Prefrontal Cortical Regions Research Articles

Examining relationships among NODDI indices of white matter structure in prefrontal cortical-thalamic-striatal circuitry and OCD symptomatology

Obsessive-compulsive disorder is a psychiatric disorder characterized by intrusive thoughts and repetitive behaviors. There are two prominent features: Harm Avoidance (HA) and Incompleteness (INC). Previous resting-state studies reported abnormally elevated connectivity between prefrontal cortical (PFC) and subcortical regions (thalamus, striatum) in OCD participants. Yet, little is known about the white matter (WM) structural abnormalities in these connections. Using brain parcellation and segmentation, whole brain tractography, and Neurite Orientation Dispersion and Density Imaging (NODDI), we aimed to characterize WM structural abnormalities in OCD vs. healthy controls and determine the extent to which NODDI indices of these connections were associated with subthreshold-threshold HA, INC and overall OCD symptom severity across all participants. Four PFC regions were segmented: ventral medial (vmPFC), ventrolateral (vlPFC), dorsomedial (dmPFC), and dorsolateral (dlPFC). NODDI Neurite Density (NDI) and Orientation Dispersion (ODI) indices of WM structure were extracted from connections between these PFC regions and the thalamus (42 OCD, 44 healthy controls, mean age[SD] = 23.65[4.25]y, 63.9% female) and striatum (38 OCD, 41 healthy controls, mean age[SD] = 23.59[4.27]y, 64.5% female). Multivariate analyses of covariance revealed no between-group differences in these indices. Multivariate regression models revealed that greater NDI in vmPFC-thalamus, greater NDI and ODI in vmPFC-striatum, and greater NDI in dmPFC-thalamus connections were associated with greater INC severity (Q ≤ 0.032). These findings highlight the utility of NODDI in the examination of WM structure in OCD, provide valuable insights into specific WM alterations underlying dimensional INC, and can facilitate the development of customized treatments for OCD individuals with treatment-resistant symptoms.

Cortical cognitive processing during reading captured using functional-near infrared spectroscopy

Neuroimaging studies using functional magnetic resonance imaging (fMRI) have provided unparalleled insights into the fundamental neural mechanisms underlying human cognitive processing, such as high-level linguistic processes during reading. Here, we build upon this prior work to capture sentence reading comprehension outside the MRI scanner using functional near infra-red spectroscopy (fNIRS) in a large sample of participants (n = 82). We observed increased task-related hemodynamic responses in prefrontal and temporal cortical regions during sentence-level reading relative to the control condition (a list of non-words), replicating prior fMRI work on cortical recruitment associated with high-level linguistic processing during reading comprehension. These results lay the groundwork towards developing adaptive systems to support novice readers and language learners by targeting the underlying cognitive processes. This work also contributes to bridging the gap between laboratory findings and more real-world applications in the realm of cognitive neuroscience.

Sex-dependent effects of amyloidosis on functional network hub topology is associated with downregulated neuronal gene signatures in the APPswe/PSEN1dE9 double transgenic mouse.

Extracellular beta-amyloid (Aβ) is thought to cause impairments in brain-wide functional connectivity, although mechanisms linking Aβ to broader functional network processing remain elusive. In the present study, we evaluated the effects of Aβ on fear memory and functional connectome measures in male and female mice. Middle-aged (9-11mo) double transgenic APP-PS1 mice and age and sex-matched controls were tested on a fear conditioning protocol and then imaged at 11.1 Tesla. Brains were harvested and processed for analysis of Aβ plaques and Iba1 immunolabeling in neocortical areas, hippocampus, and basolateral amygdala. Additional RNA sequencing data from separate age, strain, and sex-matched mice were analyzed for differentially expressed genes (DEGs) and weighted gene co-expression networks. In both male and female mice, we observed increased functional connectivity in a dorsal striatal/amygdala network as a result of Aβ. Increased functional connectivity within this network was matched by increases in APP gene expression, Aβ and Iba1 immunolabeling, and an upregulated cluster of DEGs involved in the immune response. Conversely, the network measure representing node hubness, eigenvector centrality, was increased in prefrontal cortical brain regions, but only in female APP-PS1 mice. This female-specific effect of amyloid was associated with down-regulation of a cluster of DEGs involved in cortical and striatal GABA transmission, anxiogenic responses, and motor activity, in female APP-PS1 mice, but not males. Our results contribute to a growing literature linking between Aβ, immune activation, and functional network connectivity. Furthermore, our results reveal outcomes of Aβ on gene expression patterns in female mice that may contribute to amyloidosis-induced dysregulation of non-cognitive circuitry.

