as other types of neuroimaging and electrophysiological research.1

Mapping remote subcortical ramifications of injury after ischemic strokes.

Background. The extent of brain damage in chronic stroke patients is traditionally defined as the necrotic tissue observed on magnetic resonance image (MRI). However, patients often exhibit symptoms suggesting that functional impairment may affect areas beyond the cortical necrotic lesion, for example, when cortical symptoms ensue after subcortical damage. This observation suggests that disconnection or diaschisis can lead to remote cortical dysfunction that can be functionally equivalent to direct cortical lesions. Objective. To directly measure subcortical disconnection after stroke. Methods. We describe a principled approach utilizing the whole brain connectome reconstructed from diffusion MRI to evaluate the reduction of apparent white matter fiber density in the hemisphere affected by the stroke compared with the spared hemisphere. Results. In eight chronic stroke patients, we observed subcortical disconnection extending beyond the location of tissue necrosis and affecting major white matter pathways underlying the necrotic area. Conclusions. We suggest that it is possible to detect and quantify previously unappreciated areas of subcortical and cortical disconnection. Specifically, this method can be used to evaluate the relationship between lesion location and symptoms, with emphasis on a connectivity-based approach.

Chronic Broca's Aphasia Is Caused by Damage to Broca's and Wernicke's Areas

Despite being perhaps the most studied form of aphasia, the critical lesion location for Brocas aphasia has long been debated, and in chronic patients, cortical damage often extends far beyond Brocas area. In a group of 70 patients, we examined brain damage associated with Brocas aphasia using voxel-wise lesion-symptom mapping (VLSM). We found that damage to the posterior portion of Brocas area, the pars opercularis, is associated with Brocas aphasia. However, several individuals with other aphasic patterns had considerable damage to pars opercularis, suggesting that involvement of this region is not sufficient to cause Brocas aphasia. When examining only individuals with pars opercularis damage, we found that patients with Brocas aphasia had greater damage in the left superior temporal gyrus (STG; roughly Wernickes area) than those with other aphasia types. Using discriminant function analysis and logistic regression, based on proportional damage to the pars opercularis and Wernickes area, to predict whether individuals had Brocas or another types of aphasia, over 95% were classified correctly. Our findings suggest that persons with Brocas aphasia have damage to both Brocas and Wernickes areas, a conclusion that is incongruent with classical neuropsychology, which has rarely considered the effects of damage to both areas.

Stereotaxic Magnetic Resonance Imaging Brain Atlases for Infants from 3 to 12 Months.

Background: Accurate labeling of brain structures within an individual or group is a key issue in neuroimaging. Methods for labeling infant brains have depended on the labels done on adult brains or average magnetic resonance imaging (MRI) templates based on adult brains. However, the features of adult brains differ in several ways from infant brains, so the creation of a labeled stereotaxic atlas based on infants would be helpful. The current work builds on the recent creation of age-appropriate average MRI templates during the first year (3, 4.5, 6, 7.5, 9, and 12 months) by creating anatomical label sets for each template. Methods: We created stereotaxic atlases for the age-specific average MRI templates. Manual delineation of cortical and subcortical areas was done on the average templates based on infants during the first year. We also applied a procedure for automatic computation of macroanatomical atlases for individual infant participants using two manually segmented adult atlases (Hammers, LONI Probabilistic Brain Atlas-LPBA40). To evaluate our methods, we did manual delineation of several cortical areas on selected individuals from each age. Linear and nonlinear registration of the individual and average template was used to transform the average atlas into the individual participants space, and the average-transformed atlas was compared to the individual manually delineated brain areas. We also applied these methods to an external data set - not used in the atlas creation - to test generalizability of the atlases. Results: Age-appropriate manual atlases were the best fit to the individual manually delineated regions, with more error seen at greater age discrepancy. There was a close fit between the manually delineated and the automatically labeled regions for individual participants and for the age-appropriate template-based atlas transformed into participant space. There was close correspondence between automatic labeling of individual brain regions and those from the age-appropriate template. These relationships held even when tested on an external set of images. Conclusion: We have created age-appropriate labeled templates for use in the study of infant development at 6 ages (3, 4.5, 6, 7.5, 9, and 12 months). Comparison with manual methods was quite good. We developed three stereotaxic atlases (one manual, two automatic) for each infant age, which should allow more fine-grained analysis of brain structure for these populations than was previously possible with existing tools. The template-based atlases constructed in the current study are available online (http://jerlab.psych.sc.edu/NeurodevelopmentalMRIDatabase).

The superior precentral gyrus of the insula does not appear to be functionally specialized for articulation

Broca (Broca P. Bull Soc Anat Paris 36: 330-357, 1861) influentially argued that posterior left inferior frontal gyrus supports speech articulation. According to an alternative proposal (e.g., Dronkers NF. Nature 384: 159-161, 1996; Wise RJ, Greene J, Buchel C, Scott SK. Lancet 353: 1057-1061, 1999; Baldo JV, Wilkins DP, Ogar J, Willock S, Dronkers NF. Cortex 47: 800-807, 2011), a region in the anterior insula [specifically, the superior precentral gyrus of the insula (SPGI)] is the seat of articulatory abilities. Moreover, Dronkers and colleagues have argued that the SPGI is functionally specialized for (complex) speech articulation. Here, we evaluate this claim using individual-subject functional MRI (fMRI) analyses (e.g., Fedorenko E, Hsieh PJ, Nieto-Castanon A, Whitfield-Gabrieli S, Kanwisher N. J Neurophysiol 104: 1177-1194, 2010). We find that the SPGI responds weakly, if at all, during articulation (parts of Brocas area respond 3-4 times more strongly) and does not show a stronger response to higher articulatory demands. This holds regardless of whether the SPGI is defined functionally (by selecting the most articulation-responsive voxels in the vicinity of the SPGI in each subject individually) or anatomically (by using masks drawn on each individual subjects anatomy). Critically, nonspeech oral movements activate the SPGI more strongly than articulation, especially under the anatomical definition of the SPGI. In line with Hillis et al. (Hillis AE, Work M, Barker PB, Jacobs MA, Breese EL, Maurer K. Brain 127: 1479-1487, 2004; also Trupe L, Varma DD, Gomez Y, Race D, Leigh R, Hillis AE, Gottesman RF. Stroke 44: 740-744, 2013), we argue that previous links between the SPGI, and perhaps anterior insula more generally, and articulation may be due to its high base rate of ischemic damage (and activation in fMRI; Yarkoni T, Poldrack RA, Nichols TE, Van Essen DC, Wager TD. Nat Methods 8: 665-670, 2011), combined with its proximity to regions that more directly support speech articulation, such as the precentral gyrus or the posterior aspects of the inferior frontal gyrus (Richardson JD, Fillmore P, Rorden C, Lapointe LL, Fridriksson J. Brain Lang 123: 125-130, 2012), and thus susceptibility to joint damage.