Prefronto-thalamic tract injury and cognitive outcome according to external ventricular drainage location in stroke patients.

OBJECTIVES: We investigated the characteristics of prefronto-thalamic tract (PF-TT) injuries in stroke patients using diffusion tensor tractography (DTT) and assessing cognitive outcome according to location of the external ventricular drainage (EVD). METHODS: Forty-five consecutive stroke patients who underwent EVD and 24 control subjects were recruited. The patients were classified into three groups: group A (EVD on the lesion or one side, 17 patients), group B (EVD on the hemisphere opposite to the lesion, 12 patients), and group C (EVD on both sides, 16 patients). Mini-Mental State Examination (MMSE) results were performed at the beginning (average 2.27 months from onset) and end (average 4.19 months from onset) of rehabilitation. Three parts of the PF-TT (dorsolateral PF-TT[DLPF-TT], ventrolateral PF-TT[VLPF-TT], orbitofronto-thalamic tract[OF-TT]) were reconstructed and the fractional anisotropy (FA) and tract volume (TV) measurements were obtained. RESULTS: With the EVD on the stroke-affected side, the values of FA and TV of all three parts of the PF-TTs in three patient groups were lower than those of the control group (p < 0.05). With the EVD on the unaffected side, the FA values of the DLPF-TT in groups B and C and the OF-TT in group C were lower than those of the control group (p < 0.05). There was no difference in initial MMSE score among three patient groups; however, group A had a higher mean follow-up MMSE score than that of groups B and C (p < 0.05). CONCLUSIONS: Patients who underwent EVD of the affected hemisphere showed better results in terms of the PF-TT injury and cognitive outcome than patients who underwent EVD through the unaffected hemisphere or through both hemispheres.

Degeneration of core neural tracts for emotional regulation in a patient with traumatic brain injury: A case report.

RATIONALE: Several brain structures, including the orbital prefrontal cortex, ventrolateral prefrontal cortex, dorsolateral prefrontal cortex, amygdala, and anterior cingulate cortex, are considered key structures in the neural circuitry underlying emotion regulation. We report on a patient showing behavior changes and degeneration of core neural tracts for emotional regulation following traumatic brain injury (TBI). PATIENT CONCERNS: A 51-year-old male patient suffered an in-car accident. The patient lost consciousness for approximately 30 days, and his Glasgow Coma Scale score was 3. He underwent stereotactic drainage for traumatic intraventricular and intracerebral hemorrhages. At approximately 6.5-year after onset, he began to show disinhibition behaviors such as shouting with anger, which worsened over time. At approximately 8-year after onset, he showed severe depression signs and disinhibition, including violence. DIAGNOSES: The patient who showed delayed-onset behavioral changes (disinhibition and depression). INTERVENTIONS: Diffusion tensor imaging data were acquired at 3 months and 8 years after TBI onset. OUTCOMES: The patient showed degeneration of core neural tracts for emotional regulation that was associated with delayed behavioral changes following TBI. On both 3-month and 8-year diffusion tensor tractographies (DTTs), the right dorsolateral prefronto-thalamic tract, ventrolateral prefronto-thalamic tract, orbital prefronto-thalamic tract, uncinate fasciculus, and both cinguli were reconstructed whereas other neural tracts were not reconstructed. Compared with the 3-month DTT, all reconstructed neural tracts on the 8-year DTT were narrow, except for the left cingulum, which showed new transcallosal fibers between both anterior cingula. The fractional anisotropy and tract volume of all reconstructed neural tracts were lower on the 8-year DTT than the 3-month DTT, except for the tract volume of left cingulum. LESSONS: The evaluation of dorsolateral, ventrolateral, and orbital prefronto-thalamic tract, uncinate fasciculus, and cingulum using follow-up DTTs is useful when a patient with TBI shows delayed-onset behavioral problems.

LncRNA HOTAIR Participates in Microglia Activation and Inflammatory Factor Release by Regulating the Ubiquitination of MYD88 in Traumatic Brain Injury.

