Disruptions in global network segregation and integration in adolescents and young adults with fetal alcohol spectrum disorder.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is a significant public health problem that is associated with a broad range of physical, neurocognitive, and behavioral effects resulting from prenatal alcohol exposure (PAE). Magnetic resonance imaging (MRI) has been an important tool for advancing our knowledge of abnormal brain structure and function in individuals with FASD. However, whereas only a small number of studies have applied graph theory-based network analysis to resting-state functional MRI (fMRI) data in individuals with FASD additional research in this area is needed. METHODS: Resting-state fMRI data were collected from adolescent and young adult participants (ages 12-22) with fetal alcohol syndrome (FAS) or alcohol-related neurodevelopmental disorder (ARND) and neurotypically developing controls (CNTRL) from previous studies. Group independent components analysis (gICA) was applied to fMRI data to extract components representing functional brain networks. Functional network connectivity (FNC), measured by Pearson correlation of the average independent component (IC) time series, was analyzed under a graph theory framework to compare network modularity, the average clustering coefficient, characteristic path length, and global efficiency between groups. Cognitive intelligence, measured by the Wechsler Abbreviated Scale of Intelligence (WASI), was compared and correlated to global network measures. RESULTS: Group comparisons revealed significant differences in the average clustering coefficient, characteristic path length, and global efficiency. Modularity was not significantly different between groups. The FAS and ARND groups scored significantly lower than the CNTRL group on Full Scale IQ (FS-IQ) and the Vocabulary subtest, but not the Matrix Reasoning subtest. No significant associations between intelligence and graph theory measures were detected. CONCLUSION: Our results partially agree with previous studies examining global graph theory metrics in children and adolescents with FASD and suggest that the exposure to alcohol during prenatal development leads to disruptions in aspects of functional network segregation and integration.

Framing spatial cognition: neural representations of proximal and distal frames of reference and their roles in navigation.

The most common behavioral test of hippocampus-dependent, spatial learning and memory is the Morris water task, and the most commonly studied behavioral correlate of hippocampal neurons is the spatial specificity of place cells. Despite decades of intensive research, it is not completely understood how animals solve the water task and how place cells generate their spatially specific firing fields. Based on early work, it has become the accepted wisdom in the general neuroscience community that distal spatial cues are the primary sources of information used by animals to solve the water task (and similar spatial tasks) and by place cells to generate their spatial specificity. More recent research, along with earlier studies that were overshadowed by the emphasis on distal cues, put this common view into question by demonstrating primary influences of local cues and local boundaries on spatial behavior and place-cell firing. This paper first reviews the historical underpinnings of the "standard" view from a behavioral perspective, and then reviews newer results demonstrating that an animal's behavior in such spatial tasks is more strongly controlled by a local-apparatus frame of reference than by distal landmarks. The paper then reviews similar findings from the literature on the neurophysiological correlates of place cells and other spatially correlated cells from related brain areas. A model is proposed by which distal cues primarily set the orientation of the animal's internal spatial coordinate system, via the head direction cell system, whereas local cues and apparatus boundaries primarily set the translation and scale of that coordinate system.

Dietary blueberry improves cognition among older adults in a randomized, double-blind, placebo-controlled trial.

PURPOSE: As populations shift to include a larger proportion of older adults, the necessity of research targeting older populations is becoming increasingly apparent. Dietary interventions with blueberry have been associated with positive outcomes in cell and rodent models of aging. We hypothesized that dietary blueberry would improve mobility and cognition among older adults. METHODS: In this study, 13 men and 24 women, between the ages of 60 and 75 years, were recruited into a randomized, double-blind, placebo-controlled trial in which they consumed either freeze-dried blueberry (24 g/day, equivalent to 1 cup of fresh blueberries) or a blueberry placebo for 90 days. Participants completed a battery of balance, gait, and cognitive tests at baseline and again at 45 and 90 days of intervention. RESULTS: Significant supplement group by study visit interactions were observed on tests of executive function. Participants in the blueberry group showed significantly fewer repetition errors in the California Verbal Learning test (p = 0.031, ηp2 = 0.126) and reduced switch cost on a task-switching test (p = 0.033, ηp2 = 0.09) across study visits, relative to controls. However, no improvement in gait or balance was observed. CONCLUSIONS: These findings show that the addition of easily achievable quantities of blueberry to the diets of older adults can improve some aspects of cognition.

Virtual Morris task responses in individuals in an abstinence phase from alcohol.

