Dorsolateral Frontal Cortex Research Articles

Divergent topological architecture of the default mode network as a pretreatment predictor of early antidepressant response in major depressive disorder.

Identifying a robust pretreatment neuroimaging marker would be helpful for the selection of an optimal therapy for major depressive disorder (MDD). We recruited 82 MDD patients [n = 42 treatment-responsive depression (RD) and n = 40 non-responding depression (NRD)] and 50 healthy controls (HC) for this study. Based on the thresholded partial correlation matrices of 58 specific brain regions, a graph theory approach was applied to analyse the topological properties. When compared to HC, both RD and NRD patients exhibited a lower nodal degree (Dnodal) in the left anterior cingulate gyrus; as for RD, the Dnodal of the left superior medial orbitofrontal gyrus was significantly reduced, but the right inferior orbitofrontal gyrus was increased (all P < 0.017, FDR corrected). Moreover, the nodal degree in the right dorsolateral superior frontal cortex (SFGdor) was significantly lower in RD than in NRD. Receiver operating characteristic curve analysis demonstrated that the λ and nodal degree in the right SFGdor exhibited a good ability to distinguish nonresponding patients from responsive patients, which could serve as a specific maker to predict an early response to antidepressants. The disrupted topological configurations in the present study extend the understanding of pretreatment neuroimaging predictors for antidepressant medication.

Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy.

The chronic effects of repetitive head impacts (RHI) on the development of neuroinflammation and its relationship to chronic traumatic encephalopathy (CTE) are unknown. Here we set out to determine the relationship between RHI exposure, neuroinflammation, and the development of hyperphosphorylated tau (ptau) pathology and dementia risk in CTE. We studied a cohort of 66 deceased American football athletes from the Boston University-Veteran’s Affairs-Concussion Legacy Foundation Brain Bank as well as 16 non-athlete controls. Subjects with a neurodegenerative disease other than CTE were excluded. Counts of total and activated microglia, astrocytes, and ptau pathology were performed in the dorsolateral frontal cortex (DLF). Binary logistic and simultaneous equation regression models were used to test associations between RHI exposure, microglia, ptau pathology, and dementia. Duration of RHI exposure and the development and severity of CTE were associated with reactive microglial morphology and increased numbers of CD68 immunoreactive microglia in the DLF. A simultaneous equation regression model demonstrated that RHI exposure had a significant direct effect on CD68 cell density (p < 0.0001) and ptau pathology (p < 0.0001) independent of age at death. The effect of RHI on ptau pathology was partially mediated through increased CD68 positive cell density. A binary logistic regression demonstrated that a diagnosis of dementia was significantly predicted by CD68 cell density (OR = 1.010, p = 0.011) independent of age (OR = 1.055, p = 0.007), but this effect disappeared when ptau pathology was included in the model. In conclusion, RHI is associated with chronic activation of microglia, which may partially mediate the effect of RHI on the development of ptau pathology and dementia in CTE. Inflammatory molecules may be important diagnostic or predictive biomarkers as well as promising therapeutic targets in CTE.

Differences in Regional Brain Responses to Food Ingestion After Roux-en-Y Gastric Bypass and the Role of Gut Peptides: A Neuroimaging Study.

Improved appetite control, possibly mediated by exaggerated gut peptide responses to eating, may contribute to weight loss after Roux-en-Y gastric bypass (RYGB). This study compared brain responses to food ingestion between post-RYGB (RYGB), normal weight (NW), and obese (Ob) unoperated subjects and explored the role of gut peptide responses in RYGB. Neuroimaging with [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography was performed in 12 NW, 21 Ob, and 9 RYGB (18 ± 13 months postsurgery) subjects after an overnight fast, once FED (400 kcal mixed meal), and once FASTED, in random order. RYGB subjects repeated the studies with somatostatin infusion and basal insulin replacement. Fullness, sickness, and postscan ad libitum meal consumption were measured. Regional brain FDG uptake was compared using statistical parametric mapping. RYGB subjects had higher overall fullness and food-induced sickness and lower ad libitum consumption. Brain responses to eating differed in the hypothalamus and pituitary (exaggerated activation in RYGB), left medial orbital cortex (OC) (activation in RYGB, deactivation in NW), right dorsolateral frontal cortex (deactivation in RYGB and NW, absent in Ob), and regions mapping to the default mode network (exaggerated deactivation in RYGB). Somatostatin in RYGB reduced postprandial gut peptide responses, sickness, and medial OC activation. RYGB induces weight loss by augmenting normal brain responses to eating in energy balance regions, restoring lost inhibitory control, and altering hedonic responses. Altered postprandial gut peptide responses primarily mediate changes in food-induced sickness and OC responses, likely to associate with food avoidance.