Traumatic brain injury (TBI) is one of the leading causes of death worldwide. Long non-coding RNAs (LncRNAs) have been reported to be closely associated with various diseases, but their roles in TBI has not been fully elucidated. The purpose of this study was to elucidate the underlying mechanism of LncRNA HOTAIR in TBI-induced microglial activation and inflammatory factor release. In vivo mouse TBI model and in vitro microglia activation model were established by Feeney's free-fall impact method and by LPS stimulation, respectively. The expression of LncRNA HOTAIR in activated microglia was detected by qRT-PCR. After shRNA knocked down, the expressions of LncRNA HOTAIR and microglia activation marker Iba-1 in microglia were detected by qRT-PCR and Western blot and by ELISA that detected the concentration of inflammatory factor in cell culture supernatants. The relationship between LncRNA HOTAIR and MYD88 in mouse microglia BV2 cells was observed by RNA pull-down assay. Furthermore, the effect of LncRNA HOTAIR on MYD88 stability was assessed by cycloheximide (CHX)-chase and by immunoprecipitation and ubiquitination assays that analyzed MYD88 ubiquitination. LncRNA HOTAIR was abnormally highly expressed in activated microglia. By Western blot and ELISA, the knockdown of LncRNA HOTAIR in microglia significantly repressed microglia activation and inflammatory factor release. By RNA pull-down assay, LncRNA HOTAIR could bind to MYD88 protein. Besides, by cycloheximide (CHX)-chase and immunoprecipitation and ubiquitination assays, the overexpression of the LncRNA HOTAIR enhanced the stability of MYD88 protein and inhibited Nrdp1-mediated ubiquitination of MYD88 protein. After the transfection of shRNA-HOTAIR and shRNA-HOTAIR+pcDNA-MYD88 into microglia, shRNA-HOTAIR could significantly inhibit the activation of microglia and the release of inflammatory factors, while these effects were reversed after the transfection of pcDNA-MYD88. Our experimental data indicated that LncRNA HOTAIR was highly expressed in activated microglia, and our further studies had found that the interference with LncRNA HOTAIR could repress microglia activation and inflammatory factor release via promoting Nrdp1-mediated ubiquitination of MYD88 protein.

An asymmetry in past and future mental time travel following vmPFC damage.

The role of ventromedial prefrontal cortex (vmPFC) in mental time travel toward the past and the future is debated. Here, patients with focal lesions to the vmPFC and brain-damaged and healthy controls mentally projected themselves to a past, present or future moment of subjective time (self-projection) and classified a series of events as past or future relative to the adopted temporal self-location (self-reference). We found that vmPFC patients were selectively impaired in projecting themselves to the future and in recognizing relative-future events. These findings indicate that vmPFC damage hinders the mental processing of and movement toward future events, pointing to a prominent, multifaceted role of vmPFC in future-oriented mental time travel.

Relationship between depression and dorsolateral prefronto-thalamic tract injury in patients with mild traumatic brain injury.

The prefrontal lobe has been considered to be closely related to depression. This study examined the relationship between depression and three prefronto-thalamic tract (PF-TT) regions (the dorsolateral prefronto-thalamic tract [DLPF-TT], ventrolateral prefronto-thalamic tract [VLPF-TT], and the orbitofronto-thalamic tract [OF-TT]) in patients with mild traumatic brain injury (TBI), using diffusion tensor tractography (DTT). Thirty-seven patients with depression following mild TBI were recruited based on Beck Depression Inventory-II (BDI-II) scores. Thirty-one normal control subjects were also recruited. The three regions of the PF-TTs were reconstructed using probabilistic tractography and DTT parameters for each of the three PF-TT regions were determined. The tract volume of the DLPF-TT and OF-TT in the patient group showed a significant decrease compared to that of the control group (p < 0.05). The BDI-II score of the patient group showed a moderate negative correlation with the tract volume value of the right (r = - 0.33) and left (r = - 0.41) DLPF-TT (p < 0.05). On the other hand, no significant correlations were detected between the BDI-II score of the patient group and the values of the other DTT parameters values for the three PF-TT regions (p > 0.05). Using DTT, depression was found to be closely related to a DLPF-TT injury in patients with mild TBI. We believe that evaluation of the DLPF-TT using DTT would be helpful when assessing patients with depression following mild TBI. These results can provide useful information regarding the proper application of neuromodulation in the management of depression.

A modeling framework for adaptive lifelong learning with transfer and savings through gating in the prefrontal cortex.

