Bilateral mPFC Research Articles

Risk profiles for heavy drinking in adolescence: differential effects of gender.

Abnormalities across different domains of neuropsychological functioning may constitute a risk factor for heavy drinking during adolescence and for developing alcohol use disorders later in life. However, the exact nature of such multi-domain risk profiles is unclear, and it is further unclear whether these risk profiles differ between genders. We combined longitudinal and cross-sectional analyses on the large IMAGEN sample (N≈1000) to predict heavy drinking at age 19 from gray matter volume as well as from psychosocial data at age 14 and 19-for males and females separately. Heavy drinking was associated with reduced gray matter volume in 19-year-olds' bilateral ACC, MPFC, thalamus, middle, medial and superior OFC as well as left amygdala and anterior insula and right inferior OFC. Notably, this lower gray matter volume associated with heavy drinking was stronger in females than in males. In both genders, we observed that impulsivity and facets of novelty seeking at the age of 14 and 19, as well as hopelessness at the age of 14, are risk factors for heavy drinking at the age of 19. Stressful life events with internal (but not external) locus of control were associated with heavy drinking only at age 19. Personality and stress assessment in adolescents may help to better target counseling and prevention programs. This might reduce heavy drinking in adolescents and hence reduce the risk of early brain atrophy, especially in females. In turn, this could additionally reduce the risk of developing alcohol use disorders later in adulthood.

Structural and functional connectivity in children and adolescents with and without attention deficit/hyperactivity disorder.

Attention deficit/hyperactivity disorder (ADHD) has frequently been associated with changes in resting-state functional connectivity, and decreased white matter (WM) integrity. In the current study, we investigated functional connectivity within Default Mode and frontal control resting-state networks (RSNs) in children with and without ADHD. We hypothesized the RSNs of interest would show a pattern of impaired functional integration and segregation and corresponding changes in WM structure. Resting-state fMRI and diffusion-weighted imaging data were acquired from 35 participants with ADHD and 36 matched typically developing peers, aged 6 through 18years. Functional connectivity was assessed using independent component analysis. Network topology and WM connectivity were further investigated using graph theoretical measures and tract-based spatial statistics (TBSS). Resting-state fMRI analyses showed increased functional connectivity in right inferior frontal gyrus (IFG), and bilateral medial prefrontal cortex (mPFC) within the Default Mode and frontal control networks. Furthermore, a more diffuse spatial pattern of functional connectivity was found in children with ADHD. We found no group differences in structural connectivity as assessed with TBSS or graph theoretical measures. Resting-state networks show a more diffuse pattern of connectivity in children with ADHD. The increases in functional connectivity in right IFG and bilateral mPFC in children with ADHD may reflect reduced or delayed functional segregation of prefrontal brain regions. As these functional changes were not accompanied by changes in WM, they may precede the development of the frequently reported changes in WM structure.

Ethanol Increases Mechanical Pain Sensitivity in Rats via Activation of GABAA Receptors in Medial Prefrontal Cortex.

Ethanol is widely known for its ability to cause dramatic changes in emotion, social cognition, and behavior following systemic administration in humans. Human neuroimaging studies suggest that alcohol dependence and chronic pain may share common mechanisms through amygdala-medial prefrontal cortex (mPFC) interactions. However, whether acute administration of ethanol in the mPFC can modulate pain perception is unknown. Here we showed that bilateral microinjections of ethanol into the prelimbic and infralimbic areas of the mPFC lowered the bilateral mechanical pain threshold for 48h without influencing thermal pain sensitivity in adult rats. However, bilateral microinjections of artificial cerebrospinal fluid into the mPFC or bilateral microinjections of ethanol into the dorsolateral PFC (also termed as motor cortex area 1 in Paxinos and Watson's atlas of The Rat Brain. Elsevier Academic Press, Amsterdam, 2005) failed to do so, suggesting regional selectivity of the effects of ethanol. Moreover, bilateral microinjections of ethanol did not change the expression of either pro-apoptotic (caspase-3 and Bax) or anti-apoptotic (Bcl-2) proteins, suggesting that the dose was safe and validating the method used in the current study. To determine whether γ-aminobutyric acid A (GABAA) receptors are involved in mediating the ethanol effects, muscimol, a selective GABAA receptor agonist, or bicuculline, a selective GABAA receptor antagonist, was administered alone or co-administered with ethanol through the same route into the bilateral mPFC. The results showed that muscimol mimicked the effects of ethanol while bicuculline completely reversed the effects of ethanol and muscimol. In conclusion, ethanol increases mechanical pain sensitivity through activation of GABAA receptors in the mPFC of rats.