Neural correlates of absolute pitch: A review

Absolute pitch (AP) is the ability to identify and/or produce specific music notes without a reference tone from the Western tonal system. Functional imaging studies show that AP is subserved by a network of interconnected neural structures including the left posterior dorsolateral frontal cortex (DLFC), the bilateral planum temporale (PT), and other brain regions. Neurophysiological studies show that AP possessors do not always require context updating during pitch identification due to possible “tonal templates”, and that AP appears to emerge at a late processing stage that is associated with multiple cognitive strategies and is facilitated by music training at early ages. Morphometry studies show decreased cortical thickness and gray matter concentration among those with AP, which may reflect increased efficiency of AP skill. Graph theoretical analyses of cortical thickness covariations show involvement of higher-order auditory processing, working memory, and semantic memory processes. Diffusion tensor imaging studies provide evidence for a neural pathway between the left posterior DLFC and the left PT, which establishes retrieval and manipulation of verbal-tonal associations. Compared to AP musicians, quasi-AP (QAP) musicians have an extensive right hemisphere network implicated in auditory working memory and show the bilateral structural characteristics of PT morphometry. Future research should confirm the definition of PT boundary and the role of (bi)lateralization of PT in AP ability, develop a standard AP test, identify genetic bases of AP, and describe relations between AP, tonal languages, and associated neural functions and structures among non-musicians with AP ability.

Neuropsychiatric subsyndromes and brain metabolic network dysfunctions in early onset Alzheimer's disease.

Neuropsychiatric symptoms (NPSs) often occur in early-age-of-onset Alzheimer's disease (EOAD) and cluster into sub-syndromes (SSy). The aim of this study was to investigate the association between 18 F-FDG-PET regional and connectivity-based brain metabolic dysfunctions and neuropsychiatric SSy. NPSs were assessed in 27 EOAD using the Neuropsychiatric Inventory and further clustered into four SSy (apathetic, hyperactivity, affective, and psychotic SSy). Eighty-five percent of EOAD showed at least one NPS. Voxel-wise correlations between SSy scores and brain glucose metabolism (assessed with 18 F-FDG positron emission tomography) were studied. Interregional correlation analysis was used to explore metabolic connectivity in the salience (aSN) and default mode networks (DMN) in a larger sample of EOAD (N = 51) and Healthy Controls (N = 57). The apathetic, hyperactivity, and affective SSy were highly prevalent (>60%) as compared to the psychotic SSy (33%). The hyperactivity SSy scores were associated with increase of glucose metabolism in frontal and limbic structures, implicated in behavioral control. A comparable positive correlation with part of the same network was found for the affective SSy scores. On the other hand, the apathetic SSy scores were negatively correlated with metabolism in the bilateral orbitofrontal and dorsolateral frontal cortex known to be involved in motivation and decision-making processes. Consistent with these SSy regional correlations with brain metabolic dysfunction, the connectivity analysis showed increases in the aSN and decreases in the DMN. Behavioral abnormalities in EOAD are associated with specific dysfunctional changes in brain metabolic activity, in particular in the aSN that seems to play a crucial role in NPSs in EOAD. Hum Brain Mapp 37:4234-4247, 2016. © 2016 Wiley Periodicals, Inc.

The right temporoparietal junction encodes efforts of others during action observation

Smooth social interactions require a deep understanding of others’ intentions and feelings. In the present study, to investigate brain regions that respond to inference of others’ effort level, we recorded brain activity during action observation of different effort levels using functional magnetic resonance imaging (fMRI). We used a dumbbell curl movement to depict a movement requiring effort. To dissociate the factors of effort level of the actor and weight of the dumbbell, we used four combinations of dumbbell weight and actor physique: a thin actor or a built actor lifting a heavy or light dumbbell. During observation of dumbbell curls, the bilateral front-parietal action observation network (AON) was activated. This included the premotor cortices, parietal cortices, visual areas 5/superior temporal cortices (STS), amygdalae, hippocampi, right dorsolateral and ventrolateral frontal cortices. When we evaluated brain regions associated with the actor’s effort level, activity in the right temporoparietal junction (TPJ) and STS was observed. However, activity in the front-parietal AON was independent of the actor’s effort during action observation. This finding suggests that the right TPJ and STS play an important role in the inference of others’ effort levels during the observation of others’ movements.