The prefrontal cortex encodes and stores numerous, often disparate, schemas and flexibly switches between them. Recent research on artificial neural networks trained by reinforcement learning has made it possible to model fundamental processes underlying schema encoding and storage. Yet how the brain is able to create new schemas while preserving and utilizing old schemas remains unclear. Here we propose a simple neural network framework that incorporates hierarchical gating to model the prefrontal cortex's ability to flexibly encode and use multiple disparate schemas. We show how gating naturally leads to transfer learning and robust memory savings. We then show how neuropsychological impairments observed in patients with prefrontal damage are mimicked by lesions of our network. Our architecture, which we call DynaMoE, provides a fundamental framework for how the prefrontal cortex may handle the abundance of schemas necessary to navigate the real world.

Revaluing the Role of vmPFC in the Acquisition of Pavlovian Threat Conditioning in Humans.

The role of the ventromedial prefrontal cortex (vmPFC) in human pavlovian threat conditioning has been relegated largely to the extinction or reversal of previously acquired stimulus-outcome associations. However, recent neuroimaging evidence questions this view by also showing activity in the vmPFC during threat acquisition. Here we investigate the casual role of vmPFC in the acquisition of pavlovian threat conditioning by assessing skin conductance response (SCR) and declarative memory of stimulus-outcome contingencies during a differential pavlovian threat-conditioning paradigm in eight patients with a bilateral vmPFC lesion, 10 with a lesion outside PFC and 10 healthy participants (each group included both females and males). Results showed that patients with vmPFC lesion failed to produce a conditioned SCR during threat acquisition, despite no evidence of compromised SCR to unconditioned stimulus or compromised declarative memory for stimulus-outcome contingencies. These results suggest that the vmPFC plays a causal role in the acquisition of new learning and not just in the extinction or reversal of previously acquired learning, as previously thought. Given the role of the vmPFC in schema-related processing and latent structure learning, the vmPFC may be required to construct a detailed representation of the task, which is needed to produce a sustained conditioned physiological response in anticipation of the unconditioned stimulus during threat acquisition.SIGNIFICANCE STATEMENT Pavlovian threat conditioning is an adaptive mechanism through which organisms learn to avoid potential threats, thus increasing their chances of survival. Understanding what brain regions contribute to such a process is crucial to understand the mechanisms underlying adaptive as well as maladaptive learning, and has the potential to inform the treatment of anxiety disorders. Importantly, the role of the ventromedial prefrontal cortex (vmPFC) in the acquisition of pavlovian threat conditioning has been relegated largely to the inhibition of previously acquired learning. Here, we show that the vmPFC actually plays a causal role in the acquisition of pavlovian threat conditioning.

The drift diffusion model as the choice rule in inter-temporal and risky choice: A case study in medial orbitofrontal cortex lesion patients and controls.

Sequential sampling models such as the drift diffusion model (DDM) have a long tradition in research on perceptual decision-making, but mounting evidence suggests that these models can account for response time (RT) distributions that arise during reinforcement learning and value-based decision-making. Building on this previous work, we implemented the DDM as the choice rule in inter-temporal choice (temporal discounting) and risky choice (probability discounting) using hierarchical Bayesian parameter estimation. We validated our approach in data from nine patients with focal lesions to the ventromedial prefrontal cortex / medial orbitofrontal cortex (vmPFC/mOFC) and nineteen age- and education-matched controls. Model comparison revealed that, for both tasks, the data were best accounted for by a variant of the drift diffusion model including a non-linear mapping from value-differences to trial-wise drift rates. Posterior predictive checks confirmed that this model provided a superior account of the relationship between value and RT. We then applied this modeling framework and 1) reproduced our previous results regarding temporal discounting in vmPFC/mOFC patients and 2) showed in a previously unpublished data set on risky choice that vmPFC/mOFC patients exhibit increased risk-taking relative to controls. Analyses of DDM parameters revealed that patients showed substantially increased non-decision times and reduced response caution during risky choice. In contrast, vmPFC/mOFC damage abolished neither scaling nor asymptote of the drift rate. Relatively intact value processing was also confirmed using DDM mixture models, which revealed that in both groups >98% of trials were better accounted for by a DDM with value modulation than by a null model without value modulation. Our results highlight that novel insights can be gained from applying sequential sampling models in studies of inter-temporal and risky decision-making in cognitive neuroscience.

