Study design and methods: U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER).

INTRODUCTION: The U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER) is conducted to confirm and expand the results of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) in Americans. METHODS: U.S. POINTER was planned as a 2-year randomized controlled trial of two lifestyle interventions in 2000 older adults at risk for dementia due to well-established factors. The primary outcome is a global cognition composite that permits harmonization with FINGER. RESULTS: U.S. POINTER is centrally coordinated and conducted at five clinical sites (ClinicalTrials.gov: NCT03688126). Outcomes assessments are completed at baseline and every 6 months. Both interventions focus on exercise, diet, cognitive/social stimulation, and cardiovascular health, but differ in intensity and accountability. The study partners with a worldwide network of similar trials for harmonization of methods and data sharing. DISCUSSION: U.S. POINTER is testing a potentially sustainable intervention to support brain health and Alzheimer's prevention for Americans. Impact is strengthened by the targeted participant diversity and expanded scientific scope through ancillary studies.

Optimizing quantification of MK6240 tau PET in unimpaired older adults.

Accurate measurement of Alzheimer's disease (AD) pathology in older adults without significant clinical impairment is critical to assessing intervention strategies aimed at slowing AD-related cognitive decline. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (POINTER) is a 2-year randomized controlled trial to evaluate the effect of multicomponent risk reduction strategies in older adults (60-79 years) who are cognitively unimpaired but at increased risk for cognitive decline/dementia due to factors such as cardiovascular disease and family history. The POINTER Imaging ancillary study is collecting tau-PET ([18F]MK6240), beta-amyloid (Aß)-PET ([18F]florbetaben [FBB]) and MRI data to evaluate neuroimaging biomarkers of AD and cerebrovascular pathophysiology in this at-risk sample. Here 481 participants (70.0±5.0; 66% F) with baseline MK6240, FBB and structural MRI scans were included. PET scans were coregistered to the structural MRI which was used to create FreeSurfer-defined reference regions and target regions of interest (ROIs). We also created off-target signal (OTS) ROIs to examine the magnitude and distribution of MK6240 OTS across the brain as well as relationships between OTS and age, sex, and race. OTS was unimodally distributed, highly correlated across OTS ROIs and related to younger age and sex but not race. Aiming to identify an optimal processing approach for MK6240 that would reduce the influence of OTS, we compared our previously validated MRI-guided standard PET processing and 6 alternative approaches. The alternate approaches included combinations of reference region erosion and meningeal OTS masking before spatial smoothing as well as partial volume correction. To compare processing approaches we examined relationships between target ROIs (entorhinal cortex (ERC), hippocampus or a temporal meta-ROI (MetaROI)) SUVR and age, sex, race, Aß and a general cognitive status measure, the Modified Telephone Interview for Cognitive Status (TICSm). Overall, the processing approaches performed similarly, and none showed a meaningful improvement over standard processing. Across processing approaches we observed previously reported relationships with MK6240 target ROIs including positive associations with age, an Aß+> Aß- effect and negative associations with cognition. In sum, we demonstrated that different methods for minimizing effects of OTS, which is highly correlated across the brain within subject, produced no substantive change in our performance metrics. This is likely because OTS contaminates both reference and target regions and this contamination largely cancels out in SUVR data. Caution should be used when efforts to reduce OTS focus on target or reference regions in isolation as this may exacerbate OTS contamination in SUVR data.

Basolateral amygdala response to food cues in the absence of hunger is associated with weight gain susceptibility.

In rodents, food-predictive cues elicit eating in the absence of hunger (Weingarten, 1983). This behavior is disrupted by the disconnection of amygdala pathways to the lateral hypothalamus (Petrovich et al., 2002). Whether this circuit contributes to long-term weight gain is unknown. Using fMRI in 32 healthy individuals, we demonstrate here that the amygdala response to the taste of a milkshake when sated but not hungry positively predicts weight change. This effect is independent of sex, initial BMI, and total circulating ghrelin levels, but it is only present in individuals who do not carry a copy of the A1 allele of the Taq1A polymorphism. In contrast, A1 allele carriers, who have decreased D2 receptor density (Blum et al., 1996), show a positive association between caudate response and weight change. Regardless of genotype, however, dynamic causal modeling supports unidirectional gustatory input from basolateral amygdala (BLA) to hypothalamus in sated subjects. This finding suggests that, as in rodents, external cues gain access to the homeostatic control circuits of the human hypothalamus via the amygdala. In contrast, during hunger, gustatory inputs enter the hypothalamus and drive bidirectional connectivity with the amygdala. These findings implicate the BLA-hypothalamic circuit in long-term weight change related to nonhomeostatic eating and provide compelling evidence that distinct brain mechanisms confer susceptibility to weight gain depending upon individual differences in dopamine signaling.