Neural correlates of conversion disorder: overview and meta-analysis of neuroimaging studies on motor conversion disorder.

BackgroundConversion Disorders (CD) are prevalent functional disorders. Although the pathogenesis is still not completely understood, an interaction of genetic, neurobiological, and psychosocial factors is quite likely. The aim of this study is to provide a systematic overview on imaging studies on CDs and investigate neuronal areas involved in Motor Conversion Disorders (MCD).MethodsA systematic literature search was conducted on CD. Subsequently a meta-analysis of functional neuroimaging studies on MCD was implemented using an Activation Likelihood Estimation (ALE). We calculated differences between patients and healthy controls as well as between affected versus unaffected sides in addition to an overall analysis in order to identify neuronal areas related to MCD.ResultsPatients with MCD differ from healthy controls in the amygdala, superior temporal lobe, retrosplenial area, primary motor cortex, insula, red nucleus, thalamus, anterior as well as dorsolateral prefrontal and frontal cortex. When comparing affected versus unaffected sides, temporal cortex, dorsal anterior cingulate cortex, supramarginal gyrus, dorsal temporal lobe, anterior insula, primary somatosensory cortex, superior frontal gyrus and anterior prefrontal as well as frontal cortex show significant differences.ConclusionsNeuronal areas seem to be involved in the pathogenesis, maintenance or as a result of MCD. Areas that are important for motor-planning, motor-selection or autonomic response seem to be especially relevant. Our results support the emotional unawareness theory but also underline the need of more support by conduction imaging studies on both CD and MCD.

Functional reorganization of language networks for semantics and syntax in chronic stroke: Evidence from MEG.

Using magnetoencephalography, we investigated the potential of perilesional and contralesional activity to support language recovery in patients with poststroke aphasia. In healthy young controls, left-lateralized ventral frontotemporal regions responded to semantic anomalies during sentence comprehension and bilateral dorsal frontoparietal regions responded to syntactic anomalies. Older adults showed more extensive bilateral responses to the syntactic anomalies and less lateralized responses to the semantic anomalies, with decreased activation in the left occipital and parietal regions for both semantic and syntactic anomalies. In aphasic participants, we observed compensatory recruitment in the right hemisphere (RH), which varied depending on the type of linguistic information that was processed. For semantic anomalies, aphasic patients activated some preserved left hemisphere regions adjacent to the lesion, as well as homologous parietal and temporal RH areas. Patients also recruited right inferior and dorsolateral frontal cortex that was not activated in the healthy participants. Responses for syntactic anomalies did not reach significance in patients. Correlation analyses indicated that recruitment of homologous temporoparietal RH areas is associated with better semantic performance, whereas higher accuracy on the syntactic task was related to bilateral superior temporoparietal and right frontal activity. The results suggest that better recovery of semantic processing is associated with a shift to ventral brain regions in the RH. In contrast, preservation of syntactic processing is mediated by dorsal areas, bilaterally, although recovery of syntactic processing tends to be poorer than semantic. Hum Brain Mapp 37:2869-2893, 2016. © 2016 Wiley Periodicals, Inc.

Dorso-Lateral Frontal Cortex of the Ferret Encodes Perceptual Difficulty during Visual Discrimination.

Visual discrimination requires sensory processing followed by a perceptual decision. Despite a growing understanding of visual areas in this behavior, it is unclear what role top-down signals from prefrontal cortex play, in particular as a function of perceptual difficulty. To address this gap, we investigated how neurons in dorso-lateral frontal cortex (dl-FC) of freely-moving ferrets encode task variables in a two-alternative forced choice visual discrimination task with high- and low-contrast visual input. About two-thirds of all recorded neurons in dl-FC were modulated by at least one of the two task variables, task difficulty and target location. More neurons in dl-FC preferred the hard trials; no such preference bias was found for target location. In individual neurons, this preference for specific task types was limited to brief epochs. Finally, optogenetic stimulation confirmed the functional role of the activity in dl-FC before target touch; suppression of activity in pyramidal neurons with the ArchT silencing opsin resulted in a decrease in reaction time to touch the target but not to retrieve reward. In conclusion, dl-FC activity is differentially recruited for high perceptual difficulty in the freely-moving ferret and the resulting signal may provide top-down behavioral inhibition.