Sign and goal tracker rats process differently the incentive salience of a conditioned stimulus.

Sign and goal tracker animals show different behavioral patterns in response to conditioned stimuli, which may be driven by different neural circuits involved in processing stimuli. Here, we explored whether sign and goal-tracker profiles implicated different brain regions and responses to incentive salience of stimuli. We performed three experiments using male Wistar rats. Experiment 1 showed that lesioning the medial prefrontal cortex increased the prevalence of the goal-tracker phenotype. Experiment 2 assessed the developmental trajectory of the salience incentive attribution to a conditioned stimulus, showing that increased incentive salience of stimuli increased the prevalence of the sign-tracker phenotype in mature, but not preadolescent rats. In experiment 3, the functional impact of the medial prefrontal cortex circuits was analyzed with a latent inhibition procedure. Sign tracker rats showed a reduced latent inhibition to stimuli previously exposed when compared to goal tracker or intermediate rats. The overall results of this study highlight a key role of the medial prefrontal cortex for sign tracking behavior. The expression of sign and goal tracker phenotypes changed after lesion to the medial prefrontal cortex (experiment 1), differed across development (experiment 2), and showed differences in the attentional processes to previously exposed stimuli, as preexposure to CS was ineffective in sign tracker animals (experiment 3). These data indicate that the responses to the incentive salience of stimuli in sign tracker and goal tracker profiles are likely driven by different neural circuitry, with a different role of prefrontal cortical function.

Implicit learning of artificial grammatical structures after inferior frontal cortex lesions.

OBJECTIVE: Previous research associated the left inferior frontal cortex with implicit structure learning. The present study tested patients with lesions encompassing the left inferior frontal gyrus (LIFG; including Brodmann areas 44 and 45) to further investigate this cognitive function, notably by using non-verbal material, implicit investigation methods, and by enhancing potential remaining function via dynamic attending. Patients and healthy matched controls were exposed to an artificial pitch grammar in an implicit learning paradigm to circumvent the potential influence of impaired language processing. METHODS: Patients and healthy controls listened to pitch sequences generated within a finite-state grammar (exposure phase) and then performed a categorization task on new pitch sequences (test phase). Participants were not informed about the underlying grammar in either the exposure phase or the test phase. Furthermore, the pitch structures were presented in a highly regular temporal context as the beneficial impact of temporal regularity (e.g. meter) in learning and perception has been previously reported. Based on the Dynamic Attending Theory (DAT), we hypothesized that a temporally regular context helps developing temporal expectations that, in turn, facilitate event perception, and thus benefit artificial grammar learning. RESULTS: Electroencephalography results suggest preserved artificial grammar learning of pitch structures in patients and healthy controls. For both groups, analyses of event-related potentials revealed a larger early negativity (100-200 msec post-stimulus onset) in response to ungrammatical than grammatical pitch sequence events. CONCLUSIONS: These findings suggest that (i) the LIFG does not play an exclusive role in the implicit learning of artificial pitch grammars, and (ii) the use of non-verbal material and an implicit task reveals cognitive capacities that remain intact despite lesions to the LIFG. These results provide grounds for training and rehabilitation, that is, learning of non-verbal grammars that may impact the relearning of verbal grammars.

Scene processing following damage to the ventromedial prefrontal cortex.

It has been suggested that the mental construction of scene imagery is a core process underpinning functions such as autobiographical memory, future thinking and spatial navigation. Damage to the ventromedial prefrontal cortex in humans can cause deficits in all of these cognitive domains. Moreover, it has also been reported that patients with ventromedial prefrontal cortex lesions are impaired at imagining fictitious scenes, although they seem able to describe specific scenes from autobiographical events. In general, not much is known about how ventromedial prefrontal cortex patients process scenes. Here, we deployed a recently-developed task to provide insights into this issue, which involved detecting either semantic (e.g. an elephant with butterflies for ears) or constructive (e.g. an endless staircase) violations in scene images. Identifying constructive violations typically provokes the formation of internal scene models in healthy control participants. We tested patients with bilateral ventromedial prefrontal cortex damage, brain-damaged control patients and healthy control participants. We found no evidence for statistically significant differences between the groups in detecting either type of violation. These results suggest that an intact ventromedial prefrontal cortex is not necessary for some aspects of scene processing, with implications for understanding its role in functions such as autobiographical memory and future thinking.