The present study was aimed at examining spatial learning and memory, in 33 men and 12 women with alcohol use disorder (AUD) undergoing ethanol detoxification, by using a virtual Morris task. As controls, we recruited 29 men and 10 women among episodic drinkers without a history of alcohol addiction or alcohol-related diseases. Elevated latency to the first movement in all trials was observed only in AUD persons; furthermore, control women had longer latencies compared with control men. Increased time spent to reach the hidden platform in the learning phase was found for women of both groups compared with men, in particular during trial 3. As predicted, AUD persons (more evident in men) spent less time in the target quadrant during the probe trial; however, AUD women had longer latencies to reach the platform in the visible condition during trials 6 and 7 that resulted in a greater distance moved. As for the probe trial, men of both groups showed increased virtual locomotion compared with the women of both groups. The present investigation confirms and extends previous studies showing (i) different gender responses in spatial learning tasks, (ii) some alterations due to alcohol addiction in virtual spatial learning, and (iii) differences between AUD men and AUD women in spatial-behaviour-related paradigms.

The Simple Video Coder: A free tool for efficiently coding social video data.

Videotaping of experimental sessions is a common practice across many disciplines of psychology, ranging from clinical therapy, to developmental science, to animal research. Audio-visual data are a rich source of information that can be easily recorded; however, analysis of the recordings presents a major obstacle to project completion. Coding behavior is time-consuming and often requires ad-hoc training of a student coder. In addition, existing software is either prohibitively expensive or cumbersome, which leaves researchers with inadequate tools to quickly process video data. We offer the Simple Video Coder-free, open-source software for behavior coding that is flexible in accommodating different experimental designs, is intuitive for students to use, and produces outcome measures of event timing, frequency, and duration. Finally, the software also offers extraction tools to splice video into coded segments suitable for training future human coders or for use as input for pattern classification algorithms.

Moderate Prenatal Alcohol Exposure Alters Functional Connectivity in the Adult Rat Brain.

BACKGROUND: Past studies of moderate prenatal alcohol exposure (PAE) have focused on specific brain regions, neurotransmitter systems, and behaviors. However, the effects of PAE on brain function and behavior are complex and not limited to discrete brain regions. Thus, there is a critical need to understand the global effects of moderate PAE on neural function. A primary aim of this research was to explore the functional relationships in neural activity of spatially distinct areas by applying a widely used computational algorithm-group-independent component analysis (gICA)-to resting-state functional magnetic resonance imaging data from rats exposed to either an alcohol or saccharin control solution via maternal consumption during pregnancy. METHODS: Long-Evans rat dams consumed either 5% (v/v) alcohol or a saccharin control solution throughout gestation. Adult offspring from each prenatal treatment group were anesthetized for functional, structural, and perfusion magnetic resonance-based image acquisition sequences. gICA was applied to the functional data to extract components. To determine connectivity, component time-course correlations were computed and compared. Additionally, spectral power analyses were utilized as an additional measure of functional connectivity. Finally, blood perfusion-assessed by arterial spin labeling-and whole-brain volumetric analyses were evaluated. RESULTS: Analyses revealed 17 components in several brain regions such as the cortex, hippocampus, and thalamus. PAE was associated with reductions in coordinated activity between components, especially in males. PAE was also associated with reductions in low-frequency spectral power, an effect that was more robust in females. Brain volumetric analyses revealed sex-dependent reductions in females while blood flow analyses revealed sex-dependent reductions in males. CONCLUSIONS: Moderate PAE leads to persistent changes in functional connectivity in the absence of whole-brain volume or blood flow measures. Future studies will investigate the relationships between alterations in functional network connectivity and behavior.

The importance of measurement precision and behavioral homologies in evaluating the behavioral consequences of fetal-ethanol exposure: commentary on Williams and colleagues ("Sensory-motor deficits in children with fetal alcohol spectrum disorder assessed using a robotic virtual reality platform").

The recent study by Willams and colleagues utilized a novel robotic virtual reality measurement system to measure sensory-motor processing deficits in children with fetal alcohol spectrum disorders (FASDs). This system and the precise quantitation of distinct constituent behavioral processes may hold considerable utility and importance for the study of FASD-related motor deficits, their neural bases, and translational research efforts using homologous behavioral approaches in animal and human studies..

Differential effects of the histamine H(3) receptor agonist methimepip on dentate granule cell excitability, paired-pulse plasticity and long-term potentiation in prenatal alcohol-exposed rats.