Reduced prefrontal activation during working and long-term memory tasks and impaired patient-reported cognition among cancer survivors postchemotherapy compared with healthy controls.

BACKGROUND: Patients who receive adjuvant chemotherapy have reported cognitive impairments that may last for years after the completion of treatment. Working memory-related and long-term memory-related changes in this population are not well understood. The objective of this study was to demonstrate that cancer-related cognitive impairments are associated with the under recruitment of brain regions involved in working and recognition memory compared with controls. METHODS: Oncology patients (n = 15) who were receiving adjuvant chemotherapy and had evidence of cognitive impairment according to neuropsychological testing and self-report and a group of age-matched, education group-matched, cognitively normal control participants (n = 14) underwent functional magnetic resonance imaging. During functional magnetic resonance imaging, participants performed a nonverbal n-back working memory task and a visual recognition task. RESULTS: On the working memory task, when 1-back and 2-back data were averaged and contrasted with 0-back data, significantly reduced activation was observed in the right dorsolateral prefrontal cortex for oncology patients versus controls. On the recognition task, oncology patients displayed decreased activity of the left-middle hippocampus compared with controls. Neuroimaging results were not associated with patient-reported cognition. CONCLUSIONS: Decreased recruitment of brain regions associated with the encoding of working memory and recognition memory was observed in the oncology patients compared with the control group. These results suggest that there is a reduction in neural functioning postchemotherapy and corroborate patient-reported cognitive difficulties after cancer treatment, although a direct association was not observed. Cancer 2016;122:258-268. © 2015 American Cancer Society.

Diffusion imaging of nigral alterations in early Parkinson's disease with dopaminergic deficits.

BACKGROUND: This study reports the baseline characteristics of diffusion tensor imaging data in Parkinson's disease (PD) patients and healthy control subjects from the Parkinson's Progression Markers Initiative. The main goals were to replicate previous findings of abnormal diffusion imaging values from the substantia nigra. in a large multicenter cohort and determine whether nigral diffusion alterations are associated with dopamine deficits. METHODS: Two hundred twenty subjects (PD = 153; control = 67) from 10 imaging sites were included. All subjects had a full neurological exam, a ((123) I)ioflupane dopamine transporter (DAT) single-photon emission computer tomography scan, and diffusion tensor imaging. Fractional anisotropy as well as radial and axial diffusivity was computed within multiple regions across the substantia nigra. RESULTS: A repeated-measures analysis of variance found a marginally nonsignificant interaction between regional fractional anisotropy of the substantia nigra and disease status (P = 0.08), conflicting with an earlier study. However, a linear mixed model that included control regions in addition to the nigral regions revealed a significant interaction between regions and disease status (P = 0.002), implying a characteristic distribution of reduced fractional anisotropy across the substantia nigra in PD. Reduced fractional anisotropy in PD was also associated with diminished DAT binding ratios. Both axial and radial diffusivity were also abnormal in PD. CONCLUSIONS: Although routine nigral measurements of fractional anisotropy are clinically not helpful, the findings in this study suggest that more-sophisticated diffusion imaging protocols should be used when exploring the clinical utility of this imaging modality.

When the sense of smell meets emotion: anxiety-state-dependent olfactory processing and neural circuitry adaptation.

