Joseph M. Gullett

Broca's area and its striatal and thalamic connections: a diffusion-MRI tractography study.

In the recent decades structural connectivity between Brocas area and the basal ganglia has been postulated in the literature, though no direct evidence of this connectivity has yet been presented. The current study investigates this connectivity using a novel diffusion-weighted imaging (DWI) fiber tracking method in humans in vivo. Our findings suggest direct connections between sub-regions of Brocas area and the anterior one-third of the putamen, as well as the ventral anterior nucleus of the thalamus. Thus, we are the first to provide a detailed account of inferred circuitry involving basal ganglia, thalamus, and Brocas area, which would be a prerequisite to substantiate their support of language processing.

Imaging white matter in human brainstem

The human brainstem is critical for the control of many life-sustaining functions, such as consciousness, respiration, sleep, and transfer of sensory and motor information between the brain and the spinal cord. Most of our knowledge about structure and organization of white and gray matter within the brainstem is derived from ex vivo dissection and histology studies. However, these methods cannot be applied to study structural architecture in live human participants. Tractography from diffusion-weighted magnetic resonance imaging (MRI) may provide valuable insights about white matter organization within the brainstem in vivo. However, this method presents technical challenges in vivo due to susceptibility artifacts, functionally dense anatomy, as well as pulsatile and respiratory motion. To investigate the limits of MR tractography, we present results from high angular resolution diffusion imaging of an intact excised human brainstem performed at 11.1 T using isotropic resolution of 0.333, 1, and 2 mm, with the latter reflecting resolution currently used clinically. At the highest resolution, the dense fiber architecture of the brainstem is evident, but the definition of structures degrades as resolution decreases. In particular, the inferred corticopontine/corticospinal tracts (CPT/CST), superior (SCP) and middle cerebellar peduncle (MCP), and medial lemniscus (ML) pathways are clearly discernable and follow known anatomical trajectories at the highest spatial resolution. At lower resolutions, the CST/CPT, SCP, and MCP pathways are artificially enlarged due to inclusion of collinear and crossing fibers not inherent to these three pathways. The inferred ML pathways appear smaller at lower resolutions, indicating insufficient spatial information to successfully resolve smaller fiber pathways. Our results suggest that white matter tractography maps derived from the excised brainstem can be used to guide the study of the brainstem architecture using diffusion MRI in vivo.

Broca's area - thalamic connectivity.

Brocas area is crucially involved in language processing. The sub-regions of Brocas area (pars triangularis, pars opercularis) presumably are connected via corticocortical pathways. However, growing evidence suggests that the thalamus may also be involved in language and share some of the linguistic functions supported by Brocas area. Functional connectivity is thought to be achieved via corticothalamic/thalamocortical white matter pathways. Our study investigates structural connectivity between Brocas area and the thalamus, specifically ventral anterior nucleus and pulvinar. We demonstrate that Brocas area shares direct connections with these thalamic nuclei and suggest a local Brocas area-thalamus network potentially involved in linguistic processing. Thalamic connectivity with Brocas area may serve to selectively recruit cortical regions storing multimodal features of lexical items and to bind them together during lexical-semantic processing. In addition, Brocas area-thalamic circuitry may enable cortico-thalamo-cortical information transfer and modulation between BA 44 and 45 during language comprehension and production.

Reliability of Three Benton Judgment of Line Orientation Short Forms in Idiopathic Parkinson’s Disease

Individuals with Parkinson’s disease (PD) often exhibit deficits in visuospatial functioning throughout the course of their disease. These deficits should be carefully assessed as they may have implications for patient safety and disease severity. One of the most commonly administered tests of visuospatial ability, the Benton Judgment of Line Orientation (JLO), consists of 30 pairs of lines requiring the patient to match the orientation of two lines to an array of 11 lines on a separate page. Reliable short forms have been constructed out of the full JLO form, but the reliability of these forms in PD has yet to be examined. Recent functional MRI studies examining the JLO demonstrate right parietal and occipital activation, as well as bilateral frontal activation and PD is known to adversely affect these pathways. We compared the reliability of the original full form to three unique short forms in a sample of 141 non-demented, idiopathic PD patients and 56 age- and education-matched controls. Results indicated that a two-thirds length short form can be used with high reliability and classification accuracy in patients with idiopathic PD. The other short forms performed in a similar, though slightly less reliable manner.