Differential contributions of hippocampus and medial prefrontal cortex to self-projection and self-referential processing

Converging evidence points to a neural network that supports a range of abilities including remembering the past, thinking about the future, and introspecting about oneself and others. Neuroimaging studies find hippocampal activation during event construction tasks, and patients with hippocampal amnesia are impaired in their ability to (re)construct events of the past and the future. Neuroimaging studies of constructed experiences similarly implicate the medial prefrontal cortex (mPFC), but it remains unknown whether the mPFC is critical for such processes. The current study compares performance of five patients with bilateral mPFC damage, six patients with bilateral hippocampal damage, and demographically matched comparison participants on an event construction task. Participants were given a neutral cue word and asked to (re)construct events across four time conditions: real past, imagined past, imagined present, and future. These event narratives were analyzed for the number of internal and external details to quantify the extent of episodic (re)experiencing. Given the literature on the involvement of the mPFC in self-referential processing, we also analyzed the event narratives for self-references. The patients with mPFC damage did not differ from healthy comparison participants in their ability to construct highly detailed episodic events across time periods but displayed disruptions in their incorporation of the self. Patients with hippocampal damage showed the opposite pattern; they were impaired in their ability to construct highly detailed episodic events across time periods but not in their incorporation of the self. The results suggest differential contributions of hippocampus and medial prefrontal cortex to the distributed neural network for various forms of self-projection.

Increased cerebellar-default-mode-network connectivity in drug-naive major depressive disorder at rest.

The default-mode network (DMN) has been implicated in the neurobiology of major depressive disorder (MDD), and the cerebellum is suggested to be involved in high-order cognitive network such as the DMN. However, the specific contribution of the cerebellum to the DMN alterations remains equivocal. This study was conducted to examine the cerebellar-DMN connectivity in drug-naive MDD directly by using the cerebellum Crus I as seeds.Forty-four drug-naive MDD patients and 44 healthy controls participated in the resting-state scan. Functional connectivity (FC) was applied to analyze the images.Significantly increased FCs were observed between the right Crus I and the right inferior frontal cortex (orbital part)/superior temporal pole, bilateral MPFC (orbital part), and left middle temporal gyrus in the patients compared with the controls. There was a significantly positive correlation between the z values of the right Crus I–bilateral MPFC (orbital part) connectivity and the scores of Automatic Thoughts Questionnaire in the patients (r = 0.329, P = 0.029).The findings reveal that depressed patients have increased cerebellar-DMN connectivity with clinical significance, and thus highlight the contribution of the cerebellum to the DMN alterations in neurobiology of MDD.

The role of the medial prefrontal cortex in regulating interanimal coordination of movements.

Rats with juvenile play experience display a greater ability in coordinating their movements with social partners than those deprived of such experience, and this may be due to the play-induced neural restructuring of the medial prefrontal cortex (mPFC). The present study investigates the role of the mPFC in interanimal coordination. Rats with and without bilateral mPFC lesions were tested on a robbing-and-dodging task. This food protection task measures the ability of rats to protect pieces of food by gaining and maintaining an interanimal distance between themselves and the rat attempting to rob the food. Given that mPFC lesions have been associated with sensory and motor deficits, the same rats were also subjected to a task to measure skilled motor movements. Rats with bilateral mPFC lesions had more food stolen and displayed an inability to maintain interanimal distance with partner, but did not exhibit any motor or sensory deficits. These findings suggest that the mPFC is involved in interanimal coordination and that the play-induced neural restructuring of this area may account for the enhanced coordination seen in rats with prior play experience.

Asymmetric c-fos expression in the ventral orbital cortex is associated with impaired reversal learning in a right-sided neuropathy.

BackgroundRecently we showed that unilateral peripheral neuropathic lesions impacted differentially on rat’s emotional/cognitive behavior depending on its left/right location; importantly, this observation recapitulates clinical reports. The prefrontal cortex (PFC), a brain region morphofunctionally affected in chronic pain conditions, is involved in the modulation of both emotion and executive function and displays functional lateralization. To test whether the PFC is involved in the lateralization bias associated with left/right pain, c-fos expression in medial and orbital areas was analyzed in rats with an unilateral spared nerve injury neuropathy installed in the left or in the right side after performing an attentional set-shifting, a strongly PFC-dependent task.ResultsSNI-R animals required more trials to successfully terminate the reversal steps of the attentional set-shifting task. A generalized increase of c-fos density in medial and orbital PFC (mPFC/OFC), irrespectively of the hemisphere, was observed in both SNI-L and SNI-R. However, individual laterality indexes revealed that contrary to controls and SNI-L, SNI-R animals presented a leftward shift in c-fos density in the ventral OFC (VO). None of these effects were observed in the neighboring primary motor area.ConclusionsOur results demonstrate that chronic neuropathic pain is associated with a bilateral mPFC and OFC hyperactivation. We hypothesize that the impaired performance of SNI-R animals is associated with a left/right activity inversion in the VO, whose functional integrity is critical for reversal learning.