Phylogenetically the most ancient sense, olfaction is characterized by a unique intimacy with the emotion system. However, mechanisms underlying olfaction-emotion interaction remain unclear, especially in an ever-changing environment and dynamic internal milieu. Perturbing the internal state with anxiety induction in human subjects, we interrogated emotion-state-dependent olfactory processing in a functional magnetic resonance imaging (fMRI) study. Following anxiety induction, initially neutral odors become unpleasant and take longer to detect, accompanied by augmented response to these odors in the olfactory (anterior piriform and orbitofrontal) cortices and emotion-relevant pregenual anterior cingulate cortex. In parallel, the olfactory sensory relay adapts with increased anxiety, incorporating amygdala as an integral step via strengthened (afferent or efferent) connections between amygdala and all levels of the olfactory cortical hierarchy. This anxiety-state-dependent neural circuitry thus enables cumulative infusion of limbic affective information throughout the olfactory sensory progression, thereby driving affectively charged olfactory perception. These findings could constitute an olfactory etiology model of emotional disorders, as exaggerated emotion-olfaction interaction in negative mood states turns innocuous odors aversive, fueling anxiety and depression with rising ambient sensory stress.

Brain morphometric changes associated with childhood-onset systemic lupus erythematosus and neurocognitive deficit.

OBJECTIVE: To use structural magnetic resonance imaging (MRI) to characterize changes in gray matter and white matter volumes between patients with childhood-onset systemic lupus erythematosus (SLE) and matched controls, between patients with childhood-onset SLE with and those without neurocognitive deficit, and in relation to disease duration and treatment with steroids. METHODS: Twenty-two patients with childhood-onset SLE and 19 healthy controls underwent high-resolution structural MRI. Probability density maps for gray matter and white matter were compared between groups. RESULTS: Neuropsychological testing confirmed the presence of neurocognitive deficit in 8 patients with childhood-onset SLE. Multiple brain regions had reduced gray matter volume in the patients with childhood- onset SLE with neurocognitive deficit versus controls or patients with childhood-onset SLE without neurocognitive deficit. Neither disease duration nor cumulative oral or intravenous steroid doses accounted for decreases in gray matter. White matter volume was also reduced in patients with childhood-onset SLE with neurocognitive deficit, and the reduction was positively associated with both disease duration and cumulative oral steroid dose. Conversely, higher cumulative intravenous steroid doses were associated with higher white matter volumes. CONCLUSION: Neurocognitive deficit in patients with childhood-onset SLE is associated with multifocal decreases in both gray and white matter volumes. Since only white matter volume changes are related to disease duration and cumulative oral steroid use, this may suggest that gray and white matter alterations relate to different underlying mechanisms. Further work is needed to understand the relationship between gray and white matter alterations in childhood-onset SLE, whether the underlying mechanisms relate to immunologic, vascular, or other causes, and whether the changes are reversible or preventable. Likewise, the protective properties of intravenous steroids in maintaining white matter volumes require confirmation in larger cohorts.

The anterior insular cortex represents breaches of taste identity expectation.

Despite the importance of breaches of taste identity expectation for survival, its neural correlate is unknown. We used fMRI in 16 women to examine brain response to expected and unexpected receipt of sweet taste and tasteless/odorless solutions. During expected trials (70%), subjects heard "sweet" or "tasteless" and received the liquid indicated by the cue. During unexpected trials (30%), subjects heard sweet but received tasteless or they heard tasteless but received sweet. After delivery, subjects indicated stimulus identity by pressing a button. Reaction time was faster and more accurate after valid cuing, indicating that the cues altered expectancy as intended. Tasting unexpected versus expected stimuli resulted in greater deactivation in fusiform gyri, possibly reflecting greater suppression of visual object regions when orienting to, and identifying, an unexpected taste. Significantly greater activation to unexpected versus expected stimuli occurred in areas related to taste (thalamus, anterior insula), reward [ventral striatum (VS), orbitofrontal cortex], and attention [anterior cingulate cortex, inferior frontal gyrus, intraparietal sulcus (IPS)]. We also observed an interaction between stimulus and expectation in the anterior insula (primary taste cortex). Here response was greater for unexpected versus expected sweet compared with unexpected versus expected tasteless, indicating that this region is preferentially sensitive to breaches of taste expectation. Connectivity analyses confirmed that expectation enhanced network interactions, with IPS and VS influencing insular responses. We conclude that unexpected oral stimulation results in suppression of visual cortex and upregulation of sensory, attention, and reward regions to support orientation, identification, and learning about salient stimuli.

EEG measures index neural and cognitive recovery from sleep deprivation.