Test-retest reliability of high angular resolution diffusion imaging acquisition within medial temporal lobe connections assessed via tract based spatial statistics, probabilistic tractography and a novel graph theory metric

This study examined the reliability of high angular resolution diffusion tensor imaging (HARDI) data collected on a single individual across several sessions using the same scanner. HARDI data was acquired for one healthy adult male at the same time of day on ten separate days across a one-month period. Environmental factors (e.g. temperature) were controlled across scanning sessions. Tract Based Spatial Statistics (TBSS) was used to assess session-to-session variability in measures of diffusion, fractional anisotropy (FA) and mean diffusivity (MD). To address reliability within specific structures of the medial temporal lobe (MTL; the focus of an ongoing investigation), probabilistic tractography segmented the Entorhinal cortex (ERc) based on connections with Hippocampus (HC), Perirhinal (PRc) and Parahippocampal (PHc) cortices. Streamline tractography generated edge weight (EW) metrics for the aforementioned ERc connections and, as comparison regions, connections between left and right rostral and caudal anterior cingulate cortex (ACC). Coefficients of variation (CoV) were derived for the surface area and volumes of these ERc connectivity-defined regions (CDR) and for EW across all ten scans, expecting that scan-to-scan reliability would yield low CoVs. TBSS revealed no significant variation in FA or MD across scanning sessions. Probabilistic tractography successfully reproduced histologically-verified adjacent medial temporal lobe circuits. Tractography-derived metrics displayed larger ranges of scanner-to-scanner variability. Connections involving HC displayed greater variability than metrics of connection between other investigated regions. By confirming the test retest reliability of HARDI data acquisition, support for the validity of significant results derived from diffusion data can be obtained.

Neural response to working memory demand predicts neurocognitive deficits in HIV

Human immunodeficiency virus (HIV) continues to have adverse effects on cognition and the brain in many infected people, despite a reduced incidence of HIV-associated dementia with combined antiretroviral therapy (cART). Working memory is often affected, along with attention, executive control, and cognitive processing speed. Verbal working memory (VWM) requires the interaction of each of the cognitive component processes along with a phonological loop for verbal repetition and rehearsal. HIV-related functional brain response abnormalities during VWM are evident in functional MRI (fMRI), though the neural substrate underlying these neurocognitive deficits is not well understood. The current study addressed this by comparing 24 HIV+ to 27 demographically matched HIV-seronegative (HIV−) adults with respect to fMRI activation on a VWM paradigm (n-back) relative to performance on two standardized tests of executive control, attention and processing speed (Stroop and Trail Making A–B). As expected, the HIV+ group had deficits on these neurocognitive tests compared to HIV− controls, and also differed in neural response on fMRI relative to neuropsychological performance. Reduced activation in VWM task-related brain regions on the 2-back was associated with Stroop interference deficits in HIV+ but not with either Trail Making A or B performance. Activation of the posterior cingulate cortex (PCC) of the default mode network during rest was associated with Hopkins Verbal Learning Test-2 (HVLT-2) learning in HIV+. These effects were not observed in the HIV− controls. Reduced dynamic range of neural response was also evident in HIV+ adults when activation on the 2-back condition was compared to the extent of activation of the default mode network during periods of rest. Neural dynamic range was associated with both Stroop and HVLT-2 performance. These findings provide evidence that HIV-associated alterations in neural activation induced by VWM demands and during rest differentially predict executive-attention and verbal learning deficits. That the Stroop, but not Trail Making was associated with VWM activation suggests that attentional regulation difficulties in suppressing interference and/or conflict regulation are a component of working memory deficits in HIV+ adults. Alterations in neural dynamic range may be a useful index of the impact of HIV on functional brain response and as a fMRI metric in predicting cognitive outcomes.

