The lateral and ventromedial prefrontal cortex work as a dynamic integrated system:evidence from FMRI connectivity analysis

Recent functional magnetic resonance imaging (fMRI) investigations of the interaction between cognition and reward processing have found that the lateral prefrontal cortex (PFC) areas are preferentially activated to both increasing cognitive demand and reward level. Conversely, ventromedial PFC (VMPFC) areas show decreased activation to the same conditions, indicating a possible reciprocal relationship between cognitive and emotional processing regions. We report an fMRI study of a rewarded working memory task, in which we further explore how the relationship between reward and cognitive processing is mediated. We not only assess the integrity of reciprocal neural connections between the lateral PFC and VMPFC brain regions in different experimental contexts but also test whether additional cortical and subcortical regions influence this relationship. Psychophysiological interaction analyses were used as a measure of functional connectivity in order to characterize the influence of both cognitive and motivational variables on connectivity between the lateral PFC and the VMPFC. Psychophysiological interactions revealed negative functional connectivity between the lateral PFC and the VMPFC in the context of high memory load, and high memory load in tandem with a highly motivating context, but not in the context of reward alone. Physiophysiological interactions further indicated that the dorsal anterior cingulate and the caudate nucleus modulate this pathway. These findings provide evidence for a dynamic interplay between lateral PFC and VMPFC regions and are consistent with an emotional gating role for the VMPFC during cognitively demanding tasks. Our findings also support neuropsychological theories of mood disorders, which have long emphasized a dysfunctional relationship between emotion/motivational and cognitive processes in depression.

Simultaneous estimation of global background synaptic inhibition and excitation from membrane potential fluctuations in layer III neurons of the rat entorhinal cortex in vitro

It is becoming clear that the detection and integration of synaptic input and its conversion into an output signal in cortical neurons are strongly influenced by background synaptic activity or "noise." The majority of this noise results from the spontaneous release of synaptic transmitters, interacting with ligand-gated ion channels in the postsynaptic neuron [Berretta N, Jones RSG (1996); A comparison of spontaneous synaptic EPSCs in layer V and layer II neurones in the rat entorhinal cortex in vitro. J Neurophysiol 76:1089-1110; Jones RSG, Woodhall GL (2005) Background synaptic activity in rat entorhinal cortical neurons: differential control of transmitter release by presynaptic receptors. J Physiol 562:107-120; LoTurco JJ, Mody I, Kriegstein AR (1990) Differential activation of glutamate receptors by spontaneously released transmitter in slices of neocortex. Neurosci Lett 114:265-271; Otis TS, Staley KJ, Mody I (1991) Perpetual inhibitory activity in mammalian brain slices generated by spontaneous GABA release. Brain Res 545:142-150; Ropert N, Miles R, Korn H (1990) Characteristics of miniature inhibitory postsynaptic currents in CA1 pyramidal neurones of rat hippocampus. J Physiol 428:707-722; Salin PA, Prince DA (1996) Spontaneous GABAA receptor-mediated inhibitory currents in adult rat somatosensory cortex. J Neurophysiol 75:1573-1588; Staley KJ (1999) Quantal GABA release: noise or not? Nat Neurosci 2:494-495; Woodhall GL, Bailey SJ, Thompson SE, Evans DIP, Stacey AE, Jones RSG (2005) Fundamental differences in spontaneous synaptic inhibition between deep and superficial layers of the rat entorhinal cortex. Hippocampus 15:232-245]. The function of synaptic noise has been the subject of debate for some years, but there is increasing evidence that it modifies or controls neuronal excitability and, thus, the integrative properties of cortical neurons. In the present study we have investigated a novel approach [Rudolph M, Piwkowska Z, Badoual M, Bal T, Destexhe A (2004) A method to estimate synaptic conductances from membrane potential fluctuations. J Neurophysiol 91:2884-2896] to simultaneously quantify synaptic inhibitory and excitatory synaptic noise, together with postsynaptic excitability, in rat entorhinal cortical neurons in vitro. The results suggest that this is a viable and useful approach to the study of the function of synaptic noise in cortical networks. © 2007 IBRO.