Interaction of the dorsolateral prefrontal cortex with the precuneal medial parietal cortex for the monitoring of information in working memory in the macaque monkey.

The executive control process of monitoring information in working memory depends on the mid-dorsolateral prefrontal cortical region (cytoarchitectonic areas 46 and 9/46) in interaction with the hippocampal memory system. Anatomical studies demonstrated strong connectivity between the mid-dorsolateral prefrontal cortex and the medial parietal area PGm that lies on the precuneus. Area PGm is also strongly connected with the attentional system on the lateral inferior parietal lobule (area PG) and the limbic retrosplenial/posterior cingulate region that interacts with the hippocampal memory system. Thus, in terms of anatomical connectivity, area PGm appears to be a critical node for the integration of executive control processing from the prefrontal cortex with the online attentional and memory related processing. This hypothesis was tested in macaque monkeys with the crossed unilateral lesion methodology. A unilateral lesion in the mid-dorsolateral prefrontal cortex was combined with a unilateral lesion in area PGm in the opposite hemisphere. The results demonstrated an impairment on the externally ordered working memory task that assesses the monitoring of information in working memory. Thus, the medial parietal area PGm is a critical node in mediating the functional interaction between the prefrontal region for the executive control process of monitoring information and the memory system.

Functionally linked amygdala and prefrontal cortical regions are innervated by both single and double projecting cholinergic neurons.

Cholinergic cells have been proposed to innervate simultaneously those cortical areas that are mutually interconnected with each other. To test this hypothesis, we investigated the cholinergic innervation of functionally linked amygdala and prefrontal cortical regions. First, using tracing experiments, we determined that cholinergic cells located in distinct basal forebrain (BF) areas projected to the different nuclei of the basolateral amygdala (BLA). Specifically, cholinergic cells in the ventral pallidum/substantia innominata (VP/SI) innervated the basal nucleus (BA), while the horizontal limb of the diagonal band of Broca (HDB) projected to its basomedial nucleus (BMA). In addition, cholinergic neurons in these two BF areas gave rise to overlapping innervation in the medial prefrontal cortex (mPFC), yet their axons segregated in the dorsal and ventral regions of the PFC. Using retrograde-anterograde viral tracing, we demonstrated that a portion of mPFC-projecting cholinergic neurons also innervated the BLA, especially the BA. By injecting retrograde tracers into the mPFC and BA, we found that 28% of retrogradely labeled cholinergic cells were double labeled, which typically located in the VP/SI. In addition, we found that vesicular glutamate transporter type 3 (VGLUT3)-expressing neurons within the VP/SI were also cholinergic and projected to the mPFC and BA, implicating that a part of the cholinergic afferents may release glutamate. In contrast, we uncovered that GABA is unlikely to be a co-transmitter molecule in HDB and VP/SI cholinergic neurons in adult mice. The dual innervation strategy, i.e., the existence of cholinergic cell populations with single as well as simultaneous projections to the BLA and mPFC, provides the possibility for both synchronous and independent control of the operation in these cortical areas, a structural arrangement that may maximize computational support for functionally linked regions. The presence of VGLUT3 in a portion of cholinergic afferents suggests more complex functional effects of cholinergic system in cortical structures.