Temporal lobe epilepsy affects spatial organization of entorhinal cortex connectivity

Evidence for structural connectivity patterns within the medial temporal lobe derives primarily from postmortem histological studies. In humans and nonhuman primates, the parahippocampal gyrus (PHg) is subdivided into parahippocampal (PHc) and perirhinal (PRc) cortices, which receive input from distinct cortical networks. Likewise, their efferent projections to the entorhinal cortex (ERc) are distinct. The PHc projects primarily to the medial ERc (M-ERc). The PRc projects primarily to the lateral portion of the ERc (L-ERc). Both M-ERc and L-ERc, via the perforant pathway, project to the dentate gyrus and hippocampal (HC) subfields. Until recently, these neural circuits could not be visualized in vivo. Diffusion tensor imaging algorithms have been developed to segment gray matter structures based on probabilistic connectivity patterns. However, these algorithms have not yet been applied to investigate connectivity in the temporal lobe or changes in connectivity architecture related to disease processes. In this study, this segmentation procedure was used to classify ERc gray matter based on PRc, ERc, and HC connectivity patterns in 7 patients with temporal lobe epilepsy (TLE) without hippocampal sclerosis (mean age, 14.86 ± 3.34 years) and 7 healthy controls (mean age, 23.86 ± 2.97 years). Within samples paired t-tests allowed for comparison of ERc connectivity between epileptogenic and contralateral hemispheres. In healthy controls, there were no significant within-group differences in surface area, volume, or cluster number of ERc connectivity-defined regions (CDR). Likewise, in line with histology results, ERc CDR in the control group were well-organized, uniform, and segregated via PRc/PHc afferent and HC efferent connections. Conversely, in TLE, there were significantly more PRc and HC CDR clusters in the epileptogenic than the contralateral hemisphere. The surface area of the PRc CDR was greater, and that of the HC CDRs was smaller, in the epileptogenic hemisphere as well. Further, there was no clear delineation between M-ERc and L-ERc connectivity with PRc, PHc or HC in TLE. These results suggest a breakdown of the spatial organization of PHg-ERc-HC connectivity in TLE. Whether this breakdown is the cause or result of epileptic activity remains an exciting research question.

The Impact of Alcohol Use on Frontal White Matter in HIV

BACKGROUND Alcohol use disorder (AUD) is prevalent among individuals diagnosed with human immunodeficiency virus (HIV), and both HIV and alcohol use have been shown to negatively affect the integrity of white matter pathways in the brain. Behavioral, functional, and anatomical impairments have been linked independently to HIV and alcohol use, and these impairments have bases in specific frontally mediated pathways within the brain. METHODS Magnetic resonance imaging data were acquired for 37 HIV+ participants without dementia or hepatitis C. Imaging data were processed through the FreeSurfer and TraCULA pipelines to obtain 4 bilateral frontal white matter tracts for each participant. Diffusion metrics of white matter integrity along the highest probability pathway for each tract were analyzed with respect to demographics, disease-specific variables, and reported substance use. RESULTS Significantly increased axial diffusivity (decreased axonal integrity) and a trending increase in mean diffusivity were observed along the anterior thalamic radiation (ATR) in participants with a history of AUD. A diagnosis of AUD explained over 36% of the variance in diffusivity along the ATR overall when accounting for clinical variables including nadir CD4 and age-adjusted HIV infection length. CONCLUSIONS This study provides evidence of HIV-related associations between alcohol use and indicators of axonal integrity loss along the ATR, a frontal pathway involved in the inhibition of addictive or unwanted behaviors. Reduced axonal integrity of this pathway was greatest in HIV+ participants with an AUD, even when considering the effect of age-adjusted disease length and severity (nadir CD4). This finding implicates a potential biological mechanism linking reduced integrity of frontal white matter to the high prevalence of AUD in an HIV+ population without dementia or hepatitis C.