Electron Microscopic Demonstration of Neural Connections Using Horseradish Peroxidase: A Comparison of the Tetramethylbenzidine Procedure With Seven Other Histochemical Methods

Eight methods for the electron microscopic demonstration of horseradish peroxidase (HRP) labeling have been compared in adjacent series of vibratome sections of mouse lumbar spinal cord. The tracer, a HRP-wheat germ agglutinin (WGA) conjugate, was injected into the gastrocnemius muscle complex. Following retrograde axonal transport to the lumbar motor neurons and transganglionic anterograde transport of the tracer to the dorsal horn, the HRP activity was demonstrated in eight series of adjacent sections of lumbar spinal cord using eight methods. These included procedures using tetramethylbenzidine (TMB), benzidine dihydrochloride (BDHC), o-tolidine, paraphenylenediamine-pyrocatechol (PPD-PC), and 4 methods using 3,3\u27-diaminobenzidine (DAB). All eight methods were able to demonstrate both retrograde labeling of motor neurons and transganglionic anterograde transport into the dorsal horn. However, there were differences in the appearance of the various reaction products under the electron microscope. In addition, differences in the distribution of the reaction products were observed by both light and electron microscopy. The largest distribution of reaction product was observed with TMB. BDHC and o-tolidine were next, followed by the DAB procedures and PPD-PC. The TMB, BDHC, and o-tolidine reaction products were all found to be suitable for electron microscopy. The TMB reaction product was electron dense and had a very distinctive crystalloid appearance that made identification of HRP-labeled neuronal profiles easy and unequivocal. Copyright © 1982 by The Histochemical Society, Inc

The Comportmental Learning Disabilities of Early Frontal Lobe Damage

Two adult patients are described who suffered bilateral prefrontal damage early in life and who subsequently came to psychiatric attention because of severely aberrant behaviour. A battery of developmental psychology paradigms (not previously used to assess neurologically impaired individuals) showed that social and moral development of these 2 patients was arrested at an immature stage. In comparison with other types of brain damage which disrupt cognitive development, frontal damage acquired early in life appears to provide the neurological substrate for a special type of learning disability in the realms of insight, foresight, social judgement, empathy, and complex reasoning

Phonological Facilitation of Object Naming in Agrammatic and Logopenic Primary Progressive Aphasia (PPA): Evidence for a Phonological Processing Deficit

Naming is a pervasive deficit in primary progressive aphasia. However, the source of such deficits across PPA variants is little understood. In this study, individuals with agrammatic (PPA-G) and logopenic (PPA-L) PPA, along with age-matched controls, performed a picture-word interference task to test for online phonological processing deficits during naming. All groups exhibited phonological facilitation (PF) effects, i.e., speeded picture naming in the presence of phonologically-related words. However, the PPA participants exhibited abnormally large PF effects that also were protracted, compared to the control group. These results suggest that impaired phonological processing may contribute to anomia in PPA-G and PPA-L

Shifts of Effective Connectivity within a Language Network during Rhyming and Spelling

This is the published version, also available here: http://dx.doi.org/10.1523/JNEUROSCI.0864-05.2005.We used functional magnetic resonance imaging to examine task-specific modulations of effective connectivity within a left-hemisphere language network during spelling and rhyming judgments on visually presented words. We identified sites showing task-specific activations for rhyming in the lateral temporal cortex (LTC) and for spelling in the intraparietal sulcus (IPS). The inferior frontal gyrus (IFG) and fusiform gyrus were engaged by both tasks. Dynamic causal modeling showed that each task preferentially strengthened modulatory influences converging on its task-specific site (LTC for rhyming, IPS for spelling). These remarkably selective and symmetrical findings demonstrate that the nature of the behavioral task dynamically shifts the locus of integration (or convergence) to the network component specialized for that task. Furthermore, they suggest that the role of the task-selective areas is to provide a differential synthesis of incoming information rather than providing differential control signals influencing the activity of other network components. Our findings also showed that switching tasks led to changes in the target area influenced by the IFG, suggesting that the IFG may play a pivotal role in setting the cognitive context for each task. We propose that task-dependent shifts in effective connectivity are likely to be mediated through top-down modulations from the IFG to the task-selective regions in a way that differentially enhances their sensitivity to incoming word-form information

