OBJECTIVES/SPECIFIC AIMS: Parkinson’s disease (PD) is a condition that affects over a million Americans, and despite current medical therapies, the progression of the disease results in impaired generation of internally timed or guided (IG) movements. To address this loss of motor function, previous rehabilitation therapies have focused on remediating the affected striatal-thalamic-cortical circuits (STC), primarily thought to be responsible in generating timed motor patterns. However, given the disease leads to the cell death of dopaminergic cells that are essential for proper STC function, we propose a motor therapy aimed at utilizing a compensatory parallel cerebellar-thalamic-cortical (CTC) pathway, recruited to perform externally guided (EG) movements, in which gait initiation is driven from sensory input. Our previous study has shown efficacy in our novel argentine tango therapy and improves behavioral measures above the relevant MCID threshold, but it has not been established that the CTC are in the causal pathway that are responsible for these changes. Using neural measures from task fMRI, we have begun to characterize networks that have changed and quantify any associations with behavioral metrics. METHODS/STUDY POPULATION: Patients were randomly assigned to an IG (n=18), EG (n=18), or education contact control (n=14). Participants were assessed preintervention and postintervention for behavioral motor and cognitive measures and neurophysiologically with task based fMRI. In the task, participants performed a foot tapping task under both IG (tap their foot in previously learned rhythm) or EG (tap immediately after receiving a tactile cue on their hand) conditions. The fMRI data were preprocessed using AFNI and registered to MNI standard space. The brainnetome atlas was applied and the average time series of each region of interest (ROI) was used to increase the signal to noise ratio. The activation of these ROI with respect to the stimulus was modeled using GLM, and we estimated the area under the curve during the task blocks. A 1-way ANOVA analysis on these betas were performed between the pre and the post intervention time points and the ROIs that were above a significance of 0.95 were identified and corrected for multiple comparisons. The change in beta in all ROIs for each individual were calculated and then correlated with the changes in the behavioral data, to see which changes in ROI areas matched the best with the behavioral changes. RESULTS/ANTICIPATED RESULTS: The EG group showed significant changes only in the EG task in 2 areas—inferior frontal gyrus and inferior temporal sulcus. Correlating to the cognitive behavioral measures show reduced error from the Inferior frontal gyrus (corr>0.5) best reflect changes in observed. There were no changes to either the STC or the CTC pathways. The IG group showed no changes behaviorally and showed no changes neurally as well. The control group showed no changes behaviorally, but neuronally certain DMN nodes, such as the precuneus and inferior temporal regions showed a significant change for both tasks. DISCUSSION/SIGNIFICANCE OF IMPACT: Addressing the damaged STC pathway directly through IG therapy may not be effective. The EG therapy may not be able to enhance the STC pathway. However, the therapy appears to utilize new areas in the frontal regions and correlates with positively with changes in spatial memory and balance tasks. Contrary to our hypothesis the CTC circuit was not upregulated for performance of the IG or EG task, but therapy may have enhanced recruitment of other cognitively engaged areas. The educational control group interestingly showed changes in the DMN network, which has been shown to be linked to attention during tasks blocks.

Objectives: The cerebellum (CB) is known for its role in supporting processing speed (PS) and cognitive efficiencies. The CB often sustains damage from treatment and resection in pediatric patients with posterior fossa tumors. Limited research suggests that CB atrophy may be associated with the radiation treatment experienced during childhood. The purpose of the study was to measure cerebellar atrophy to determine its neurobehavioral correlates. Methods: Brain magnetic resonance images were collected from 25 adult survivors of CB tumors and age- and gender-matched controls (Mage=24 years (SD=5), 52% female). Average age at diagnosis was 9 years (SD=5) and average time since diagnosis was 15 years (SD=5). PS was measured by the Symbol Digit Modality Test. To quantify atrophy, an objective formula was developed based on prior literature, in which Atrophy=[(CB White+CB Gray Volume)/Intracranial Vault (ICV)]controls-[(CB White+CB Gray+Lesion Size Volume)/ICV]survivors. Results: Regression analyses found that the interaction term (age at diagnosis*radiation) predicts CB atrophy; regression equations included the Neurological Predictor Scale, lesion size, atrophy, and the interaction term and accounted for 33% of the variance in oral PS and 48% of the variance in written PS. Both interactions suggest that individuals with smaller CB lesion size but a greater degree of CB atrophy had slower PS, whereas individuals with a larger CB lesion size and less CB atrophy were less affected. Conclusion: The results of the current study suggest that young age at diagnosis and radiation is associated with CB atrophy, which interacts with lesion size to impact both written and oral PS. (JINS, 2016, 23, 1–11)