STN-PFC circuit related to attentional fluctuations during non-movement decision-making

Decision-making is a cognitive process, in which participants need to attend to relevant information and ignore the irrelevant information. Previous studies have described a set of cortical areas important for attention. It is unclear whether subcortical areas also serve a role. The subthalamic nucleus (STN), a part of basal ganglia, is traditionally considered a critical node in the cortico-basal ganglia-thalamus-cortico network. Given the location of the STN and its widespread connections with cortical and subcortical brain regions, the STN plays an important role in motor and non-motor cognitive processing. We would like to know if STN is also related to fluctuations in attentional task performance, and how the STN interacts with prefrontal cortical regions during the process. We examined neural activities within STN covaried with lapses of attention (defined as behavior error). We found that decreased neural activities in STN were associated with sustained attention. By examining connectivity across STN and various sub-regions of the prefrontal cortex (PFC), we found that decreased connectivity across areas was associated with sustained attention. Our results indicated that decreased STN activities were associated with sustained attention, and the STN-PFC circuit supported this process.

Effects of sleep deprivation on anxiety-depressive-like behavior and neuroinflammation

BackgroundDepression is defined by a persistent low mood and disruptions in sleep patterns, with the WHO forecasting that major depression will rank as the third most prevalent contributor to the global burden of disease by the year 2030. Sleep deprivation serves as a stressor that triggers inflammation within the central nervous system, a process known as neuroinflammation. This inflammatory response plays a crucial role in the development of depression by upregulating the expression of inflammatory mediators that contribute to symptoms such as anxiety, hopelessness, and loss of pleasure. MethodsIn this study, sleep deprivation was utilized as a method to induce anxiety and depressive-like behaviors in mice. The behavioral changes in the mice were then evaluated using the EZM, EPM, TST, FST, and SPT. H&E staining and Nissl staining was used to detect morphological changes in the medial prefrontal cortical (mPFC) regions. Elisa to assess serum CORT levels. Detection of mRNA levels and protein expression of clock genes, high mobility genome box-1 (Hmgb1), silent message regulator 6 (Sirt6), and pro-inflammatory factors by RT-qPCR, Western blotting, and immunofluorescence techniques. ResultsSleep deprivation resulted in decreased exploration of unfamiliar territory, increased time spent in a state of despair, and lower sucrose water intake in mice. Additionally, sleep deprivation led to increased secretion of serum CORT and upregulation of clock genes, IL6, IL1β, TNFα, Cox-2, iNOS, Sirt6, and Hmgb1. Sleep. ConclusionsSleep deprivation induces anxiety-depressive-like behaviors and neuroinflammation in the brain. Transcription of clock genes and activation of the Sirt6/Hmgb1 pathway may contribute to inflammatory responses in the mPFC.

Distinct neural mechanisms for action access and execution in the human brain: insights from an fMRI study.

Goal-directed actions are fundamental to human behavior, whereby inner goals are achieved through mapping action representations to motor outputs. The left premotor cortex (BA6) and the posterior portion of Broca's area (BA44) are two modulatory poles of the action system. However, how these regions support the representation-output mapping within the system is not yet understood. To address this, we conducted a finger-tapping functional magnetic resonance imaging experiment using action categories ranging from specific to general. Our study found distinct neural behaviors in BA44 and BA6 during action category processing and motor execution. During access of action categories, activity in a posterior portion of BA44 (pBA44) decreased linearly as action categories became less specific. Conversely, during motor execution, activity in BA6 increased linearly with less specific categories. These findings highlight the differential roles of pBA44 and BA6 in action processing. We suggest that pBA44 facilitates access to action categories by utilizing motor information from the behavioral context while the premotor cortex integrates motor information to execute the selected action. This finding enhances our understanding of the interplay between prefrontal cortical regions and premotor cortex in mapping action representation to motor execution and, more in general, of the cortical mechanisms underlying human behavior.

The neural oscillations serving task switching are altered in cannabis users.