Brain Networks for Analyzing Eye Gaze

The eyes convey a wealth of information in social interactions. This information is analyzed by multiple brain networks, which we identified using functional magnetic resonance imaging (MRI). Subjects attempted to detect a particular directional cue provided either by gaze changes on an image of a face or by an arrow presented alone or by an arrow superimposed on the face. Another control condition was included in which the eyes moved without providing meaningful directional information. Activation of the superior temporal sulcus accompanied extracting directional information from gaze relative to directional information from an arrow and relative to eye motion without relevant directional information. Such selectivity for gaze processing was not observed in face-responsive fusiform regions. Brain activations were also investigated while subjects viewed the same face but attempted to detect when the eyes gazed directly at them. Most notably, amygdala activation was greater during periods when direct gaze never occurred than during periods when direct gaze occurred on 40% of the trials. In summary, our results suggest that increases in neural processing in the amygdala facilitate the analysis of gaze cues when a person is actively monitoring for emotional gaze events, whereas increases in neural processing in the superior temporal sulcus support the analysis of gaze cues that provide socially meaningful spatial information.Psycholog

Neural correlates of grammatical impairment in primary progressive aphasia

Primary progressive aphasia (PPA) is characterized by distinct patterns of left-lateralized neural degeneration and declining language functioning. Although deficits in grammatical processing (e.g., complex sentence production and comprehension, production of grammatical morphology) are primarily seen in the agrammatic variant (PPA-G), subtle impairments also may be observed in the logopenic (PPA-L) and semantic (PPA-S) variants (see Wilson, et al., 2012; Thompson & Mack, in press, for a review). In cognitively healthy individuals, production and comprehension of syntactically complex structures involves both the left middle temporal cortex (Ben-Shalom & Poeppel, 2008; Indefrey & Levelt, 2004) and the left inferior frontal and motor cortices (Friederici, 2002; Kielar et al., 2011; Shapiro, et al., 2012; Tyler et al., 2005), with similar regions engaged for production of grammatical morphology. However, impaired complex sentence production and comprehension in PPA has been linked primarily to atrophy in the left inferior frontal gyrus (IFG) (Amici et al., 2007; Rogalski et al., 2011; Wilson et al., 2011) and atrophy patterns associated with deficits in grammatical morphology have not been previously studied. The present study aimed to identify the cortical areas of atrophy associated with deficits in complex sentence production, complex sentence comprehension, and production of grammatical morphology in PPA. Identification of these patterns has relevance for understanding the neural mechanisms of grammatical processing and as well as for clinical management of individuals with PPA

Sentence Comprehension and Production in Stroke-induced and Primary Progressive Aphasia (PPA): The Northwestern Assessment of Verbs and Sentences (NAVS)

This study examined comprehension and production of both canonical and noncanonical sentences in 46 individuals with stroke-induced (StrAph) [26 Broca’s aphasic with agrammatism (StrAg); 20 anomic (StrAn)] and 32 with primary progressive aphasia (PPA) [15 agrammatic (PPA-G); 17 logopenic (PPA-L)], using the Northwestern Assessment of Verbs and Sentences (NAVS; Thompson, experimental version). The two agrammatic, StrAg and PPA-G, groups performed in a very similar manner, with both showing significantly greater difficulty with noncanonical compared to canonical sentences in both modalities, compared to StrAn and PPA-L participants

The Influence of Stimulus Deviance on Electrophysiologic and Behavioral Responses to Novel Events

