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Selective activation of the ventrolateral prefrontal cortex in the human brain during active retrieval processing.

The present study examined the role of the prefrontal cortex in retrieval processing using functional magnetic resonance imaging in human subjects. Ten healthy subjects were scanned while they performed a task that required retrieval of specific aspects of visual information. In order to examine brain activity specifically associated with retrieval, we designed a task that had retrieval and control conditions that were perfectly matched in terms of depth of encoding, decision making and postretrieval monitoring and differed only in terms of whether retrieval was required. In the retrieval condition, based on an instructional cue, the subjects had to retrieve either the particular stimulus that was previously presented or its location. In the control condition, the cue did not instruct retrieval but shared with the instructional cues the function of alerting the subjects of the impending test phase. The comparison of activity between the retrieval and control conditions demonstrated a significant and selective increase in activity related to retrieval processes within the ventrolateral prefrontal cortical region, more specifically within area 47/12. These activity increases were bilateral but stronger in the right hemisphere. The present study by strictly controlling the level of encoding, postretrieval monitoring, and decision making has demonstrated a specific increase in the ventrolateral prefrontal region that could be clearly related to active retrieval processing, i.e. the active selection of particular stored visual representations.

Adult↗

Reduced GAP-43 mRNA in dorsolateral prefrontal cortex of patients with schizophrenia.

Schizophrenia has been associated with anatomical and functional abnormalities of the dorsolateral prefrontal cortex (DLPFC), which may reflect abnormal connections of DLPFC neurons. We measured mRNA levels of growth-associated protein (GAP-43), a peptide linked to the modifiability of neuronal connections, in post-mortem brain tissue from two cohorts of patients with schizophrenia and controls. Using the RNase protection assay (RPA), we found a significant reduction in GAP-43 mRNA in the DLPFC, but not in the hippocampus, of patients with schizophrenia. With in situ hybridization histo- chemistry (ISHH), performed on a separate cohort, we confirmed the reduction of GAP-43 mRNA in the DLPFC of patients with schizophrenia. We detected reduced GAP-43 mRNA per neuron in layers III, V and VI of patients with schizophrenia compared with normal controls and patients with bipolar disorder. Thus, glutamate neurons in DLPFC of schizophrenic patients may synthesize less GAP-43, which could reflect fewer and/or less modifiable connections than those in normal human brain, and which may be consistent with the deficits of prefrontal cortical function that characterize schizophrenia.

Adult↗

Intensity-dependent regional cerebral blood flow during 1-Hz repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers studied with H215O positron emission tomography: II. Effects of prefrontal cortex rTMS.

BACKGROUND: The changes in brain activity produced by repetitive transcranial magnetic stimulation (rTMS) of the prefrontal cortex (PFC) remain unclear. We examined intensity-related changes in brain activity with positron emission tomography (PET) in normal volunteers during rTMS delivered to the left PFC. METHODS: In 10 healthy volunteers, we delivered 1-Hz rTMS at randomized intensities over left PFC with a figure-eight coil. Intensities were 80, 90, 100, 110, and 120% of the right-hand muscle twitch threshold. Regional cerebral blood flow (rCBF) scans were acquired with H(2)(15)O PET during rTMS at each intensity. RESULTS: Repetitive transcranial magnetic stimulation intensity was inversely correlated with rCBF in the stimulated and contralateral PFC, ipsilateral medial temporal lobe, both parahippocampi, and posterior middle temporal gyri. Positive correlations of rCBF with intensity occurred in ipsilateral anterior cingulate, cerebellum, contralateral insula, primary auditory cortex, and somatosensory face area. CONCLUSIONS: The intensity-related inverse relationship between 1-Hz rTMS and prefrontal activity appears opposite to that seen with rTMS over the motor cortex in a companion study. Intensity-dependent increases in rCBF were seen in a number of distant cortical and subcortical areas with PFC rTMS, suggesting activation of left anterior cingulate, claustrum, and cerebellum. The regional differences in direction of rTMS effects and the greater activation of distant structures at higher intensities suggest the potential importance of higher-intensity prefrontal rTMS for therapeutic applications in neuropsychiatric patients.

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Direct injection of 5-HT2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats.

The serotonin (5-HT)(2A/2c) agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), the 5-HT2C agonist 6-chloro-2-[1-piperazinyl]-pyrazine and the 5-HT2A partial agonist m-chloro-phenylpiperazine (mCPP) were injected bilaterally into the medial prefrontal cortex of male rats. DOI and mCPP, but not 6-chloro-2-[1-piperazinly]-pyrazine, elicited a dose-dependent head-twitch response (HTR). DOI-induced HTR had an ED50 of 12.8 nmoles/0.5 microl/side and was inhibited by the 5-HT2A antagonists ketanserin and MDL 100,907 but was not blocked by pretreatment with the selective 5-HT(2C/2B) antagonist SDZ SER 082. The HTR to mCPP demonstrated a bell-shaped dose-response curve with an ED50 of 1.5 nmoles/0.5 microl/side and a peak effect after 3 nmoles/side. The response to mCPP was greatly diminished by both ketanserin and MDL 100,907 and was partially reversed by SDZ SER 082. These findings suggest that the HTR produced by the direct injection of serotonergic agonists into the medial prefrontal cortex is, in part, mediated by the activation of 5-HT2A receptors. Pretreatment of rats with the 5-HT1A agonist (+/-)-8-hydroxy-dipropylaminotetralin hydrobromide inhibited the HTR to DOI. This is consistent with other evidence that suggests a functional antagonism between 5-HT1A and 5-HT2A receptor activation. The HTR to DOI was potentiated by the novel 5-HT1A selective antagonist WAY 100,635, which suggests that 5-HT1A receptors tonically regulate this behavioral response to stimulation of cortical 5-HT2A receptors.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

Contribution of ventrolateral prefrontal cortex to the acquisition and extinction of conditioned fear in rats.