Sleep deprivation impairs many cognitive abilities, but these impairments can be reversed after a certain quantity and quality of sleep. The ability to inhibit responding is particularly susceptible to disruption after prolonged wakefulness. How recovery sleep (RS) alters brain activity, leading to improved performance on a variety of cognitive tasks, remains unclear. This issue was examined in the current study using spectral analysis of electroencephalogram (EEG) data during sleep. These measures of sleep physiology were acquired after both normal sleep (NS) and RS, and were related to measures of inhibitory control and concurrent brain activity. Subjects were nine young adults who underwent functional magnetic resonance imaging twice, after 9 h of NS and after 10 h of RS that followed 38 h of being awake. A multiple regression model was used to examine differences between conditions in (1) EEG spectral power during sleep, (2) probability of successful inhibition in a go/no-go task, and (3) activation within a region of right prefrontal cortex during the task. Performance recovery, as indexed by reduced performance differences between conditions, was predicted by increased delta power and decreased sigma power in RS compared with NS. These EEG variables predicted most of the variance in inhibitory performance difference between conditions. Regressions also suggested that RS improved performance because of changes in brain function including prefrontal regions that resulted from delta rebound. We thus propose that slow waves, reflected in delta power during RS, act to restore brain function, thereby improving cognitive performance that entails response inhibition.

Cognitive Impairment in Aging Physicians: Current Challenges and Possible Solutions.

Aging physicians are at a higher risk of cognitive impairment, undermining patient safety and unraveling physicians' careers. Neurologists, occupational health physicians, and psychiatrists will participate in both health system policy decisions and individual patient evaluations. We address cognitive impairment in aging physicians and attendant risks and benefits. If significant cognitive impairment is found after an appropriate evaluation, precautions to confidentially support physicians' practicing safely for as long as possible should be instituted. Understanding that there is heterogeneity and variability in the course of cognitive disorders is crucial to supporting cognitively impaired, practicing physicians. Physicians who are no longer able to practice clinically have other meaningful options.

Orienting attention based on long-term memory experience.

Attentional orienting and memory are intrinsically bound, but their interaction has rarely been investigated. Here we introduce an experimental paradigm using naturalistic scenes to investigate how long-term memory can guide spatial attention and thereby enhance identification of events in the perceptual domain. In the task, stable memories of objects embedded within complex scenes guide spatial orienting. We compared the behavioral effects and neural systems of memory-guided orienting with those in a more traditional attention-orienting task in which transient spatial cues guide attention. Memory-guided attention operated within surprisingly short intervals and conferred reliable and sizeable advantages for detection of objects embedded in scenes. Event-related functional magnetic resonance imaging showed that memory-guided attention involves the interaction between brain areas participating in retrieval of memories for spatial context with the parietal-frontal network for visual spatial orienting. Activity in the hippocampus was specifically engaged in memory-guided spatial attention and correlated with the ensuing behavioral advantage.

Identification of critical areas for motor function recovery in chronic stroke subjects using voxel-based lesion symptom mapping.

INTRODUCTION: Previous stroke studies using fMRI or lesion characterization methods to study the preservation of motor performance have been limited in defining anatomical structure critical for functional performance. This study attempts to overcome this limitation by using voxel-based lesion symptom mapping (VLSM) to identify specific anatomical regions required for preservation of motor function. METHODS: Forty-one moderate to moderately severe stroke subjects (upper extremity Fugl-Meyer between 28 and 50, Arm Motor Ability Test >35) were imaged with a 1 mm isotropic T1-weighted volumetric sequence, and their motor performance was assessed. The T1 volume images were normalized to a symmetric template using SPM5 and oriented so the lesion appeared in the left hemisphere. The lesioned areas were manually segmented on the normalized T1 image. All 3D lesion maps were entered into the VLSM analysis. Areas showing significant correlations with functional performance measures were identified using the false discovery rate corrected at p< or =0.05. RESULTS: The areas most correlated with a decrease in motor performance were at the junction of the corona radiata leading into the corticospinal tract. The Arm Motor Ability Test scores produced the most significant results, while the other measures showed similar anatomical patterns. CONCLUSION: The use of lesion symptom mapping in conjunction with behavioral measures produced anatomically specific results demonstrating that the area leading from the corticospinal tract to cortical motor areas is critical for maintaining hand motor performance after a stroke. This area may represent the joining of parallel redundant tracts that, when damaged, limit recovery potential.