Ethosuximide modifies network excitability in the rat entorhinal cortex via an increase in GABA release

Ethosuximide is the drug of choice for treating generalized absence seizures, but its mechanism of action is still a matter of debate. It has long been thought to act by disrupting a thalamic focus via blockade of T-type channels and, thus, generation of spike-wave activity in thalamocortical pathways. However, there is now good evidence that generalized absence seizures may be initiated at a cortical focus and that ethosuximide may target this focus. In the present study we have looked at the effect ethosuximide on glutamate and GABA release at synapses in the rat entorhinal cortex in vitro, using two experimental approaches. Whole-cell patch-clamp studies revealed an increase in spontaneous GABA release by ethosuximide concurrent with no change in glutamate release. This was reflected in studies that estimated global background inhibition and excitation from intracellularly recorded membrane potential fluctuations, where there was a substantial rise in the ratio of network inhibition to excitation, and a concurrent decrease in excitability of neurones embedded in this network. These studies suggest that, in addition to well-characterised effects on ion channels, ethosuximide may directly elevate synaptic inhibition in the cortex and that this could contribute to its anti-absence effects. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

Reduced gray matter volume in ventral prefrontal cortex but not amygdala in bipolar disorder:significant effects of gender and trait anxiety

Neuroimaging studies in bipolar disorder report gray matter volume (GMV) abnormalities in neural regions implicated in emotion regulation. This includes a reduction in ventral/orbital medial prefrontal cortex (OMPFC) GMV and, inconsistently, increases in amygdala GMV. We aimed to examine OMPFC and amygdala GMV in bipolar disorder type 1 patients (BPI) versus healthy control participants (HC), and the potential confounding effects of gender, clinical and illness history variables and psychotropic medication upon any group differences that were demonstrated in OMPFC and amygdala GMV. Images were acquired from 27 BPI (17 euthymic, 10 depressed) and 28 age- and gender-matched HC in a 3T Siemens scanner. Data were analyzed with SPM5 using voxel-based morphometry (VBM) to assess main effects of diagnostic group and gender upon whole brain (WB) GMV. Post-hoc analyses were subsequently performed using SPSS to examine the extent to which clinical and illness history variables and psychotropic medication contributed to GMV abnormalities in BPI in a priori and non-a priori regions has demonstrated by the above VBM analyses. BPI showed reduced GMV in bilateral posteromedial rectal gyrus (PMRG), but no abnormalities in amygdala GMV. BPI also showed reduced GMV in two non-a priori regions: left parahippocampal gyrus and left putamen. For left PMRG GMV, there was a significant group by gender by trait anxiety interaction. GMV was significantly reduced in male low-trait anxiety BPI versus male low-trait anxiety HC, and in high- versus low-trait anxiety male BPI. Our results show that in BPI there were significant effects of gender and trait-anxiety, with male BPI and those high in trait-anxiety showing reduced left PMRG GMV. PMRG is part of medial prefrontal network implicated in visceromotor and emotion regulation.

Mobility of NMDA autoreceptors but not postsynaptic receptors at glutamate synapses in the rat entorhinal cortex

NMDA receptors (NMDAr) are known to undergo recycling and lateral diffusion in postsynaptic spines and dendrites. However, NMDAr are also present as autoreceptors on glutamate terminals, where they act to facilitate glutamate release, but it is not known whether these receptors are also mobile. We have used functional pharmacological approaches to examine whether NMDA receptors at excitatory synapses in the rat entorhinal cortex are mobile at either postsynaptic sites or in presynaptic terminals. When NMDAr-mediated evoked EPSCs (eEPSCs) were blocked by MK-801, they showed no evidence of recovery when the irreversible blocker was removed, suggesting that postsynaptic NMDAr were relatively stably anchored at these synapses. However, using frequency-dependent facilitation of AMPA receptor (AMPAr)-mediated eEPSCs as a reporter of presynaptic NMDAr activity, we found that when facilitation was blocked with MK-801 there was a rapid (similar to 30-40 min) anomalous recovery upon removal of the antagonist. This was not observed when global NMDAr blockade was induced by combined perfusion with MK-801 and NMDA. Anomalous recovery was accompanied by an increase in frequency of spontaneous EPSCs, and a variable increase in frequency-facilitation. Following recovery from blockade of presynaptic NMDAr with a competitive antagonist, frequency-dependent facilitation of AMPAr-mediated eEPSCs was also transiently enhanced. Finally, an increase in frequency of miniature EPSCs induced by NMDA was succeeded by a persistent decrease. Our data provide the first evidence for mobility of NMDAr in the presynaptic terminals, and may point to a role of this process in activity-dependent control of glutamate release.