Dorso-Lateral Frontal Cortex of the Ferret Encodes Perceptual Difficulty during VisualDiscrimination

Dorso-Lateral Frontal Cortex of the Ferret Encodes Perceptual Difficulty during VisualDiscrimination

Network-Dependent Modulation of COMT and DRD2 Polymorphisms in Healthy Young Adults.

Nonlinear modulation of the dopamine signaling on brain functions can be estimated by the interaction effects of dopamine-related genetic variations. We aimed to explore the interaction effects of COMT rs4680 and DRD2 rs1076560 on intra-network connectivity using independent component analysis. In 250 young healthy adults, we identified 11 meaningful resting-state networks (RSNs), including the salience, visual, auditory, default-mode, sensorimotor, attention and frontoparietal networks. A two-way analysis of covariance was used to investigate COMT×DRD2 interactions on intra-network connectivity in each network, controlling for age, gender and education. Significant COMT×DRD2 interaction was found in intra-network connectivity in the left medial prefrontal cortex of the anterior default-mode network, in the right dorsolateral frontal cortex of the right dorsal attention network, and in the left dorsal anterior cingulate cortex of the salience network. Post hoc tests revealed that these interactions were driven by the differential effects of DRD2 genotypes on intra-network connectivity in different COMT genotypic subgroups. Moreover, even in the same COMT subgroup, the modulation effects of DRD2 on intra-network connectivity were different across RSNs. These findings suggest a network-dependent modulation of the DA-related genetic variations on intra-network connectivity.

Enhancing switching abilities: Improving practice effect by stimulating the dorsolateral pre frontal cortex

Task switching is our ability to abandon an old, irrelevant task in order to perform a new, more relevant one. Data from neuropsychology and neuroimaging studies indicate hemispheric asymmetries in task switching, however the neural mechanisms subtending switching, and in particular protocols to improve switching abilities are yet to be established. The present study aimed to assess hemispheric asymmetry and practice effects in task switching by using transcranial direct current stimulation (tDCS). To this end, tDCS has been applied to the dorsolateral prefrontal cortex (DLPFC) of both hemispheres while subjects were performing a well-established task-switching paradigm. The task was repeated three times in three separate sessions in order to test practice effects with and without stimulation. Results show that increased hemispheric asymmetry in dorsolateral prefrontal areas improved switching performance as measured by a better practice effect, compared to sham condition. Our results support the hypothesis of dynamic hemispheric asymmetry in task switching and reinforce the notion of utilizing brain stimulation with traditional training methods in order to enhance cognitive abilities.

Preliminary findings demonstrating latent effects of early adolescent marijuana use onset on cortical architecture

BackgroundAs the most commonly used illicit substance during early adolescence, long-term or latent effects of early adolescent marijuana use across adolescent developmental processes remain to be determined. MethodsWe examined cortical thickness, gray/white matter border contrast (GWR) and local gyrification index (LGI) in 42 marijuana (MJ) users. Voxelwise regressions assessed early-onset (age <16) vs. late-onset (≥16 years-old) differences and relationships to continued use while controlling for current age and alcohol use. ResultsAlthough groups did not differ by onset status, groups diverged in their correlations between cannabis use and cortical architecture. Among early-onset users, continued years of MJ use and current MJ consumption were associated with thicker cortex, increased GWR and decreased LGI. Late-onset users exhibited the opposite pattern. This divergence was observed in all three morphological measures in the anterior dorsolateral frontal cortex (p<.05, FWE-corrected). ConclusionsDivergent patterns between current MJ use and elements of cortical architecture were associated with early MJ use onset. Considering brain development in early adolescence, findings are consistent with disruptions in pruning. However, divergence with continued use for many years thereafter suggests altered trajectories of brain maturation during late adolescence and beyond.

Multi-modal representation of effector modality in frontal cortex during rule switching.