A recommended scale for cognitive screening in clinical trials of Parkinson's disease.

Cognitive impairment is common in Parkinson's disease (PD). There is a critical need for a brief, standard cognitive screening measure for use in PD trials whose primary focus is not on cognition. The Parkinson Study Group (PSG) Cognitive/Psychiatric Working Group formed a Task Force to make recommendations for a cognitive scale that could screen for dementia and mild cognitive impairment in clinical trials of PD where cognition is not the primary outcome. This Task Force conducted a systematic literature search for cognitive assessments previously used in a PD population. Scales were then evaluated for their appropriateness to screen for cognitive deficits in clinical trials, including brief administration time (<15 minutes), assessment of the major cognitive domains, and potential to detect subtle cognitive impairment in PD. Five scales of global cognition met the predetermined screening criteria and were considered for review. Based on the Task Force's evaluation criteria the Montreal Cognitive Assessment (MoCA), appeared to be the most suitable measure. This Task Force recommends consideration of the MoCA as a minimum cognitive screening measure in clinical trials of PD where cognitive performance is not the primary outcome measure. The MoCA still requires further study of its diagnostic utility in PD populations but appears to be the most appropriate measure among the currently available brief cognitive assessments. Widespread adoption of a single instrument such as the MoCA in clinical trials can improve comparability between research studies on PD.

Attention to odor modulates thalamocortical connectivity in the human brain.

It is widely assumed that the thalamus is functionally irrelevant for the sense of smell. Although animal studies suggest that the mediodorsal (MD) thalamus links primary olfactory (piriform) cortex to olfactory neocortical projection sites in orbitofrontal cortex (OFC), this transthalamic route is regarded to be inconsequential, particularly compared with a direct monosynaptic pathway linking piriform cortex and OFC. In this study, we combined functional magnetic resonance imaging with novel effective connectivity techniques to measure attention-dependent network coherence within direct (nonthalamic) and indirect (transthalamic) olfactory pathways. Human subjects were presented with (or without) an odor and with (or without) a tone, while selectively attending to either modality. Attention to odor significantly modulated neural coupling within the indirect pathway, strengthening MD thalamus-OFC connectivity. Critically, these effects were modality specific (odor > tone attention), directionally sensitive (forward > backward connections), and selective to route (indirect > direct pathway). Our findings support the idea that the human transthalamic pathway is an active modulatory target of olfactory attention. The results imply that olfaction, like all other sensory modalities, requires a thalamic relay, if only to consciously analyze a smell.

Neural correlates of evaluative compared with passive tasting.

We used functional magnetic resonance imaging to test the hypothesis that the nature of the neural response to taste varies as a function of the task the subject is asked to perform. Subjects received sweet, sour, salty and tasteless solutions passively and while evaluating stimulus presence, pleasantness and identity. Within the insula and overlying operculum the location of maximal response to taste vs. tasteless varied as a function of task; however, the primary taste cortex (anterior dorsal insula/frontal operculum--AIFO), as well as a more ventral region of anterior insula, responded to taste vs. tasteless irrespective of task. Although the response here did not depend upon task, preferential connectivity between AIFO and the amygdala (bilaterally) was observed when subjects tasted passively compared with when they performed a task. This suggests that information transfer between AIFO and the amygdala is maximal during implicit processing of taste. In contrast, a region of the left lateral orbitofrontal cortex (OFC) responded preferentially to taste and to tasteless when subjects evaluated pleasantness, and was preferentially connected to earlier gustatory relays (caudomedial OFC and AIFO) when a taste was present. This suggests that processing in the lateral OFC organizes the retrieval of gustatory information from earlier relays in the service of computing perceived pleasantness. These findings show that neural encoding of taste varies as a function of task beyond that of the initial cortical representation.

The spatial attention network interacts with limbic and monoaminergic systems to modulate motivation-induced attention shifts.