Regular cannabis is known to impact higher-order cognitive processes such as attention, but far less is known regarding cognitive flexibility, a component of executive function. Moreover, whether such changes are related to aberrations in the neural oscillatory dynamics serving flexibility remains poorly understood. Quantify the neural oscillatory dynamics serving cognitive flexibility by having participants complete a task-switching paradigm during magnetoencephalography (MEG). Probe whole-brain maps to identify alterations in chronic cannabis users relative to nonusers and determine how these alterations relate to the degree of cannabis use involvement. In all, 25 chronic cannabis users and 30 demographically matched nonuser controls completed neuropsychological testing, an interview regarding their substance use, a urinalysis, and a task switch paradigm during MEG. Time-frequency windows of interest were identified using a data-driven statistical approach and these were imaged using a beamformer. Whole-brain neural switch cost maps were computed by subtracting the oscillatory maps of the no-switch condition from the switch condition per participant. These were examined for group differences. Cannabis users had weaker theta switch cost responses in the dorsolateral and dorsomedial prefrontal cortices, while nonusers showed the typical pattern of greater recruitment during switch relative to no switch trials. In addition, theta activity in the dorsomedial prefrontal cortex was significantly correlated with cannabis use involvement. Cannabis users exhibited altered theta switch cost activity compared to nonusers in prefrontal cortical regions, which are critical for cognitive flexibility. This activity scaled with cannabis use involvement, indicating a link between cannabis use and aberrant oscillatory activity underlying cognitive flexibility.

Impaired value-based decision-making in Parkinson's disease apathy.

Apathy is a common and disabling complication of Parkinson's disease characterized by reduced goal-directed behaviour. Several studies have reported dysfunction within prefrontal cortical regions and projections from brainstem nuclei whose neuromodulators include dopamine, serotonin and noradrenaline. Work in animal and human neuroscience have confirmed contributions of these neuromodulators on aspects of motivated decision-making. Specifically, these neuromodulators have overlapping contributions to encoding the value of decisions, and influence whether to explore alternative courses of action or persist in an existing strategy to achieve a rewarding goal. Building upon this work, we hypothesized that apathy in Parkinson's disease should be associated with an impairment in value-based learning. Using a four-armed restless bandit reinforcement learning task, we studied decision-making in 75 volunteers; 53 patients with Parkinson's disease, with and without clinical apathy, and 22 age-matched healthy control subjects. Patients with apathy exhibited impaired ability to choose the highest value bandit. Task performance predicted an individual patient's apathy severity measured using the Lille Apathy Rating Scale (R = -0.46, P < 0.001). Computational modelling of the patient's choices confirmed the apathy group made decisions that were indifferent to the learnt value of the options, consistent with previous reports of reward insensitivity. Further analysis demonstrated a shift away from exploiting the highest value option and a reduction in perseveration, which also correlated with apathy scores (R = -0.5, P < 0.001). We went on to acquire functional MRI in 59 volunteers; a group of 19 patients with and 20 without apathy and 20 age-matched controls performing the Restless Bandit Task. Analysis of the functional MRI signal at the point of reward feedback confirmed diminished signal within ventromedial prefrontal cortex in Parkinson's disease, which was more marked in apathy, but not predictive of their individual apathy severity. Using a model-based categorization of choice type, decisions to explore lower value bandits in the apathy group activated prefrontal cortex to a similar degree to the age-matched controls. In contrast, Parkinson's patients without apathy demonstrated significantly increased activation across a distributed thalamo-cortical network. Enhanced activity in the thalamus predicted individual apathy severity across both patient groups and exhibited functional connectivity with dorsal anterior cingulate cortex and anterior insula. Given that task performance in patients without apathy was no different to the age-matched control subjects, we interpret the recruitment of this network as a possible compensatory mechanism, which compensates against symptomatic manifestation of apathy in Parkinson's disease.

Fronto-limbic white matter microstructural changes in psychiatrically healthy adults with childhood trauma.