BACKGROUND: We previously reported that prenatal alcohol-induced deficits in dentate gyrus (DG) long-term potentiation (LTP) are ameliorated by the histamine H3 receptor inverse agonist ABT-239. ABT-239 did not enhance LTP in control rats, suggesting that the possibility of a heightened H3 receptor-mediated inhibition of LTP in prenatal alcohol-exposed (PAE) offspring. METHODS: To further investigate this mechanism, we examined the effect of methimepip, a selective histamine H3 receptor agonist, on DG granule cell responses and LTP in saccharin control and PAE rats. Long-Evans rat dams voluntarily consumed either a 0 or 5% ethanol solution 4 hours each day throughout gestation. Adult male offspring from these dams were anesthetized with urethane and electrodes implanted into the entorhinal cortical perforant path and the DG. RESULTS: In control offspring, methimepip reduced the coupling of fast excitatory postsynaptic field potentials to population spikes (E-S coupling), the probability of glutamate release, as measured by paired-pulse ratio (PPR) and diminished DG LTP. Similar reductions in E-S coupling and LTP were observed in saline-treated PAE offspring. In contrast to the control group, methimepip did not exacerbate PAE-induced reductions in E-S coupling or LTP. CONCLUSIONS: While the effects of methimepip in control offspring were consistent with speculation of a PAE-induced enhancement of H3 receptor-mediated inhibition of E-S coupling and LTP, the absence of an added effect of methimepip in PAE offspring could indicate either an inability to further inhibit these responses with methimepip in PAE rats or the presence of more complex regulatory neural interactions with in vivo recordings in PAE rats. Follow-up studies of H3 receptor-mediated responses in DG slice preparations are under way to provide clearer insights into the role of the H3 receptor regulation of excitatory transmission in PAE rats.

The histamine H3 receptor inverse agonist SAR-152954 reverses deficits in long-term potentiation associated with moderate prenatal alcohol exposure.

Prenatal alcohol exposure can have persistent effects on learning, memory, and synaptic plasticity. Previous work from our group demonstrated deficits in long-term potentiation (LTP) of excitatory synapses on dentate gyrus granule cells in adult offspring of rat dams that consumed moderate levels of alcohol during pregnancy. At present, there are no pharmacotherapeutic agents approved for these deficits. Prior work established that systemic administration of the histaminergic H3R inverse agonist ABT-239 reversed deficits in LTP observed following moderate PAE. The present study examines the effect of a second H3R inverse agonist, SAR-152954, on LTP deficits following moderate PAE. We demonstrate that systemic administration of 1 mg/kg of SAR-152954 reverses deficits in potentiation of field excitatory post-synaptic potentials (fEPSPs) in adult male rats exposed to moderate PAE. Time-frequency analyses of evoked responses revealed PAE-related reductions in power during the fEPSP, and increased power during later components of evoked responses which are associated with feedback circuitry that are typically not assessed with traditional amplitude-based measures. Both effects were reversed by SAR-152954. These findings provide further evidence that H3R inverse agonism is a potential therapeutic strategy to address deficits in synaptic plasticity associated with PAE.

Fluoxetine restores spatial learning but not accelerated forgetting in mesial temporal lobe epilepsy.

Learning and memory dysfunction is the most common neuropsychological effect of mesial temporal lobe epilepsy, and because the underlying neurobiology is poorly understood, there are no pharmacological strategies to help restore memory function in these patients. We have demonstrated impairments in the acquisition of an allocentric spatial task, in patients with unilateral hippocampal sclerosis. We also show that patients have accelerated forgetting of the learned spatial task and that this is associated with damage to the non-dominant hippocampal formation. We go on to show a very similar pattern of chronic allocentric learning and accelerated forgetting in a status epilepticus model of mesial temporal lobe epilepsy in rats, which is associated with reduced and abnormal hippocampal neurogenesis. Finally, we show that reversal of the neurogenic deficit using fluoxetine is associated with reversal of the learning deficit but not the accelerated forgetting, pointing to a possible dissociation in the underlying mechanisms, as well as a potential therapeutic strategy for improving hippocampal-dependent learning in patients with mesial temporal lobe epilepsy.

Overshadowing of geometric cues by a beacon in a spatial navigation task.