Upregulation of presynaptic proteins and protein kinases associated with enhanced glutamate release from axonal terminals (synaptosomes) of the medial prefrontal cortex in rats with neuropathic pain

Although nerve injury-induced long-term postsynaptic changes have been investigated, less is known regarding the molecular mechanisms within presynaptic axonal terminals. We investigated the molecular changes in presynaptic nerve terminals underlying chronic pain-induced plastic changes in the medial prefrontal cortex (mPFC). After neuropathic pain was induced by spared nerve injury (SNI) in rats, we assessed the release of the excitatory neurotransmitter glutamate by using in vitro synaptosomal preparations from the mPFC. We also measured the levels of synaptic proteins and protein kinases in synaptosomes using Western blotting. The results showed that unilateral long-term SNI augmented depolarization-evoked glutamate release from synaptosomes of the bilateral mPFC. This result was confirmed by a rapid destaining rate of FM1-43 dye in SNI-operated rats. Unilateral long-term nerve injury also significantly increased synaptic proteins (including synaptophysin, synaptotagmin, synaptobrevin, syntaxin, and 25-kDa synaptosome-associated protein) in synaptosomal fractions from the bilateral mPFC, and ultrastructure images demonstrated increased synaptic vesicular profiles in synaptosomes from SNI animals. Chronic pain upregulated the phosphorylation of endogenous protein kinases, including extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Ca2+/calmodulin-dependent kinase II (CaMKII), and synapsin I, the primary presynaptic target of ERK1/2 and CaMKII. Both presynaptic proteins and protein kinases were upregulated after SNI in a time-dependent manner. These results indicate that the long-term neuropathic pain-induced enhancement of glutamate release in the mPFC is linked to increased synaptic vesicle proteins and the activation of the ERK1/2- and CaMKII-synapsin signaling cascade in presynaptic axonal terminals.

The role of medial prefrontal cortex in theory of mind: A deep rTMS study

Neuroimaging studies suggest that the medial prefrontal cortex (mPFC) plays a central role in cognitive theory of mind (ToM). This can be assessed more definitively, however, using repetitive transcranial magnetic stimulation (rTMS). Sixteen healthy participants (10 females, 6 males) completed tasks assessing cognitive and affective ToM following low-frequency deep rTMS to bilateral mPFC in active-stimulation and placebo-stimulation sessions. There was no effect of deep rTMS on either cognitive or affective ToM performance. When examining self-reported empathy, however, there was evidence for a double dissociation: deep rTMS disrupted affective ToM performance for those with high self-reported empathy, but improved affective ToM performance for those with low self-reported empathy. mPFC appears to play a role in affective ToM processing, but the present study suggest that stimulation outcomes are dependent on baseline empathic abilities.

Microinjection of Different Doses of Corticotropin-releasing Factor into the Medial Prefrontal Cortex Produces Effects Opposing Anxiety-related Behavior in Rats

Corticotropin-releasing factor (CRF) in the medial prefrontal cortex (mPFC) is suggested to play an important role in mediating fear, anxiety, and depression. The results of the studies of the actions of CRF in the mPFC regarding anxiety-related behavior, however, seem contradictory. In one study, microinjection of CRF into the mPFC produced an increase in anxiety-related behavior on the elevated plus maze, whereas in another study CRF produced an anxiolytic-like effect. To test whether the different doses of CRF used in these experiments are responsible for the differing results, we examined the dose-dependent effects of CRF (0.015, 0.05, 0.15, 0.5, and 1.0 µg/0.5 µL/site) microinjected into the bilateral mPFC of male Wistar rats on anxiety-related behavior in the elevated plus maze. We found that microinjection of 0.05 µg CRF significantly decreased the number of open-arm entries, whereas 1.0 µg CRF significantly increased the time spent on the open arms. The results indicate that CRF has effects opposing anxiety-related behavior in the elevated plus maze: anxiety-related behavior at a lower dose and an anxiolytic-like effect at a higher dose.

Medial prefrontal administration of MK-801 impairs T-maze discrimination reversal learning in weanling rats

Several executive functions rely on the medial prefrontal cortex (mPFC) in the rat. Aspiration and neurotoxic lesions of the mPFC impair reversal learning in adult rats. Systemic administration of MK-801, an NMDA-receptor antagonist, impairs T-maze reversal learning in weanling rats but the role of mPFC NMDA-receptor antagonism in this effect is not known in either adult or young animals. This set of studies showed that mPFC NMDA receptors are specifically involved in T-maze discrimination reversal in weanling rats. In Experiment 1, 26-day-old rats (P26) demonstrated a dose-dependent impairment following bilateral mPFC administration of either 2.5 or 5.0 μg MK-801 or saline (vehicle) during the reversal training phase only. In Experiment 2, P26 rats were trained on the same task, but four groups of rats received bilateral mPFC infusions during acquisition only (MK–SAL), reversal only (SAL–MK), both phases (MK–MK), or neither phase (SAL–SAL). MK-801 impaired performance only when infused during reversal. This suggests that NMDA-receptor antagonism in the mPFC is selectively involved in reversal learning during development and this may account for the previously reported effects of systemic MK-801 on T-maze discrimination reversal in weanling rats.