Childhood trauma (CT) may influence brain white matter microstructure; however, few studies have examined the differential impact of distinct CT types on white matter microstructure in psychiatrically healthy adults living in a developing country. In adults without significant medical or psychiatric disorders, we investigated the association(s) between CT, including abuse and neglect, and fractional anisotropy (FA) of limbic tracts previously shown to be associated with CT. Participants underwent diffusion tensor imaging and completed the Childhood Trauma Questionnaire. Multivariate analysis of variance models were used to test the effects of total overall CT, as well as CT subtypes, on FA in six fronto-limbic tracts, adjusting for age, sex, and educational level. The final sample included 69 adults (age 47 ± 17 years; 70% female). Overall, CT had a significant main effect on FA for tracts of interest (p < .001). Greater CT severity was associated with lower FA for the bilateral and left stria terminalis (uncorrected) as well as the bilateral, left, and right anterior limb of the internal capsule (ALIC; corrected). Exposure to total non-violent/deprivational trauma specifically was associated with lower FA of the bilateral, left, and right ALIC, suggesting that distinct types of CT are associated with differential white matter changes in apparently healthy adults. The ALIC predominantly carries fibers connecting the thalamus with prefrontal cortical regions. Microstructural alterations in the ALIC may be associated with functional brain changes, which may be adaptive or increase the risk of accelerated age-related cognitive decline, maladaptive behaviors, and subsyndromal psychiatric symptoms.

Dynamic vagal-mediated connectivity of cortical and subcortical central autonomic hubs predicts chronotropic response to submaximal exercise in healthy adults

BackgroundDespite accumulation of a substantial body of literature supporting the role of exercise on frontal lobe functioning, relatively less is understood of the interconnectivity of ventromedial prefrontal cortical (vmPFC) regions that underpin cardio-autonomic regulation predict cardiac chronotropic competence (CC) in response to sub-maximal exercise. MethodsEligibility of 161 adults (mean age = 48.6, SD = 18.3, 68% female) was based upon completion of resting state brain scan and sub-maximal bike test. Sliding window analysis of the resting state signal was conducted over 45-s windows, with 50% overlap, to assess how changes in photoplethysmography-derived HRV relate to vmPFC functional connectivity with the whole brain. CC was assessed based upon heart rate (HR) changes during submaximal exercise (HR change /HRmax (206–0.88 × age) – HRrest). ResultsDuring states of elevated HRV the vmPFC showed greater rsFC with an 83-voxel region of the hypothalamus (p < 0.001, uncorrected). Beta estimates of vmPFC connectivity extracted from a 6-mm sphere around this region emerged as the strongest predictor of CC (b = 0.283, p <.001) than age, BMI, and resting HRV F(8,144) = 6.30, p <.001. ConclusionExtensive glutamatergic innervation of the hypothalamus by the vmPFC allows for top-down control of the hypothalamus and its various autonomic efferents which facilitate chronotropic response during sub-maximal exercise.

Mapping causal links between prefrontal cortical regions and intra-individual behavioral variability

Intra-individual behavioral variability is significantly heightened by aging or neuropsychological disorders, however it is unknown which brain regions are causally linked to such variabilities. We examine response time (RT) variability in 21 macaque monkeys performing a rule-guided decision-making task. In monkeys with selective-bilateral lesions in the anterior cingulate cortex (ACC) or in the dorsolateral prefrontal cortex, cognitive flexibility is impaired, but the RT variability is significantly diminished. Bilateral lesions within the frontopolar cortex or within the mid-dorsolateral prefrontal cortex, has no significant effect on cognitive flexibility or RT variability. In monkeys with lesions in the posterior cingulate cortex, the RT variability significantly increases without any deficit in cognitive flexibility. The effect of lesions in the orbitofrontal cortex (OFC) is unique in that it leads to deficits in cognitive flexibility and a significant increase in RT variability. Our findings indicate remarkable dissociations in contribution of frontal cortical regions to behavioral variability. They suggest that the altered variability in OFC-lesioned monkeys is related to deficits in assessing and accumulating evidence to inform a rule-guided decision, whereas in ACC-lesioned monkeys it results from a non-adaptive decrease in decision threshold and consequently immature impulsive responses.