Childhood abuse is associated with structural impairment in the ventrolateral prefrontal cortex and aggressiveness in patients with borderline personality disorder

Volume reduction and functional impairment in areas of the prefrontal cortex (PFC) have been found in borderline personality disorder (BPD), particularly in patients with a history of childhood abuse. These abnormalities may contribute to the expression of emotion dysregulation and aggressiveness. In this study we investigated whether the volume of the PFC is reduced in BPD patients and whether a history of childhood abuse would be associated with greater PFC structural changes. Structural MRI data were obtained from 18 BPD patients and 19 healthy individuals matched for age, sex, handedness, and education and were analyzed using voxel based morphometry. The Child Abuse Scale was used to elicit a past history of abuse; aggression was evaluated using the Buss-Durkee Hostility Inventory (BDHI). The volume of the right ventrolateral PFC (VLPFC) was significantly reduced in BPD subjects with a history of childhood abuse compared to those without this risk factor. Additionally, right VLPFC gray matter volume significantly correlated with the BDHI total score and with BDHI irritability and negativism subscale scores in patients with a history of childhood abuse. Our results suggest that a history of childhood abuse may lead to increased aggression mediated by an impairment of the right VLPFC. © 2013 Elsevier Ireland Ltd.

Disturbing visual working memory:electrophysiological evidence for a role of the prefrontal cortex in recovery from interference

Single cell recordings in monkeys support the notion that the lateral prefrontal cortex (PFC) controls reactivation of visual working memory representations when rehearsal is disrupted. In contrast, recent fMRI findings yielded a double dissociation for PFC and the medial temporal lobe (MTL) in a letter working memory task. PFC was engaged in interference protection during reactivation while MTL was prominently involved in the retrieval of the letter representations. We present event-related potential data (ERP) that support PFC involvement in the top-down control of reactivation during a visual working memory task with endogenously triggered recovery after visual interference. A differentiating view is proposed for the role of PFC in working memory with respect to endogenous/exogenous control and to stimulus type. General implications for binding and retention mechanisms are discussed.

Astroglial d-serine is the endogenous co-agonist at the presynaptic NMDA receptor in rat entorhinal cortex

Presynaptic NMDA receptors facilitate the release of glutamate at excitatory cortical synapses and are involved in regulation of synaptic dynamics and plasticity. At synapses in the entorhinal cortex these receptors are tonically activated and provide a positive feedback modulation of the level of background excitation. NMDA receptor activation requires obligatory occupation of a co-agonist binding site, and in the present investigation we have examined whether this site on the presynaptic receptor is activated by endogenous glycine or d-serine. We used whole-cell patch clamp recordings of spontaneous AMPA receptor-mediated synaptic currents from rat entorhinal cortex neurones in vitro as a monitor of presynaptic glutamate release. Addition of exogenous glycine or d-serine had minimal effects on spontaneous release, suggesting that the co-agonist site was endogenously activated and likely to be saturated in our slices. This was supported by the observation that a co-agonist site antagonist reduced the frequency of spontaneous currents. Depletion of endogenous glycine by enzymatic breakdown with a bacterial glycine oxidase had little effect on glutamate release, whereas d-serine depletion with a yeast d-amino acid oxidase significantly reduced glutamate release, suggesting that d-serine is the endogenous agonist. Finally, the effects of d-serine depletion were mimicked by compromising astroglial cell function, and this was rescued by exogenous d-serine, indicating that astroglial cells are the provider of the d-serine that tonically activates the presynaptic NMDA receptor. We discuss the significance of these observations for the aetiology of epilepsy and possible targeting of the presynaptic NMDA receptor in anticonvulsant therapy. © 2014 Elsevier Ltd. All rights reserved.