Functional magnetic resonance imaging (fMRI) studies have identified consistent age-related changes during various cognitive tasks, such that older individuals display more positive and less negative task-related activity than young adults. Recently, evidence shows that chronic physical exercise may alter aging-related changes in brain activity; however, the effect of exercise has not been studied for the neural substrates of language function. Additionally, the potential mechanisms by which aging alters neural recruitment remain understudied. To address these points, the present study enrolled elderly adults who were either sedentary or physically active to characterize the neural correlates of language function during semantic fluency between these groups in comparison to a young adult sample. Participants underwent fMRI during semantic fluency and transcranial magnetic stimulation to collect the ipsilateral silent period, a measure of interhemispheric inhibition. Results indicated that sedentary older adults displayed reductions in negative task-related activity compared to the active old group in areas of the attention network. Longer interhemispheric inhibition was associated with more negative task-related activity in the right and left posterior perisylvian cortex, suggesting that sedentary aging may result in losses in task facilitatory cortical inhibition. However, these losses may be mitigated by regular engagement in physical exercise. (JINS, 2013, 19, 1–10)

Six individuals with probable Alzheimer’s disease (AD) participated in a phase 1 study employing a repeated measures, parallel baseline design testing the hypothesis that error-free experience during word production practice combined with an acetyl cholinesterase inhibitor would improve confrontation naming ability. While acetyl cholinesterase inhibitors are safe and delay cognition decline associated with AD, improvement over baseline cognition is less evident; clinically significant cognitive deficits persist and progress. Both animal and clinical research strongly implicate acetylcholine in learning, a form of neuroplasticity. In clinical practice, however, people with AD are given cholinergic medications without concomitant systematic/targeted retraining. In this study six participants with probable AD and taking donepezil participated in targeted word production practice using an errorless learning strategy. Results showed that combining behavioral enrichment training and an acetyl cholinesterase inhibitor resulted in significant improvements in verbal confrontation naming of trained items for three of six participants. Differences in baseline dementia severity, living conditions, and medications may have influenced the training response. Detection of substantial treatment effects in 50% of subjects suggests further language treatment studies in AD in combination with an acetyl cholinesterase inhibitor are warranted and provide useful information on inclusion/exclusion criteria for use in subsequent studies. (JINS, 2009, 15, 311–322.)

Recent findings suggest that neural representations of semantic knowledge contain information about category, modality, and attributes. Although an object’s category is defined according to shared attributes that uniquely distinguish it from other category members, a clear dissociation between visual attribute and category representation has not yet been reported. We investigated the contribution of category (living and nonliving) and visual attribute (global form and local details) to semantic representation in the fusiform gyrus. During functional magnetic resonance imaging (fMRI), 40 adults named pictures of animals, tools, and vehicles. In a preliminary study, identification of objects in these categories was differentially dependent on global versus local visual feature processing. fMRI findings indicate that activation in the lateral and medial regions of the fusiform gyrus distinguished stimuli according to category, that is, living versus nonliving, respectively. In contrast, visual attributes of global form (animals) were associated with higher activity in the right fusiform gyrus, while local details (tools) were associated with higher activity in the left fusiform gyrus. When both global and local attributes were relevant to processing (vehicles), cortex in both left and right medial fusiform gyri was more active than for other categories. Taken together, results support distinctions in the role of visual attributes and category in semantic representation. (JINS, 2009, 15, 169–181.)

Adult readers with developmental phonological dyslexia exhibit significant difficulty comparing pseudowords and pure tones in auditory working memory (AWM). This suggests deficient AWM skills for adults diagnosed with dyslexia. Despite behavioral differences, it is unknown whether neural substrates of AWM differ between adults diagnosed with dyslexia and normal readers. Prior neuroimaging of adults diagnosed with dyslexia and normal readers, and post-mortem findings of neural structural anomalies in adults diagnosed with dyslexia support the hypothesis of atypical neural activity in temporoparietal and inferior frontal regions during AWM tasks in adults diagnosed with dyslexia. We used fMRI during two binaural AWM tasks (pseudowords or pure tones comparisons) in adults diagnosed with dyslexia (n = 11) and normal readers (n = 11). For both AWM tasks, adults diagnosed with dyslexia exhibited greater activity in left posterior superior temporal (BA 22) and inferior parietal regions (BA 40) than normal readers. Comparing neural activity between groups and between stimuli contrasts (pseudowords vs. tones), adults diagnosed with dyslexia showed greater primary auditory cortex activity (BA 42; tones > pseudowords) than normal readers. Thus, greater activity in primary auditory, posterior superior temporal, and inferior parietal cortices during linguistic and non-linguistic AWM tasks for adults diagnosed with dyslexia compared to normal readers indicate differences in neural substrates of AWM comparison tasks. (JINS, 2008, 14, 629–639.)