This study investigated the role of stimulus deviance in determining electrophysiologic and behavioral responses to “novelty.” Stimulus deviance was defined in terms of differences either from the immediately preceding context or from long-term experience. Subjects participated in a visual event-related potential (ERP) experiment, in which they controlled the duration of stimulus viewing with a button press, which served as a measure of exploratory behavior. Each of the three experimental conditions included a frequent repetitive background stimulus and infrequent stimuli that deviated from the background stimulus. In one condition, both background and deviant stimuli were simple, easily recognizable geometric figures. In another condition, both background and deviant stimuli were unusual/unfamiliar figures, and in a third condition, the background stimulus was a highly unusual figure, and the deviant stimuli were simple, geometric shapes. Deviant stimuli elicited larger N2-P3 amplitudes and longer viewing durations than the repetitive background stimulus, even when the deviant stimuli were simple, familiar shapes and the background stimulus was a highly unusual figure. Compared to simple, familiar deviant stimuli, unusual deviant stimuli elicited larger N2-P3 amplitudes and longer viewing times. Within subjects, the deviant stimuli that evoked the largest N2-P3 responses also elicited the longest viewing durations. We conclude that deviance from both immediate context and long-term prior experience contribute to the response to novelty, with the combination generating the largest N2-P3 amplitude and the most sustained attention. The amplitude of the N2-P3 may reflect how much “uncertainty” is evoked by a novel visual stimulus and signal the need for further exploration and cognitive processing

Frontotemporal networks and behavioral symptoms in primary progressive aphasia

OBJECTIVE: To determine if behavioral symptoms in patients with primary progressive aphasia (PPA) were associated with degeneration of a ventral frontotemporal network. METHODS: We used diffusion tensor imaging tractography to quantify abnormalities of the uncinate fasciculus that connects the anterior temporal lobe and the ventrolateral frontal cortex. Two additional ventral tracts were studied: the inferior fronto-occipital fasciculus and the inferior longitudinal fasciculus. We also measured cortical thickness of anterior temporal and orbitofrontal regions interconnected by these tracts. Thirty-three patients with PPA and 26 healthy controls were recruited. RESULTS: In keeping with the PPA diagnosis, behavioral symptoms were distinctly less prominent than the language deficits. Although all 3 tracts had structural pathology as determined by tractography, significant correlations with scores on the Frontal Behavioral Inventory were found only for the uncinate fasciculus. Cortical atrophy of the orbitofrontal and anterior temporal lobe cortex was also correlated with these scores. CONCLUSIONS: Our findings indicate that damage to a frontotemporal network mediated by the uncinate fasciculus may underlie the emergence of behavioral symptoms in patients with PPA

Activated Microglia in Cortical White Matter Across Cognitive Aging Trajectories

Activation of microglia, the primary mediators of inflammation in the brain, is a major component of gliosis and neuronal loss in a number of age-related neurodegenerative disorders, such as Alzheimer’s disease (AD). The role of activated microglia in white matter, and its relationship with cognitive decline during aging are unknown. The current study evaluated microglia densities in the white matter of postmortem specimens from cognitively normal young adults, cognitively normal older adults, and cognitive “SuperAgers,” a unique group of individuals over age 80 whose memory test scores are at a level equal to or better than scores of 50-to-65-year-olds. Whole hemisphere sections from cognitively normal old, young, and “SuperAgers” were used to quantify densities of human leukocyte antigen-D related (HLA-DR)-positive activated microglia underlying five cortical regions. Statistical findings showed a significant main effect of group on differences in microglia density where cognitively normal old showed highest densities. No difference between SuperAgers and young specimens were detected. In two autopsied SuperAgers with MRI FLAIR scans available, prominent hyperintensities in periventricular regions were observed, and interestingly, examination of corresponding postmortem sections showed only sparse microglia densities. In conclusion, activated microglia appear to respond to age-related pathologic changes in cortical white matter, and this phenomenon is largely spared in SuperAgers. Findings offer insights into the relationship between white matter neuroinflammatory changes and cognitive integrity during aging