In three experiments, we examined whether overshadowing of geometric cues by a discrete landmark (beacon) is due to the relative saliences of the cues. Using a virtual water maze task, human participants were required to locate a platform marked by a beacon in a distinctively shaped pool. In Experiment 1, the beacon overshadowed geometric cues in a trapezium, but not in an isosceles triangle. The longer escape latencies during acquisition in the trapezium control group with no beacon suggest that the geometric cues in the trapezium were less salient than those in the triangle. In Experiment 2, we evaluated whether generalization decrement, caused by the removal of the beacon at test, could account for overshadowing. An additional beacon was placed in an alternative corner. For the control groups, the beacons were identical; for the overshadow groups, they were visually unique. Overshadowing was again found in the trapezium. In Experiment 3, we tested whether the absence of overshadowing in the triangle was due to the geometric cues being more salient than the beacon. Following training, the beacon was relocated to a different corner. Participants approached the beacon rather than the trained platform corner, suggesting that the beacon was more salient. These results suggest that associative processes do not fully explain cue competition in the spatial domain.

Anxiety and Alzheimer's disease pathogenesis: focus on 5-HT and CRF systems in 3xTg-AD and TgF344-AD animal models.

Dementia remains one of the leading causes of morbidity and mortality in older adults. Alzheimer's disease (AD) is the most common type of dementia, affecting over 55 million people worldwide. AD is characterized by distinct neurobiological changes, including amyloid-beta protein deposits and tau neurofibrillary tangles, which cause cognitive decline and subsequent behavioral changes, such as distress, insomnia, depression, and anxiety. Recent literature suggests a strong connection between stress systems and AD progression. This presents a promising direction for future AD research. In this review, two systems involved in regulating stress and AD pathogenesis will be highlighted: serotonin (5-HT) and corticotropin releasing factor (CRF). Throughout the review, we summarize critical findings in the field while discussing common limitations with two animal models (3xTg-AD and TgF344-AD), novel pharmacotherapies, and potential early-intervention treatment options. We conclude by highlighting promising future pharmacotherapies and translational animal models of AD and anxiety.

Heart rate variability may index emotion dysregulation in alcohol-related intimate partner violence.

Introduction: Intimate partner violence is a serious public health problem that costs the United States more than $4.1 billion in direct medical and mental health costs alone. Furthermore, alcohol use contributes to more frequent and more severe intimate partner violence incidents. Compounding this problem is treatments for intimate partner violence have largely been socially informed and demonstrate poor efficacy. We argue that improvements in intimate partner treatment will be gained through systematic scientific study of mechanisms through which alcohol is related to intimate partner violence. We hypothesize that poor emotional and behavioral regulation as indexed by the respiratory sinus arrythymia measure of heart rate variability is a key mechanism between alcohol use and intimate partner violence. Method: The present study is a placebo-controlled alcohol administration study with an emotion-regulation task that investigated heart rate variability in distressed violent and distressed nonviolent partners. Results: We found a main effect for alcohol on heart rate variability. We also found a four-way interaction whereby distressed violent partners exhibited significant reductions in heart rate variability when acutely intoxicated and attempting to not respond to their partners evocative stimuli. Discussion: These findings suggest that distressed violent partners may adopt maladaptive emotion regulation strategies such as rumination and suppression when intoxicated and attempting to not respond to partner conflict. Such strategies of emotion regulation have been shown to have many deleterious emotional, cognitive and social consequences for individuals who adopt them, possibly including intimate partner violence. These findings also highlight an important novel treatment target for intimate partner violence and suggest that novel treatments should focus on teaching effective conflict resolution and emotion-regulation strategies that may be augmented by biobehavioral treatments such as heart rate variability biofeedback.

Is all motivation good for learning? Dissociable influences of approach and avoidance motivation in declarative memory.

The present study investigated the effects of approach versus avoidance motivation on declarative learning. Human participants navigated a virtual reality version of the Morris water task, a classic spatial memory paradigm, adapted to permit the experimental manipulation of motivation during learning. During this task, participants were instructed to navigate to correct platforms while avoiding incorrect platforms. To manipulate motivational states participants were either rewarded for navigating to correct locations (approach) or punished for navigating to incorrect platforms (avoidance). Participants' skin conductance levels (SCLs) were recorded during navigation to investigate the role of physiological arousal in motivated learning. Behavioral results revealed that, overall, approach motivation enhanced and avoidance motivation impaired memory performance compared to nonmotivated spatial learning. This advantage was evident across several performance indices, including accuracy, learning rate, path length, and proximity to platform locations during probe trials. SCL analysis revealed three key findings. First, within subjects, arousal interacted with approach motivation, such that high arousal on a given trial was associated with performance deficits. In addition, across subjects, high arousal negated or reversed the benefits of approach motivation. Finally, low-performing, highly aroused participants showed SCL responses similar to those of avoidance-motivation participants, suggesting that for these individuals, opportunities for reward may evoke states of learning similar to those typically evoked by threats of punishment. These results provide a novel characterization of how approach and avoidance motivation influence declarative memory and indicate a critical and selective role for arousal in determining how reinforcement influences goal-oriented learning.