Background synaptic activity in rat entorhinal cortex shows a progressively greater dominance of inhibition over excitation from deep to superficial layers

The entorhinal cortex (EC) controls hippocampal input and output, playing major roles in memory and spatial navigation. Different layers of the EC subserve different functions and a number of studies have compared properties of neurones across layers. We have studied synaptic inhibition and excitation in EC neurones, and we have previously compared spontaneous synaptic release of glutamate and GABA using patch clamp recordings of synaptic currents in principal neurones of layers II (L2) and V (L5). Here, we add comparative studies in layer III (L3). Such studies essentially look at neuronal activity from a presynaptic viewpoint. To correlate this with the postsynaptic consequences of spontaneous transmitter release, we have determined global postsynaptic conductances mediated by the two transmitters, using a method to estimate conductances from membrane potential fluctuations. We have previously presented some of this data for L3 and now extend to L2 and L5. Inhibition dominates excitation in all layers but the ratio follows a clear rank order (highest to lowest) of L2>L3>L5. The variance of the background conductances was markedly higher for excitation and inhibition in L2 compared to L3 or L5. We also show that induction of synchronized network epileptiform activity by blockade of GABA inhibition reveals a relative reluctance of L2 to participate in such activity. This was associated with maintenance of a dominant background inhibition in L2, whereas in L3 and L5 the absolute level of inhibition fell below that of excitation, coincident with the appearance of synchronized discharges. Further experiments identified potential roles for competition for bicuculline by ambient GABA at the GABAA receptor, and strychnine-sensitive glycine receptors in residual inhibition in L2. We discuss our results in terms of control of excitability in neuronal subpopulations of EC neurones and what these may suggest for their functional roles. © 2014 Greenhill et al.

Diverse antiepileptic drugs increase the ratio of background synaptic inhibition to excitation and decrease neuronal excitability in neurones of the rat entorhinal cortex in vitro

Although most anti-epileptic drugs are considered to have a primary molecular target, it is clear that their actions are unlikely to be limited to effects on a single aspect of inhibitory synaptic transmission, excitatory transmission or voltage-gated ion channels. Systemically administered drugs can obviously simultaneously access all possible targets, so we have attempted to determine the overall effect of diverse agents on the balance between GABAergic inhibition, glutamatergic excitation and cellular excitability in neurones of the rat entorhinal cortex in vitro. We used an approach developed for estimating global background synaptic excitation and inhibition from fluctuations in membrane potential obtained by intracellular recordings. We have previously validated this approach in entorhinal cortical neurones [. Greenhill and Jones (2007a) Neuroscience 147:884-892]. Using this approach, we found that, despite their differing pharmacology, the drugs tested (phenytoin, lamotrigine, valproate, gabapentin, felbamate, tiagabine) were unified in their ability to increase the ratio of background GABAergic inhibition to glutamatergic excitation. This could occur as a result of decreased excitation concurrent with increased inhibition (phenytoin, lamotrigine, valproate), a decrease in excitation alone (gabapentin, felbamate), or even with a differential increase in both (tiagabine). Additionally, we found that the effects on global synaptic conductances agreed well with whole cell patch recordings of spontaneous glutamate and GABA release (our previous studies and further data presented here). The consistency with which the synaptic inhibition:excitation ratio was increased by the antiepileptic drugs tested was matched by an ability of all drugs to concurrently reduce intrinsic neuronal excitability. Thus, it seems possible that specific molecular targets among antiepileptic drugs are less important than the ability to increase the inhibition:excitation ratio and reduce overall neuronal and network excitability. © 2010 IBRO.