How does the human brain integrate information from multiple domains to guide spatial attention according to motivational needs? To address this question, we measured hemodynamic responses to central cues predicting locations of peripheral attentional targets (food or tool images) in a novel covert spatial attention paradigm. The motivational relevance of food-related attentional targets was experimentally manipulated via hunger and satiety. Amygdala, posterior cingulate, locus coeruleus, and substantia nigra showed selective sensitivity to food-related cues when hungry but not when satiated, an effect that did not generalize to tools. Posterior parietal cortex (PPC), including intraparietal sulcus, posterior cingulate, and the orbitofrontal cortex displayed correlations with the speed of attentional shifts that were sensitive not just to motivational state but also to the motivational value of the target. Stronger functional coupling between PPC and posterior cingulate occurred during attentional biasing toward motivationally relevant food targets. These results reveal conjoint limbic and monoaminergic encoding of motivational salience in spatial attention. They emphasize the interactive role of posterior parietal and cingulate cortices in integrating motivational information with spatial attention, a process that is critical for selective allocation of attentional resources in an environment where target position and relevance can change rapidly.

Neural Connectivity in Syntactic Movement Processing.

Linguistic theory suggests non-canonical sentences subvert the dominant agent-verb-theme order in English via displacement of sentence constituents to argument (NP-movement) or non-argument positions (wh-movement). Both processes have been associated with the left inferior frontal gyrus and posterior superior temporal gyrus, but differences in neural activity and connectivity between movement types have not been investigated. In the current study, functional magnetic resonance imaging data were acquired from 21 adult participants during an auditory sentence-picture verification task using passive and active sentences contrasted to isolate NP-movement, and object- and subject-cleft sentences contrasted to isolate wh-movement. Then, functional magnetic resonance imaging data from regions common to both movement types were entered into a dynamic causal modeling analysis to examine effective connectivity for wh-movement and NP-movement. Results showed greater left inferior frontal gyrus activation for Wh > NP-movement, but no activation for NP > Wh-movement. Both types of movement elicited activity in the opercular part of the left inferior frontal gyrus, left posterior superior temporal gyrus, and left medial superior frontal gyrus. The dynamic causal modeling analyses indicated that neither movement type significantly modulated the connection from the left inferior frontal gyrus to the left posterior superior temporal gyrus, nor vice-versa, suggesting no connectivity differences between wh- and NP-movement. These findings support the idea that increased complexity of wh-structures, compared to sentences with NP-movement, requires greater engagement of cognitive resources via increased neural activity in the left inferior frontal gyrus, but both movement types engage similar neural networks.

Dissociation of neural representation of intensity and affective valuation in human gustation.

We used a 2 x 2 factorial design to dissociate regions responding to taste intensity and taste affective valence. Two intensities each of a pleasant and unpleasant taste were presented to subjects during event-related fMRI scanning. The cerebellum, pons, middle insula, and amygdala responded to intensity irrespective of valence. In contrast, valence-specific responses were observed in anterior insula/operculum extending into the orbitofrontal cortex (OFC). The right caudolateral OFC responded preferentially to pleasant compared to unpleasant taste, irrespective of intensity, and the left dorsal anterior insula/operculuar region responded preferentially to unpleasant compared to pleasant tastes equated for intensity. Responses best characterized as an interaction between intensity and pleasantness were also observed in several limbic regions. These findings demonstrate a functional segregation within the human gustatory system. They also show that amygdala activity may be driven by stimulus intensity irrespective of valence, casting doubt upon the notion that the amygdala responds preferentially to negative stimuli.

Altered effective connectivity within the language network in primary progressive aphasia.

Primary progressive aphasia (PPA) is a neurodegenerative dementia syndrome principally characterized by the gradual dissolution of language functions, especially in the early stages of disorder. In a previous functional neuroimaging study, PPA patients were found to activate core language areas similarly to control subjects when performing semantic and phonological processing tasks (Sonty et al., 2003). In the present study, functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM) were used to study multiregional effective connectivity in early-stage PPA (n = 8) and control (n = 8) subjects performing semantic word matching and visual letter matching tasks. fMRI analysis showed semantic task-specific activations in the left inferior frontal (Broca's area) and posterior superior temporal (Wernicke's area) regions, in addition to other language regions, in both groups. Using a model language network consisting of six left hemisphere regions, the DCM analysis demonstrated reduced language-specific effective connectivity between Wernicke's and Broca's areas in the PPA patient group. Furthermore, this decrement in connectivity was predictive of semantic task accuracy. These results demonstrate for the first time that dysfunctional network interactions (effective connectivity), rather than hypoactivity within individual brain regions, may contribute to the emergence of language deficits seen in PPA.