Medial prefrontal cortex supports recollection, but not familiarity, in the rat.

There is continuing controversy about the extent to which the rodent medial prefrontal cortical area (mPFC) is functionally homologous to the dorsolateral prefrontal cortex in humans and nonhuman primates. Previous studies have compared the effects of mPFC lesions in rats to those of dorsolateral prefrontal lesions in working memory, strategy switching, and temporal ordering. None, however, has examined the role of the rodent mPFC in recognition memory, wherein, in humans, dorsolateral prefrontal damage results in a deficit in source monitoring resulting in impaired recollection. In the present study, we examined recognition memory in rats with bilateral mPFC lesions (prelimbic/infralimbic regions; ibotenic acid) using a variant of a non-match-to-sample task with manipulations of response bias that allowed for a signal detection analysis that distinguishes recollection and familiarity contributions to recognition memory. Animals with medial prefrontal lesions had a modest overall deficit in recognition with no general change in their tendency to elicit "old" or "new" responses. Signal detection analyses indicated that rats with mPFC damage had a curvilinear and symmetrical receiver operating characteristic (ROC) curve, compared with a curvilinear and asymmetrical ROC curve in control subjects, indicating that mPFC damage severely reduced recollection-based performance, while sparing familiarity. The recollection failure was associated with an impaired ability to reject new items (increased false alarm rate), whereas the identification of old items (hit rate) was normal. This pattern of findings is similar to that observed in humans with dorsolateral prefrontal damage and is complementary to the selective deficit in hit rate observed after hippocampal damage.

Prefrontal cortical-ventral striatal interactions involved in affective modulation of attentional performance: implications for corticostriatal circuit function.

Anatomically segregated systems linking the frontal cortex and the striatum are involved in various aspects of cognitive, affective, and motor processing. In this study, we examined the effects of combined unilateral lesions of the medial prefrontal cortex (mPFC) and the core subregion of the nucleus accumbens (AcbC) in opposite hemispheres (disconnection) on a continuous performance, visual attention test [five-choice serial reaction-time task (5CSRTT)]. The disconnection lesion produced a set of specific changes in performance of the 5CSRTT, resembling changes that followed bilateral AcbC lesions while, in addition, comprising a subset of the behavioral changes after bilateral mPFC lesions previously reported using the same task. Specifically, both mPFC/AcbC disconnection and bilateral AcbC lesions markedly affected aspects of response control related to affective feedback, as indexed by perseverative responding in the 5CSRTT. These effects were comparable, although not identical, to those in animals with either bilateral AcbC or mPFC/AcbC disconnection lesions. The mPFC/AcbC disconnection resulted in a behavioral profile largely distinct from that produced by disconnection of a similar circuit described previously, between the mPFC and the dorsomedial striatum, which were shown to form a functional network underlying aspects of visual attention and attention to action. This distinction provides an insight into the functional specialization of corticostriatal circuits in similar behavioral contexts.

Lateralized Effects of Medial Prefrontal Cortex Lesions on Neuroendocrine and Autonomic Stress Responses in Rats

The medial prefrontal cortex (mPFC) is highly activated by stress and modulates neuroendocrine and autonomic function. Dopaminergic inputs to mPFC facilitate coping ability and demonstrate considerable hemispheric functional lateralization. The present study investigated the potentially lateralized regulation of stress responses at the level of mPFC output neurons, using ibotenic acid lesions. Neuroendocrine function was assessed by plasma corticosterone increases in response to acute or repeated 20 min restraint stress. The primary index of autonomic activation was gastric ulcer development during a separate cold restraint stress. Restraint-induced defecation was also monitored. Plasma corticosterone levels were markedly lower in response to repeated versus acute restraint stress. In acutely restrained animals, right or bilateral, but not left mPFC lesions, decreased prestress corticosterone levels, whereas in repeatedly restrained rats, the same lesions significantly reduced the peak stress-induced corticosterone response. Stress ulcer development (after a single cold restraint stress) was greatly reduced by either right or bilateral mPFC lesions but was unaffected by left lesions. Restraint-induced defecation was elevated in animals with left mPFC lesions. Finally, a left-biased asymmetry in adrenal gland weights was observed across animals, which was unaffected by mPFC lesions. The results suggest that mPFC output neurons demonstrate an intrinsic right brain specialization in both neuroendocrine and autonomic activation. Such findings may be particularly relevant to clinical depression which is associated with both disturbances in stress regulatory systems and hemispheric imbalances in prefrontal function.