Resting state morphology predicts the effect of theta burst stimulation in false belief reasoning:ventrolateral prefrontal cortex in false belief reasoning

When required to represent a perspective that conflicts with one's own, functional magnetic resonance imaging (fMRI) suggests that the right ventrolateral prefrontal cortex (rvlPFC) supports the inhibition of that conflicting self-perspective. The present task dissociated inhibition of self-perspective from other executive control processes by contrasting belief reasoning-a cognitive state where the presence of conflicting perspectives was manipulated-with a conative desire state wherein no systematic conflict existed. Linear modeling was used to examine the effect of continuous theta burst stimulation (cTBS) to rvlPFC on participants' reaction times in belief and desire reasoning. It was anticipated that cTBS applied to rvlPFC would affect belief but not desire reasoning, by modulating activity in the Ventral Attention System (VAS). We further anticipated that this effect would be mediated by functional connectivity within this network, which was identified using resting state fMRI and an unbiased model-free approach. Simple reaction-time analysis failed to detect an effect of cTBS. However, by additionally modeling individual measures from within the stimulated network, the hypothesized effect of cTBS to belief (but, importantly, not desire) reasoning was demonstrated. Structural morphology within the stimulated region, rvlPFC, and right temporoparietal junction were demonstrated to underlie this effect. These data provide evidence that inconsistencies found with cTBS can be mediated by the composition of the functional network that is being stimulated. We suggest that the common claim that this network constitutes the VAS explains the effect of cTBS to this network on false belief reasoning. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.

Representation, control, or reasoning? Distinct functions for theory of mind within the medial prefrontal cortex

The medial pFC (mPFC) is frequently reported to play a central role in Theory of Mind (ToM). However, the contribution of this large cortical region in ToM is not well understood. Combining a novel behavioral task with fMRI, we sought to demonstrate functional divisions between dorsal and rostral mPFC. All conditions of the task required the representation of mental states (beliefs and desires). The level of demands on cognitive control (high vs. low) and the nature of the demands on reasoning (deductive vs. abductive) were varied orthogonally between conditions. Activation in dorsal mPFC was modulated by the need for control, whereas rostral mPFC was modulated by reasoning demands. These findings fit with previously suggested domain-general functions for different parts of mPFC and suggest that these functions are recruited selectively in the service of ToM.

Abnormal amygdala-prefrontal effective connectivity to happy faces differentiates bipolar from major depression

Background - Bipolar disorder is frequently misdiagnosed as major depressive disorder, delaying appropriate treatment and worsening outcome for many bipolar individuals. Emotion dysregulation is a core feature of bipolar disorder. Measures of dysfunction in neural systems supporting emotion regulation might therefore help discriminate bipolar from major depressive disorder. Methods - Thirty-one depressed individuals—15 bipolar depressed (BD) and 16 major depressed (MDD), DSM-IV diagnostic criteria, ages 18–55 years, matched for age, age of illness onset, illness duration, and depression severity—and 16 age- and gender-matched healthy control subjects performed two event-related paradigms: labeling the emotional intensity of happy and sad faces, respectively. We employed dynamic causal modeling to examine significant among-group alterations in effective connectivity (EC) between right- and left-sided neural regions supporting emotion regulation: amygdala and orbitomedial prefrontal cortex (OMPFC). Results - During classification of happy faces, we found profound and asymmetrical differences in EC between the OMPFC and amygdala. Left-sided differences involved top-down connections and discriminated between depressed and control subjects. Furthermore, greater medication load was associated with an amelioration of this abnormal top-down EC. Conversely, on the right side the abnormality was in bottom-up EC that was specific to bipolar disorder. These effects replicated when we considered only female subjects. Conclusions - Abnormal, left-sided, top-down OMPFC–amygdala and right-sided, bottom-up, amygdala–OMPFC EC during happy labeling distinguish BD and MDD, suggesting different pathophysiological mechanisms associated with the two types of depression.