Association of low frequency variants with regional cortical grey matter volumes in genetic frontotemporal dementia: Results from GENFI

AbstractBackgroundFrontotemporal dementia (FTD) is a neurodegenerative condition characterized by heterogeneous clinical, pathological, and genetic features. Mutations in three genes account for the majority of autosomal dominant FTD: GRN, MAPT, and C9orf72. We tested whether gene‐based aggregate burden of genome‐wide low‐frequency variants contribute to variation in regional cortical and subcortical grey matter volumes in the GENetic Frontotemporal dementia Initiative (GENFI), after controlling for effects of autosomal dominant mutations.MethodGENFI recruits symptomatic and presymptomatic participants from families segregating genetic FTD. We included 517 participants with genotype (Neurochip; imputed against TOPMed), and T1w‐MRI brain volumetric data. Gene‐based burden tests that aggregate the number of uncommon/rare variants by gene were used to examine the association of low‐frequency variants (minor allele frequency: 0.000001 to &lt;0.05) with regional cortical and subcortical grey matter volumes, controlling for age, sex, total intracranial volume, mutation status, population stratification, and family membership (kinship matrix). In two separate analyses, we used the following set of annotations to account for (i) loss of function mutations (LOF): start gain, stop loss, start loss, essential splice site, stop gain, normal splice site, and non‐synonymous, (ii) insertions, deletions, and frameshift mutations (indel‐fs).ResultOf the 517 participants (300 women), 307 were mutation carriers (symptomatic = 82). For LOF mutations (731 genes tested; significance threshold: p = 0.05/731 = 6.8×10−5), aggregate burden of variants in BSND were associated with lower volumes in: temporal (p = 6.6×10−6), left insula (p = 5.0×10−5), and ventromedial prefrontal cortical (p = 2.8×10−5) regions. For indel‐fs mutations (826 genes tested; significance threshold: p = 0.05/826 = 6.05×10−5), aggregate burden of variants in: (i) E2F2 was associated with lower volumes in occipital (p = 8.7×10−6) regions; (ii) TMEM61 was associated with lower volumes in left temporal (p = 7.8×10−7), and left cingulate regions (p = 5.5×10−5); (iii) KDM4A‐AS1 was associated with lower volumes in the right temporal (p = 3.2×10‐7) region. All genes are variably expressed in the brain.ConclusionIdentification of deleterious or protective low‐frequency variants contributing to FTD imaging phenotypes may help identify genetic modifiers of familial FTD. Replication of results followed by functional studies are needed.

Social behavior and neuronal activation in adolescent female Fos-LacZ transgenic rats: Impact of acute ethanol challenge and baseline levels of social preference

In human adolescents, females often report drinking for coping reasons to avoid negative affective states. We have shown previously that adolescent female rats with elevated levels of anxiety-like behavior under social test circumstances, indexed via low social preference, are sensitive to anxiolytic effects of ethanol given intraperitoneally (i.p.) in a low-to-moderate dose range. This study was designed to test the hypothesis that patterns of neuronal activation across brain regions implicated in social activity and social preference (used as an index of low versus high anxiety-like social responding) would be affected by acute ethanol differently in adolescent females with high and low social preference, with initial levels of social preference also predicting ethanol-induced changes in social behavior. Adolescent female Fos-LacZ rats were given social interaction tests on postnatal day (P)33 for determination of baseline levels of responding to an unfamiliar social partner and on P35 following administration of 0 or 0.75 g/kg ethanol. Brain tissue was collected, and expression of β-galactoside (β-gal) was used as an index of neuronal activation. Baseline levels of social preference did not predict social responsiveness to an acute ethanol challenge, whereas significant decreases in this social measure that reflects anxiety-like behavioral alterations were evident in adolescent females challenged with ethanol relative to saline-injected controls, suggesting high sensitivity to the anxiogenic effects of ethanol. Ethanol precipitated negative relationships between social preference and prefrontal cortical activation, decreased neuronal activation of the anterior cingulate cortex, but substantially increased β-gal expression in the central amygdala. These results suggest high sensitivity of the prefrontal cortical regions and central amygdala to ethanol-induced alterations in adolescent Fos-LacZ females and provide a background for further phenotyping of neurons activated by ethanol under social test circumstances.