Baseline heart rate variability (HRV) and performance during a set-shifting visuospatial learning task: The moderating effect of trait negative affectivity (NA) on behavioral flexibility✰.

Higher negative affectivity (NA) has an association with decreased executive function and cognitive control. Heart rate variability (HRV) may index cardiac vagal regulation differences in the autonomic nervous system (ANS) for both cognition and emotion. The current study investigates this association using a set-shifting variant of the Virtual Morris Water Task (VMWT) to study discrimination learning, spatial learning, reversal learning, and attentional set-shifting in a virtual environment. 73 participants completed affective questionnaires (Beck Depression Inventory-II, Beck Anxiety Inventory, Positive and Negative Affective Scale), a 5-minute baseline electrocardiogram, and the VMWT. Individuals who failed to complete the task exhibited significantly lower baseline RMSSD then those who completed the task. There was no direct effect between affective measures and task performance. Higher baseline HRV was predictive of better performance during set-shifting. Trait NA moderated the effect of baseline HRV, as well as trait positive affectivity (PA), on performance during the extradimensional shift condition. Increased behavioral flexibility performance was only predicted by higher HRV and PA in low NA individuals. High trait NA negates the positive effects of HRV and PA on behavioral flexibility.

Perceived stress and rejection associated with functional network strength during memory retrieval in adolescents.

The brain undergoes substantial structural and functional remodeling during adolescence, including alterations in memory-processing regions influenced by stress. This study evaluated brain activation using functional magnetic resonance imaging (fMRI) during spatial memory performance using a virtual Morris water task (MWT) and examined the associations between default mode network (DMN) activation, task performance, and perceived stress and rejection. Functional magnetic resonance imaging data were acquired at 3 Tesla from 59 (34 female) adolescents (13-14 years). The NIH Emotion Toolbox was used to measure perceived stress and rejection. During the MWT, hippocampus and prefrontal cortex showed greater activation during memory retrieval relative to motor performance. Templates of brain functional networks from the Human Connectome Project study were used to extract individual participants' brain network activation strengths for the retrieval > motor contrast for two sub-networks of the default mode network: medial temporal lobe (MTL-DMN) and dorsomedial prefrontal (dMPFC-DMN). For the MTL-DMN sub-network only, activation was significantly associated with worse MWT performance (p = .008) and greater perceived stress (p = .008) and perceived rejection (p = .002). Further, MWT performance was negatively associated with perceived rejection (p = .007). These findings suggest that perceived stress and rejection are related to engagement of MTL-DMN during spatial memory and that engagement of this network impacts performance. These findings also demonstrate the utility of examining task-related network activation strength to identify the impact of perceived stress and rejection on large-scale brain network functioning during adolescence.

Structural and functional plasticity of the hippocampal formation in professional dancers and slackliners.

The acquisition of special skills can induce plastic changes in the human hippocampus, a finding demonstrated in expert navigators (Maguire et al. (2000) Proc Natl Acad Sci USA 97:4,398-403). Conversely, patients with acquired chronic bilateral vestibular loss develop atrophy of the hippocampus, which is associated with impaired spatial memory (Brandt et al. (2005) Brain 128:2,732-741). This suggests that spatial memory relies on vestibular input. In this study 21 professional dancers and slackliners were examined to assess whether balance training with extensive vestibulo-visual stimulation is associated with altered hippocampal formation volumes or spatial memory. Gray matter voxel-based morphometry showed smaller volumes in the anterior hippocampal formation and in parts of the parieto-insular vestibular cortex of the trained subjects but larger volumes in the posterior hippocampal formation and the lingual and fusiform gyri bilaterally. The local volumes in the right anterior hippocampal formation correlated negatively and those in the right posterior hippocampal formation positively with the amount of time spent training ballet/ice dancing or slacklining at the time of the study. There were no differences in general memory or in spatial memory as assessed by the virtual Morris water task. Trained subjects performed significantly better on a hippocampal formation-dependent task of nonspatial memory (transverse patterning). The smaller anterior hippocampal formation volumes of the trained subjects may be the result of a long-term suppression of destabilizing vestibular input. This is supported by the associated volume loss in the parieto-insular vestibular cortex. The larger volumes in the posterior hippocampal formation of the trained subjects might result from their increased utilization of visual cues for balance. This is supported by the concomitant larger volumes in visual areas like the lingual and fusiform gyri. Our findings indicate that there is a spatial separation of vestibular and visual processes in the human hippocampus.