Recovery of contralesional saccade choice and reaction time deficits after a unilateral endothelin-1-induced lesion in the macaque caudal prefrontal cortex.

The caudal primate prefrontal cortex (PFC) is involved in target selection and visually guided saccades through both covert attention and overt orienting eye movements. Unilateral damage to the caudal PFC often leads to decreased awareness of a contralesional target alone, referred to as "neglect," or when it is presented simultaneously with an ipsilesional target, referred to as "extinction." In the current study, we examined whether deficits in contralesional target selection were due to contralesional oculomotor deficits, such as slower reaction times. We experimentally induced a focal ischemic lesion in the right caudal PFC of 4 male macaque monkeys using the vasoconstrictor endothelin-1 and measured saccade choice and reaction times on double-stimulus free-choice tasks and single-stimulus trials before and after the lesion. We found that 1) endothelin-1-induced lesions in the caudal PFC produced contralesional target selection deficits that varied in severity and duration based on lesion volume and location; 2) contralesional neglect-like deficits were transient and recovered by week 4 postlesion; 3) contralesional extinction-like deficits were longer lasting and recovered by weeks 8-16 postlesion; 4) contralesional reaction time returned to baseline well before the contralesional choice deficit had recovered; and 5) neither the mean reaction times nor the reaction time distributions could account for the degree of contralesional extinction on the free-choice task throughout recovery. These findings demonstrate that the saccade choice bias observed after a right caudal PFC lesion is not exclusively due to contralesional motor deficits, but instead reflects a combination of impaired motor and attentional processing.NEW & NOTEWORTHY Unilateral damage to the caudal prefrontal cortex in macaque monkeys results in impaired contralesional target selection during the simultaneous presentation of an ipsilesional target. We show that the recovery of contralesional target selection cannot be explained by the recovery of prolonged contralesional saccadic reaction times alone. This indicates that an impairment in contralesional attentional processing contributes to the magnitude of the saccade choice bias in the weeks following a unilateral caudal prefrontal cortex lesion.

Conscious perception in patients with prefrontal damage.

We are conscious and verbally report some of the information reaching our senses, although a big amount of information is processed unconsciously. There is no agreement about the neural correlates of consciousness, with low-level theories proposing that neural processing on primary sensory brain regions is the most important neural correlate of consciousness, while high-level theories propose that activity within the fronto-parietal network is the key component of conscious processing (Block, 2009). Contrary to the proposal of high-level theories, patients with prefrontal lobe damage do not present clinical symptoms associated to consciousness deficits. In the present study, we explored the conscious perception of near-threshold stimuli in a group of patients with right prefrontal damage and a group of matched healthy controls. Results demonstrated that perceptual contrast to perceive the near-threshold targets was related to damage to the right dorsolateral prefrontal cortex, and with reduced integrity of the ventral branch of the right superior longitudinal fascicule (SLF III). These results suggest a causal role of the prefrontal lobe in conscious processing.

Impaired Interneuron Development in a Novel Model of Neonatal Brain Injury.

Prematurity is associated with significantly increased risk of neurobehavioral pathologies, including autism and schizophrenia. A common feature of these psychiatric disorders is prefrontal cortex (PFC) inhibitory circuit disruption due to GABAergic interneuron alteration. Cortical interneurons are generated and migrate throughout late gestation and early infancy, making them highly susceptible to perinatal insults such as preterm birth. Term and preterm PFC pathology specimens were assessed using immunohistochemical markers for interneurons. Based on the changes seen, a new preterm encephalopathy mouse model was developed to produce similar PFC interneuron loss. Maternal immune activation (MIA; modeling chorioamnionitis, associated with 85% of extremely preterm births) was combined with chronic sublethal hypoxia (CSH; modeling preterm respiratory failure), with offspring of both sexes assessed anatomically, molecularly and neurobehaviorally. In the PFC examined from the human preterm samples compared to matched term samples at corrected age, a decrease in somatostatin (SST) and calbindin (CLB) interneurons was seen in upper cortical layers. This pattern of interneuron loss in upper cortical layers was mimicked in the mouse PFC following the combination of MIA and CSH, but not after either insult alone. This persistent interneuron loss is associated with postnatal microglial activation that occurs during CSH only after MIA. The combined insults lead to long-term neurobehavioral deficits which parallel human psychopathologies that may be seen after extremely preterm birth. This new preclinical model supports a paradigm in which specific cellular alterations seen in preterm encephalopathy can be linked with a risk of neuropsychiatric sequela. Specific interneuron subtypes may provide therapeutic targets to prevent or ameliorate these neurodevelopmental risks.