Cortical Lewy body injections induce long-distance pathogenic alterations in the non-human primate brain

Aggregation of α-synuclein (α-syn) is the cornerstone of neurodegenerative diseases termed synucleinopathies, which include Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). These synucleinopathies are characterized by the deposit of aggregated α-syn in intracellular inclusions observable in neurons and glial cells. In PD and DLB, these aggregates, predominantly located in neurons, are called Lewy Bodies (LBs). These LBs are one of the pathological hallmarks of PD and DLB, alongside dopaminergic neuron loss in the substantia nigra. Previous studies have demonstrated the ability of PD patient-derived LB fractions to induce nigrostriatal neurodegeneration and α-syn pathology when injected into the striatum or the enteric nervous system of non-human primates. Here, we report the pathological consequences of injecting these LB fractions into the cortex of non-human primates. To this end, we inoculated mesencephalic PD patient-derived LB fractions into the prefrontal cortex of baboon monkeys terminated one year later. Extensive analyses were performed to evaluate pathological markers known to be affected in LB pathologies. We first assessed the hypothesized presence of phosphorylated α-syn at S129 (pSyn) in the prefrontal cortices. Second, we quantified the neuronal, microglial, and astrocytic cell survival in the same cortices. Third, we characterized these cortical LB injections’ putative impact on the integrity of the nigrostriatal system. Overall, we observed pSyn accumulation around the injection site in the dorsal prefrontal cortex, in connected cortical regions, and further towards the striatum, suggesting α-syn pathological propagation. The pathology was also accompanied by neuronal loss in these prefrontal cortical regions and the caudate nucleus, without, however, loss of nigral dopamine neurons. In conclusion, this pilot study provides novel data demonstrating the toxicity of patient-derived extracts, their potential to propagate from the cortex to the striatum in non-human primates, and a possible primate model of DLB.

Identification of the Neural Correlates Underlying Conflict Resolution Performance Using a Rodent Analogue of the Stroop Tests

The Stroop test is a widely used neuropsychological test measuring attention and conflict resolution, which shows sensitivity across a range of diseases, including Alzheimer’s, Parkinson’s and Huntington’s diseases. A rodent analogue of the Stroop test, the Response-Conflict task (rRCT), allows for systematic investigation of the neural systems underpinning performance in this test. Little is known about the involvement of the basal ganglia in this neural process. The aim of this study was to use the rRCT to determine whether striatal subregions are recruited during conflict resolution processing. To achieve this, rats were exposed to Congruent or Incongruent stimuli in the rRCT and the expression patterns of the immediate early gene Zif268 were analysed throughout cortical, hippocampal and basal ganglia subregions. The results confirmed the previously reported involvement of prefrontal cortical and hippocampal regions, as well as identifying a specific role for the dysgranular (but not granular) retrosplenial cortex in conflict resolution. Finally, performance accuracy correlated significantly with reduced neural activation in the dorsomedial striatum. Involvement of the basal ganglia in this neural process has not previously been reported. These data demonstrate that the cognitive process of conflict resolution requires not only prefrontal cortical regions, but also recruits the dysgranular retrosplenial cortex and the medial region of the neostriatum. These data have implications for understanding the neuroanatomical changes that underpin impaired Stroop performance in people with neurological disorders.

Sex differences in atypical fronto-subcortical structural connectivity among children with attention-deficit/hyperactivity disorder: Associations with delay discounting

PurposeAtypical fronto-subcortical neural circuitry has been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD), including connections between prefrontal cortical regions involved in top-down cognitive control and subcortical limbic structures (striatum and amygdala) involved in bottom-up reward and emotional processing. The integrity of fronto-subcortical connections may also relate to interindividual variability in delay discounting, or a preference for smaller, immediate over larger, delayed rewards, which is associated with ADHD, with recent evidence of ADHD-related sex differences. MethodsWe applied diffusion tensor imaging to compare the integrity of the white matter connections within fronto-subcortical tracts among 187 8–12 year-old children either with ADHD ((n = 106; 29 girls) or typically developing (TD) controls ((n = 81; 28 girls). Analyses focused on diagnostic group differences in fractional anisotropy (FA) within fronto-subcortical circuitry implicated in delay discounting, connecting subregions of the striatum (dorsal executive and ventral limbic areas) and amygdala with prefrontal regions of interest (dorsolateral [dlPFC], orbitofrontal [OFC] and anterior cingulate cortex [ACC]), and associations with two behavioral assessments of delay discounting. ResultsChildren with ADHD showed reduced FA in tracts connecting OFC with ventral striatum, regardless of sex, whereas reduced FA in the OFC-amygdala and ventral ACC-amygdala tracts were specific to boys with ADHD. Across diagnostic groups and sex, reduced FA in the dorsal ACC-executive striatum tract correlated with greater game time delay discounting. ConclusionsThese results suggest a potential neurobiological substrate of heightened delay discounting in children with ADHD and support the need for additional studies including larger sample sizes of girls with ADHD to further elucidate ADHD-related sex differences in these relationships.