Cued platform training reveals early development of directional responding among preweanling rats in the Morris water task.

Previous studies on the ontogeny of spatial learning report that rats younger than 19-21 days of age are incapable of learning the location of a platform relative to distal cues in the Morris water task. Here, we manipulated the spatial relationship of a cued platform to the pool and the distal visual room cues to investigate whether distal cues can control navigation among 16- to 24-day-old rats. Rats were trained to navigate to a cued platform in a rich distal cue environment. During critical test trials, the pool was shifted to a different, overlapping position and the cued platform was placed either in the same absolute location in the room or the same relative location in the pool as during training. Rats aged 17 days and older exhibited a disruption in performance when the cued platform was in the absolute location but not the relative location, indicating that rats had learned the direction of the cued platform within the distal cue environment. These observations indicate that (1) information acquired from distal room cues influences navigation as early as 17 days of age, (2) this distal cue information is preferentially used to guide navigation in a particular direction rather than to a precise place in the room, and (3) the directional nature of the influence of distal cues on navigation is invariant across development.

Detection of prenatal alcohol exposure using machine learning classification of resting-state functional network connectivity data.

Fetal Alcohol Spectrum Disorder (FASD), a wide range of physical and neurobehavioral abnormalities associated with prenatal alcohol exposure (PAE), is recognized as a significant public health concern. Advancements in the diagnosis of FASD have been hindered by a lack of consensus in diagnostic criteria and limited use of objective biomarkers. Previous research from our group utilized resting-state functional magnetic resonance imaging (fMRI) to measure functional network connectivity (FNC), which revealed several sex- and region-dependent alterations in FNC as a result of moderate PAE relative to controls. Considering that FNC is sensitive to moderate PAE, this study explored the use of FNC data and machine learning methods to detect PAE among a sample of rodents exposed to alcohol prenatally and controls. We utilized previously acquired resting state fMRI data collected from adult rats exposed to moderate levels of prenatal alcohol (PAE) or a saccharin control solution (SAC) to assess FNC of resting state networks extracted by spatial group independent component analysis (GICA). FNC data were subjected to binary classification using support vector machine (SVM) -based algorithms and leave-one-out-cross validation (LOOCV) in an aggregated sample of males and females (n = 48; 12 male PAE, 12 female PAE, 12 male SAC, 12 female SAC), a males-only sample (n = 24; 12 PAE, 12 SAC), and a females-only sample (n = 24; 12 PAE, 12 SAC). Results revealed that a quadratic SVM (QSVM) kernel was significantly effective for PAE detection in females. QSVM kernel-based classification resulted in accuracy rates of 62.5% for all animals, 58.3% for males, and 79.2% for females. Additionally, qualitative evaluation of QSVM weights implicates an overarching theme of several hippocampal and cortical networks in contributing to the formation of correct classification decisions by QSVM. Our results suggest that binary classification using QSVM and adult female FNC data is a potential candidate for the translational development of novel and non-invasive techniques for the identification of FASD.

Brain Activation during Memory Retrieval is Associated with Depression Severity in Women.

Major depressive disorder (MDD) is a debilitating disorder that interferes with daily functioning, and that occurs at higher rates in women than in men. Structural and functional alterations in hippocampus and frontal lobe have been reported in MDD, which likely contribute to the multifaceted nature of MDD. One area impacted by MDD is hippocampal-mediated memory, which can be probed using a spatial virtual Morris water task (MWT). Women (n=24) across a spectrum of depression severity underwent functional magnetic resonance imaging (fMRI) during MWT. Depression severity, assessed via Beck Depression Inventory (BDI), was examined relative to brain activation during task performance. Significant brain activation was evident in areas traditionally implicated in spatial memory processing, including right hippocampus and frontal lobe regions, for retrieval > motor contrast. When BDI was included as a regressor, significantly less functional activation was evident in left hippocampus, and other non-frontal, task relevant regions for retrieval > rest contrast. Consistent with previous studies, depression severity was associated with functional alterations observed during spatial memory performance. These findings may contribute to understanding neurobiological underpinnings of depression severity and associated memory impairments, which may have implications for treatment approaches aimed at alleviating effects of depression in women.