Abnormally increased effective connectivity between parahippocampal gyrus and ventromedial prefrontal regions during emotion labeling in bipolar disorder

Emotional liability and mood dysregulation characterize bipolar disorder (BD), yet no study has examined effective connectivity between parahippocampal gyrus and prefrontal cortical regions in ventromedial and dorsal/lateral neural systems subserving mood regulation in BD. Participants comprised 46 individuals (age range: 18-56 years): 21 with a DSM-IV diagnosis of BD, type I currently remitted; and 25 age- and gender-matched healthy controls (HC). Participants performed an event-related functional magnetic resonance imaging paradigm, viewing mild and intense happy and neutral faces. We employed dynamic causal modeling (DCM) to identify significant alterations in effective connectivity between BD and HC. Bayes model selection was used to determine the best model. The right parahippocampal gyrus (PHG) and right subgenual cingulate gyrus (sgCG) were included as representative regions of the ventromedial neural system. The right dorsolateral prefrontal cortex (DLPFC) region was included as representative of the dorsal/lateral neural system. Right PHG-sgCG effective connectivity was significantly greater in BD than HC, reflecting more rapid, forward PHG-sgCG signaling in BD than HC. There was no between-group difference in sgCG-DLPFC effective connectivity. In BD, abnormally increased right PHG-sgCG effective connectivity and reduced right PHG activity to emotional stimuli suggest a dysfunctional ventromedial neural system implicated in early stimulus appraisal, encoding and automatic regulation of emotion that may represent a pathophysiological functional neural mechanism for mood dysregulation in BD.

Elevated left and reduced right orbitomedial prefrontal fractional anisotropy in adults with bipolar disorder revealed by tract-based spatial statistics

Context - Diffusion tensor imaging (DTI) studies in adults with bipolar disorder (BD) indicate altered white matter (WM) in the orbitomedial prefrontal cortex (OMPFC), potentially underlying abnormal prefrontal corticolimbic connectivity and mood dysregulation in BD. Objective - To use tract-based spatial statistics (TBSS) to examine WM skeleton (ie, the most compact whole-brain WM) in subjects with BD vs healthy control subjects. Design - Cross-sectional, case-control, whole-brain DTI using TBSS. Setting - University research institute. Participants - Fifty-six individuals, 31 having a DSM-IV diagnosis of BD type I (mean age, 35.9 years [age range, 24-52 years]) and 25 controls (mean age, 29.5 years [age range, 19-52 years]). Main Outcome Measures - Fractional anisotropy (FA) longitudinal and radial diffusivities in subjects with BD vs controls (covarying for age) and their relationships with clinical and demographic variables. Results - Subjects with BD vs controls had significantly greater FA (t > 3.0, P = .05 corrected) in the left uncinate fasciculus (reduced radial diffusivity distally and increased longitudinal diffusivity centrally), left optic radiation (increased longitudinal diffusivity), and right anterothalamic radiation (no significant diffusivity change). Subjects with BD vs controls had significantly reduced FA (t > 3.0, P = .05 corrected) in the right uncinate fasciculus (greater radial diffusivity). Among subjects with BD, significant negative correlations (P < .01) were found between age and FA in bilateral uncinate fasciculi and in the right anterothalamic radiation, as well as between medication load and FA in the left optic radiation. Decreased FA (P < .01) was observed in the left optic radiation and in the right anterothalamic radiation among subjects with BD taking vs those not taking mood stabilizers, as well as in the left optic radiation among depressed vs remitted subjects with BD. Subjects having BD with vs without lifetime alcohol or other drug abuse had significantly decreased FA in the left uncinate fasciculus. Conclusions - To our knowledge, this is the first study to use TBSS to examine WM in subjects with BD. Subjects with BD vs controls showed greater WM FA in the left OMPFC that diminished with age and with alcohol or other drug abuse, as well as reduced WM FA in the right OMPFC. Mood stabilizers and depressed episode reduced WM FA in left-sided sensory visual processing regions among subjects with BD. Abnormal right vs left asymmetry in FA in OMPFC WM among subjects with BD, likely reflecting increased proportions of left-sided longitudinally aligned and right-sided obliquely aligned myelinated fibers, may represent a biologic mechanism for mood dysregulation in BD.