Identification of brain aging subtypes in multiple brain regions from cognitively normal individuals

AbstractBackgroundAlthough late‐onset Alzheimer’s disease (LOAD) occurs in older individuals (age 65 or older), multiple lines of evidence suggests that the dysregulation of brain functions initiates decades earlier. Through examining multiple large‐scale human brain transcriptomic data, we demonstrated that cognitively normal brain aging from donors in their 40s‐60s can group into several subtypes based on their hippocampal transcriptomes. One subtype represents healthy brain aging and some evidence suggests these donors may remain cognitively normal in much older ages, while some brain aging subtypes showed gene expression changes highly similar to those observed in AD, supporting molecular changes linked to AD have occurred much earlier than the manifestation of cognitive impairment. However, whether the brain aging subtype is a common phenomenon across multiple brain regions or very specific to the hippocampus remains unknown.MethodWe compiled and studied transcriptomic data in another commonly studied human brain region (prefrontal cortex) from donors who were cognitively normal. We performed hierarchical clustering in these samples to infer subtypes, differential gene expression analysis was done between samples from different subtypes. We annotated and compared these DEGs with other AD gene expression signatures.ResultWe discovered that aging subtypes could also be observed in the prefrontal cortical region. Similarly to the hippocampus, the differentially expressed genes among aging subtypes also highly overlapped with AD gene signatures. By comparing aging subtypes defined from hippocampal vs. cortical transcriptomes from the same individuals, we found that an AD similar hippocampal sample does not necessarily correspond to AD similar cortical sample in the same donor, suggesting the brain regional complexity of the disease.ConclusionOur analysis of the transcriptomic data from multiple brain regions from cognitively normal individual supports that gene regulation changes related to AD occurs decades earlier than the manifestation of clinical phenotype. Understanding the molecular changes in these early changes in multiple brain regions could be critical to gain new insights into the mechanisms of AD initiation.

Sex-Dependent Attentional Impairments in a Subchronic Ketamine Mouse Model for Schizophrenia

BackgroundThe development of more effective treatments for schizophrenia targeting cognitive and negative symptoms has been limited, partly due to a disconnect between rodent models and human illness. Ketamine administration is widely used to model symptoms of schizophrenia in both humans and rodents. In mice, subchronic ketamine treatment reproduces key dopamine and glutamate dysfunction; however, it is unclear how this translates into behavioral changes reflecting positive, negative, and cognitive symptoms. MethodsIn male and female mice treated with either subchronic ketamine or saline, we assessed spontaneous and amphetamine-induced locomotor activity to measure behaviors relevant to positive symptoms, and used a touchscreen-based progressive ratio task of motivation and the rodent continuous performance test of attention to capture specific negative and cognitive symptoms, respectively. To explore neuronal changes underlying the behavioral effects of subchronic ketamine treatment, we quantified expression of the immediate early gene product, c-Fos, in key corticostriatal regions using immunofluorescence. ResultsWe showed that spontaneous locomotor activity was unchanged in male and female subchronic ketamine–treated animals, and amphetamine-induced locomotor response was reduced. Subchronic ketamine treatment did not alter motivation in either male or female mice. In contrast, we identified a sex-specific effect of subchronic ketamine on attentional processing wherein female mice performed worse than control mice due to increased nonselective responding. Finally, we showed that subchronic ketamine treatment increased c-Fos expression in prefrontal cortical and striatal regions, consistent with a mechanism of widespread disinhibition of neuronal activity. ConclusionsOur results highlight that the subchronic ketamine mouse model reproduces a subset of behavioral symptoms that are relevant for schizophrenia.