Twenty-three chronic nonfluent aphasia patients with moderate or severe word-finding impairments and 11 with profound word-finding impairments received two novel picture-naming treatments. The intention treatment initiated picture-naming trials with a complex left-hand movement and was designed to enhance right frontal participation during word retrieval. The attention treatment required patients to view visual stimuli for picture-naming trials in their left hemispace and was designed to enhance right posterior perisylvian participation during word retrieval. Because the intention treatment addressed action mechanisms and nonfluent aphasia reflects difficulty initiating or maintaining action (i.e., language output), it was hypothesized that intention component of the treatment would enhance re-acquisition of picture naming more than the attention component. Patients with moderate and severe word-finding impairment showed gains with both treatments but greater incremental improvement from one treatment phase to the next with the intention than the attention treatment. Thus, the hypothesis that intention component would be a more active constituent than the attention component was confirmed for these patients. Patients with profound word-finding impairment showed some improvement with both treatments but no differential effects for the intention treatment. Almost all patients who showed treatment gains on either treatment also demonstrated generalization from trained to untrained items. (JINS, 2007, 13, 582–594.)

Two patients (G01, J02) with chronic nonfluent aphasia and sentence production deficits received syntactic mapping treatment to improve sentence production. The patients had dramatically different outcomes in that improved syntax production generalized to nontreatment tasks for G01, but not for JO2. To learn how treatment influenced the neural substrates for syntax production, both patients underwent pre- and posttreatment functional magnetic resonance imaging (fMRI) of sentence generation. G01 showed more robust activity posttreatment than pretreatment in Broca's area; ventral temporal activity decreased slightly from pre- to posttreatment. Comparison of J02's pretreatment and posttreatment images revealed little change, although activity was more diffuse pre- than posttreatment. Findings suggest that for G01, rehabilitation led to engagement of an area (Broca's area) used minimally during the pretreatment scan, whereas for J02, rehabilitation may have led to more efficient use of areas already involved in sentence generation during the pretreatment scan. fMRI findings are discussed in the context of sentence-production outcome and generalization. (JINS, 2006, 12, 132–146.)

Past research has shown that lesions in the left cerebral hemisphere often result in aphasia, while lesions in the right hemisphere frequently impair the production of emotional prosody and facial expression. At least 3 processing deficits might account for these affective symptoms: (1) failure to understand the conditions that evoke emotional response; (2) inability to experience emotions; (3) disruption in the capacity to encode non-verbal signals. To better understand these disorders and their underlying mechanisms, we investigated spontaneous affective communication in right hemisphere damaged (RHD) stroke patients with aprosody and left hemisphere damaged (LHD) stroke patients with aphasia. Nine aprosodic RHD patients and 14 aphasic LHD patients participated in a videotaped interview within a larger treatment protocol. Two naïve raters viewed segments of videotape and rated facial expressivity. Verbal affect production was tabulated using specialized software. Results indicated that RHD patients smiled and laughed significantly less than LHD patients. In contrast, RHD patients produced a greater percentage of emotion words relative to total words than did LHD patients. These findings suggest that impairments in emotional prosodic production and facial expressivity associated with RHD are not induced by affective–conceptual deficits or an inability to experience emotions. Rather, they likely represent channel-specific nonverbal encoding abnormalities. (JINS, 2005, 11, 677–685.)