We report a functional magnetic resonance imaging (fMRI) study which investigated whether brain areas involved in updating task rules within the frontal lobe of the cerebral cortex show activity related to the modality of motor response used in the task. Participants performed a rule switching task using different effector modalities. In some blocks participants responded with left/right button presses, whilst in other blocks left/right saccades were required. The color of a Cue event instructed a left or right response based upon a rule, followed by a Feedback which indicated whether the rule was to stay the same or “Flip” on the next trial. The findings revealed variation in the locus of activity within the ventrolateral frontal cortex dependent upon effector modality. Other frontal areas showed no significant difference in activity between response epochs but changed their pattern of connectivity with posterior cortical areas dependent upon response. Multivariate analysis revealed that the pattern of activity evoked by Flip rule Feedbacks within an apparently supra modal frontal region (dorsolateral frontal cortex) discriminated between response epochs. The results are consistent with the existence of multi-modal representations of stimulus-response (SR) rules within the frontal cerebral cortex.

Anterior and posterior subareas of the dorsolateral frontal cortex in socially relevant decisions based on masked affect expressions

Socially-relevant decisions are based on clearly recognizable but also not consciously accessible affective stimuli. We studied the role of the dorsolateral frontal cortex (DLFC) in decision-making on masked affect expressions using functional magnetic resonance imaging. Our paradigm permitted us to capture brain activity during a pre-decision phase when the subjects viewed emotional expressions below the threshold of subjective awareness, and during the decision phase, which was based on verbal descriptions as the choice criterion. Using meta-analytic connectivity modeling, we found that the preparatory phase of the decision was associated with activity in a right-posterior portion of the DLFC featuring co-activations in the left-inferior frontal cortex. During the subsequent decision a right-anterior and more dorsal portion of the DLFC became activated, exhibiting a different co-activation pattern. These results provide evidence for partially independent sub-regions within the DLFC, supporting the notion of dual associative processes in intuitive judgments.

An EEG-fMRI Study on the Termination of Generalized Spike-And-Wave Discharges in Absence Epilepsy.

IntroductionDifferent studies have investigated by means of EEG-fMRI coregistration the brain networks related to generalized spike-and-wave discharges (GSWD) in patients with idiopathic generalized epilepsy (IGE). These studies revealed a widespread GSWD-related neural network that involves the thalamus and regions of the default mode network. In this study we investigated which brain regions are critically involved in the termination of absence seizures (AS) in a group of IGE patients.MethodsEighteen patients (6 male; mean age 25 years) with AS were included in the EEG-fMRI study. Functional data were acquired at 3T with continuous simultaneous video-EEG recording. Event-related analysis was performed with SPM8 software, using the following regressors: (1) GSWD onset and duration; (2) GSWD offset. Data were analyzed at single-subject and at group level with a second level random effect analysis.ResultsA mean of 17 events for patient was recorded (mean duration of 4.2 sec). Group-level analysis related to GSWD onset respect to rest confirmed previous findings revealing thalamic activation and a precuneus/posterior cingulate deactivation. At GSWD termination we observed a decrease in BOLD signal over the bilateral dorsolateral frontal cortex respect to the baseline (and respect to GSWD onset). The contrast GSWD offset versus onset showed a BOLD signal increase over the precuneus-posterior cingulate region bilaterally. Parametric correlations between electro-clinical variables and BOLD signal at GSWD offset did not reveal significant effects.ConclusionThe role of the decreased neural activity of lateral prefrontal cortex at GSWD termination deserve future investigations to ascertain if it has a role in promoting the discharge offset, as well as in the determination of the cognitive deficits often present in patients with AS. The increased BOLD signal at precuneal/posterior cingulate cortex might reflect the recovery of neural activity in regions that are “suspended” during spike and waves activity, as previously hypothesized.

Conflict awareness dissociates theta-band neural dynamics of the medial frontal and lateral frontal cortex during trial-by-trial cognitive control

Recent findings have refuted the common assumption that executive control functions of the prefrontal cortex exclusively operate consciously, suggesting that many, if not all, cognitive processes could potentially operate unconsciously. However, although many cognitive functions can be launched unconsciously, several theoretical models of consciousness assume that there are crucial qualitative differences between conscious and unconscious processes. We hypothesized that the potential benefit of awareness in cognitive control mechanisms might become apparent when high control has to be maintained across time and requires the interaction between a set of distant frontal brain regions. To test this, we extracted oscillatory power dynamics from electroencephalographic data recorded while participants performed a task in which conflict awareness was manipulated by masking the conflict-inducing stimulus. We observed that instantaneous conflict as well as across trial conflict adaptation mechanisms were associated with medial frontal theta-band power modulations, irrespective of conflict awareness. However, and crucially, across-trial conflict adaptation processes reflected in increased theta-band power over dorsolateral frontal cortex were observed after fully conscious conflict only. This suggests that initial conflict detection and subsequent control adaptation by the medial frontal cortex are automatic and unconscious, whereas the routing of information from the medial frontal cortex to the lateral prefrontal cortex is a unique feature of conscious cognitive control.