Damage to the right temporoparietal junction, but not lateral prefrontal or insular cortex, amplifies the role of goal-directed attention.

Whether an object captures attention depends on the interplay between its saliency and current behavioral predispositions of the observer. Neuroimaging work has implied a ventral attention network, comprising the temporoparietal junction (TPJ), lateral prefrontal cortex (lPFC) and the insula, in attentional orienting toward salient events. Activity of the TPJ is driven by novel and unexpected objects, while the lateral prefrontal cortex is involved in stimulus-driven as well as goal-directed processing. The insula in turn, is part of a saliency network, which has been implicated in detecting biologically salient signals. These roles predict that damage to the TPJ, lPFC, or insula should affect performance in tasks measuring the capture of attention by salient and behaviorally relevant events. Here, we show that patients with lesions to the right TPJ have a characteristic increase of attentional capture by relevant distracters. In contrast, damage to the lPFC or insular cortex only increases reaction times, irrespective of the task-relevant properties of distracters. These findings show that acquired damage to the TPJ pathologically amplifies the capture of attention by task-relevant information, and thus indicate that the TPJ has a decisive role in goal-directed orienting.

Heavy metals obtained from waterways induced neurodegeneration in the prefrontal cortex of Wistar rats

The level of heavy metals in Nigeria waterways is grossly influenced by the irrepressible disposal and recycling of electronic waste. The impact of heavy metals obtained from waterways on the prefrontal cortex of experimental rats was investigated in this study. Thirty (30) adult male Wistar rats weighing about 150-180 g were used in this study. Ten rats apiece were assigned randomly into three groups. Pooled sampled water and water containing the highest average concentration of combined heavy metals recorded in the waterways was given to the Wistar rats within the treatment groups ad libitum for 65 days. Blood sera were obtained for analysis of oxidative stress markers. The prefrontal cortex was processed for paraffin embedding, and sections stained for histological, histochemical and immunochemical evaluations. P < 0.05 was regarded as significant for data using one-way analysis of variance. Oxidative damage was observed in animals from the treatment groups when compared to the control. The analysed levels of oxidative stress markers showed statistically significant differences, except between groups given pooled sampled water and combined metals. Neurodegeneration was attested from the histological and histochemical evaluations, and the immunohistochemical evaluation revealed marked astrocytosis with induced oxidative stress while comparing the experimental groups

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Relationships between executive function, working memory, and decision-making on the Iowa Gambling Task: Evidence from ventromedial patients, dorsolateral patients, and normal subjects.

The results of previous studies are inconsistent in regard to the relationship between the Iowa Gambling Task (IGT), working-memory (WM), and executive tasks, and whether these cognitive processes could be considered as mechanisms underlying a decision-making deficit. Moreover, the relationship between the IGT and executive measures is examined based on a limited number of executive tasks, within different populations showing diffuse damage. In addition, there are fewer studies carried out within control participants, with those studies also being inconclusive. It is also suggested that the association of the IGT performance with executive tasks depends on whether the IGT was running under ambiguity or under risk. In this work, all of these issues are studied. Results showed that both patients with ventromedial (VMPFC, N = 10) and dorsolateral (DLPFC, N = 10) prefrontal cortex lesions are significantly impaired on almost all executive tasks, WM tasks, and the IGT. Furthermore, when the IGT is run under risk, there are significant correlations between executive measures and the IGT for the DLPFC patients and the control participants (N = 34) but not the VMPFC patients. No correlation was found between WM tasks and the IGT for both frontal subgroups and control participants. These findings suggested that the mechanisms underlying the IGT deficit differ according to the lesion locations.