Behavioral neurologists and neuropsychologists have debated the role of the thalamus and basal ganglia in cognition and behavior for more than a century (e.g., Bucy, 1942; Marie, 1906; Penfield & Roberts, 1959; Wernicke, 1874). However, over these 100-plus years, there is little consensus regarding whether or how these structures contribute to cognition. Fortunately, recent research findings are rapidly changing this state of affairs. It is now obvious we will not understand how the brain controls complex activities until we understand the contribution of these deep brain structures. In healthy and brain-damaged individuals, application of methodologies such as semantic priming, event related potentials, and functional neuroimaging to the question of subcortical functions is beginning to resolve this conundrum. This symposium demonstrates the utility of combining these different approaches. It features empirical work from six laboratories that have engaged in systematic inquiries regarding the role of the thalamus and basal ganglia in cognition. This body of work represents both new directions and convergence of recent findings in the quest to integrate our understanding of this complex issue.

fMRI was used to determine the frontal, basal ganglia, and thalamic structures engaged by three facets of language generation: lexical status of generated items, the use of semantic vs. phonological information during language generation, and rate of generation. During fMRI, 21 neurologically normal subjects performed four tasks: generation of nonsense syllables given beginning and ending consonant blends, generation of words given a rhyming word, generation of words given a semantic category at a fast rate (matched to the rate of nonsense syllable generation), and generation of words given a semantic category at a slow rate (matched to the rate of generating of rhyming words). Components of a left pre-SMA–dorsal caudate nucleus–ventral anterior thalamic loop were active during word generation from rhyming or category cues but not during nonsense syllable generation. Findings indicate that this loop is involved in retrieving words from pre-existing lexical stores. Relatively diffuse activity in the right basal ganglia (caudate nucleus and putamen) also was found during word-generation tasks but not during nonsense syllable generation. Given the relative absence of right frontal activity during the word generation tasks, we suggest that the right basal ganglia activity serves to suppress right frontal activity, preventing right frontal structures from interfering with language production. Current findings establish roles for the left and the right basal ganglia in word generation. Hypotheses are discussed for future research to help refine our understanding of basal ganglia functions in language generation. (JINS, 2003, 9, 1061–1077.)

Previous studies showed that cortex in the anterior portions of the left frontal and temporal lobes participates in generating words with emotional connotations and processing pictures with emotional content. If these cortices process the semantic attribute of emotional connotation, they should be active whenever processing emotional connotation, without respect to modality of input or mode of output. Thus, we hypothesized that they would activate during monitoring of words with emotional connotations. Sixteen normal subjects performed semantic monitoring of words with emotional connotations, animal names, and implement names during fMRI. Cortex in the anterior left frontal lobe demonstrated significant activity for monitoring words with emotional connotations compared to monitoring tone sequences, animal names, or implement names. Together, the current and previous results implicate cortex in the anterior left frontal lobe in semantic processing of emotional connotation, consistent with connections of this cortex to paralimbic association areas. Current findings also indicate that neural substrates for processing emotional connotation are independent of substrates for processing the categories of living and nonliving things.

Patients with probable Alzheimer's disease (AD) often have difficulties associated with semantic knowledge. Therefore, conceptual apraxia, a defect of action semantics and mechanical knowledge, may be an early sign of this disease. The Florida Action Recall Test (FLART), developed to assess conceptual apraxia, consists of 45 line drawings of objects or scenes. The subject must imagine the proper tool to apply to each pictured object or scene and then pantomime its use. Twelve participants with Alzheimer's disease (NINCDS–ADRDA criteria) and 21 age- and education-matched controls were tested. Nine Alzheimer's disease participants scored below a 2-standarddeviation cutoff on conceptual accuracy, and the three who scored above the cutoff were beyond a 2-standard-deviation cutoff on completion time. The FLART appears to be a sensitive measure of conceptual apraxia in the early stages of Alzheimer's disease. (JINS, 2000, 6, 265–270.)

Phonological alexia and agraphia are acquired disorders characterized by an impaired ability to convert graphemes to phonemes (alexia) or phonemes to graphemes (agraphia). These disorders result in phonological errors typified by adding, omitting, shifting, or repeating phonemes in words during reading or graphemes when spelling. In developmental dyslexia, similar phonological errors are believed to result from deficient phonological awareness, an oral language skill that manifests itself in the ability to notice, think about, or manipulate the individual sounds in words. The Auditory Discrimination in Depth (ADD) program has been reported to train phonological awareness in developmental dyslexia and dysgraphia. We used a multiple-probe design to evaluate the ADD program's effectiveness with a patient with a mild phonological alexia and mixed agraphia following a left hemisphere infarction. Large gains in phonological awareness, reading and spelling nonwords, and reading and spelling real words were demonstrated. A follow-up reassessment, 2 months posttreatment, found the patient had maintained treatment gains in phonological awareness and reading, and attained additional improvement in real word reading. (JINS, 1998, 4, 608–620.)