Anterior and posterior subareas of the dorsolateral frontal cortex in socially relevant decisions based on masked affect expressions.

Socially-relevant decisions are based on clearly recognizable but also not consciously accessible affective stimuli. We studied the role of the dorsolateral frontal cortex (DLFC) in decision-making on masked affect expressions using functional magnetic resonance imaging. Our paradigm permitted us to capture brain activity during a pre-decision phase when the subjects viewed emotional expressions below the threshold of subjective awareness, and during the decision phase, which was based on verbal descriptions as the choice criterion. Using meta-analytic connectivity modeling, we found that the preparatory phase of the decision was associated with activity in a right-posterior portion of the DLFC featuring co-activations in the left-inferior frontal cortex. During the subsequent decision a right-anterior and more dorsal portion of the DLFC became activated, exhibiting a different co-activation pattern. These results provide evidence for partially independent sub-regions within the DLFC, supporting the notion of dual associative processes in intuitive judgments.

MRI signatures of the frontotemporal lobar degeneration continuum.

To identify overlapping and unique grey (GM) and white matter (WM) signatures within the frontotemporal lobar degeneration (FTLD) continuum, and discriminate likely FTLD-TAU and FTLD-TDP patients using structural and diffusion tensor (DT) magnetic resonance imaging (MRI). T1-weighted and DT MRI were collected from 121 subjects: 35 motor neuron disease (MND), 14 behavioral variant of frontotemporal dementia, 12 semantic and 11 nonfluent primary progressive aphasia, 21 progressive supranuclear palsy syndrome patients, and 28 healthy controls. Patterns of GM atrophy were established using voxel-based morphometry. Tract-based spatial statistics was used to perform a WM voxelwise analysis of mean diffusivity and fractional anisotropy. In all clinical FTLD phenotypes, the pattern of WM damage was more distributed than that of GM atrophy. All patient groups, with the exception of MND cases with a pure motor syndrome, shared a focal GM atrophy centered around the dorsolateral and medial frontal cortex and a largely overlapping pattern of WM damage involving the genu and body of the corpus callosum and ventral frontotemporal and dorsal frontoparietal WM pathways. Surrounding this common area, phenotype (symptom)-specific GM and WM regions of damage were found in each group. In the FTLD spectrum, WM disruption is more severe than GM damage. Frontal cortex and WM pathways represent the common target of neurodegeneration in these conditions. The topographic pattern of damage supports a "prion-like" protein propagation through WM connections as underlying mechanism of the stereotyped progression of FTLD.

Brain structure and function related to depression in Alzheimer's disease: contributions from neuroimaging research.

The development of minimally invasive in vivo methods for imaging the brain has allowed for unprecedented advancement in our understanding of brain-behavior relationships. Structural, functional, and multimodal neuroimaging techniques have become more sophisticated in detecting structural and physiological abnormalities that may underlie various affective disorders and neurological illnesses such as depression in Alzheimer's disease (AD). In general, neuroimaging studies of depression in AD investigate whether depression is associated with damage to structures in specific neural networks involving frontal and subcortical structures or with functional disruption of cortical neural systems. This review provides an overview of how various imaging modalities have contributed to our understanding of the neurobiology of depression in AD. At present, the literature does not conclusively support any specific pathogenesis for depression, and it is not clear whether patients with AD and depression have histopathological and neurochemical characteristics that contribute to mood symptoms that are different from cognitively intact individuals with depression. Neuroimaging studies suggest that atrophy of temporal or frontal structures, white matter lesions in frontal lobe or subcortical systems, reduced activity in dorsolateral frontal cortex, or small vessel cerebrovascular disease may be associated with depression in AD. Conceptual, clinical, and methodological challenges in studying this relationship are discussed. Further work is needed to understand the specific brain structures, relevant white matter tracts, and interactions among them that are most important. This review concludes with potential directions for future research.