The ventrolateral, agranular insular portion of prefrontal cortex (PFC) in rats is involved in visceral functions and has been shown to be involved in emotional processes. However, its contribution to aversive learning has not been well defined. Classical fear conditioning has been a powerful tool for illuminating some of the primary neural structures involved in aversive emotional learning. We measured both the acquisition and the extinction of conditioned fear following lesions of the ventrolateral PFC of rats. Lesions reduced fear reactivity to contextual stimuli associated with conditioning without affecting CS acquisition, and had no effect on response extinction. Ventrolateral PFC may normally be involved in the processing of contextual information while not being directly involved in extinction processes within the aversive domain.

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Neonatal ventral hippocampus lesion leads to reductions in nerve growth factor inducible-B mRNA in the prefrontal cortex and increased amphetamine response in the nucleus accumbens and dorsal striatum.

Converging evidence in schizophrenia suggests prefrontal cortical neuronal deficits that correlate with exaggerated subcortical dopamine (DA) functions: Excitotoxic lesion of the ventral hippocampus (VH) in neonatal rats is widely considered a putative animal model of schizophrenia as they lead to characteristic post-pubertal emergence of behavioral and cognitive abnormalities suggesting a developmental change in the neural circuits comprising the prefrontal cortex (PFC) and subcortical DA. Nerve growth factor inducible-B (NGFI-B, also known as Nur77), an orphan nuclear receptor and transcriptional regulator, is constitutively expressed in the target structures of DA pathways. It acts as an immediate early gene with rapid modulation of its mRNA expression by stress, DA and antipsychotic drugs. The present study assessed the effects of neonatal VH (nVH) lesion and amphetamine treatment on the expression of NGFI-B mRNA in pre- and post-pubertal rats. Sprague-Dawley rat pups received bilateral injection of ibotenic acid or phosphate buffered saline in VH at postnatal (PD) 7. At PD35 and PD56, groups of sham and lesioned animals were administered with D-amphetamine (1.5 mg/kg) or saline and killed 20 min later. In situ hybridization analyses showed that the basal level of NGFI-B mRNA in saline-treated lesioned rats was significantly reduced in the medial PFC (mPFC) and cingulate cortex (CC) only at post-pubertal (PD56) age. No significant difference in NGFI-B mRNA levels was seen in the dorsal striatum or nucleus accumbens (NAcc). Amphetamine treatment increased the expression of NGFI-B mRNA in the mPFC, CC, striatum and NAcc in both control and lesioned animals of both ages. Interestingly, however, striatal and NAcc regions of lesioned rats showed a significantly greater effect of amphetamine at PD56. The data suggest that nVH lesions lead to delayed changes in PFC gene expression along with functional DAergic hyperactivity in subcortical regions.

Amphetamine↗

Cue- versus probe-dependent prefrontal cortex activity during contextual remembering.

Functional neuroimaging comparisons of context and item memory frequently implicate the left prefrontal cortex (PFC) during the recovery of contextually specific memories. However, because cues and probes are often presented simultaneously, this activity could reflect operations involved in planning retrieval or instead reflect later operations dependent upon the memory probes themselves, such as evaluation of probe-evoked recollections. More importantly, planning-related activity, wherein subjects reinstate details outlining the nature of desired remembrances, should occur in response to contextual memory cues even before retrieval probes are available. Using event-related functional magnetic resonance imaging, we tested this by dissociating cue- from probe-related activity during context memory for pictures. Cues forewarning contextual memory demands yielded more activity than those forewarning item memory in the left lateral precentral gyrus, midline superior frontal gyrus, and right frontopolar cortex. Thus, these anticipatory, cue-based activations indicated whether upcoming probe decisions would require contextually specific memories or not. In contrast, the left dorsolateral/midventrolateral and anterior ventrolateral PFC areas did not show differential activity until the probes were actually presented, demonstrating greater activity for context than for item memory probes. Direct comparison of proximal left PFC regions demonstrated qualitatively different response profiles across cue versus probe periods for lateral precentral versus dorsolateral regions. These results potentially isolate contextual memory-planning-related processes from subsequent processes such as the evaluation of recollections, which are necessarily dependent on individual probe features. They also demonstrate that contextual remembering recruits multiple, functionally distinct PFC processes.

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A simulation model for compensatory plasticity in the prefrontal cortex inducing a cortico-cortical dysconnection in early brain development.

In the present work, an abstract prefrontal cortex simulation model is used to predict compensatory structural alterations of the cortico-cortical connectivity pattern in the normal and pathologic forebrain maturation. The simulation network shows different representative courses of morphogenesis when developing undisturbed or when suffering from disturbing excitatory afferences. The simulative results could be affirmed by an immuno-histochemical study, revealing a qualitatively comparable development of the glutamatergic projection fibre density in gerbils (Meriones unguiculatus) after juvenile and adult methamphetamine intoxication. The simulation model further allows to consider different rearing conditions (enriched-environment model), and claims contradictory effects of an equal disturbance after enriched or impoverished rearing which are in accordance with the experimental findings.

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FMRI evidence for an organization of prefrontal cortex by both type of process and type of information.

Neuroimaging evidence is conflicting regarding whether human prefrontal cortex (PFC) shows functional organization by type of processes engaged or type of information processed. Most studies use complex working or long-term memory tasks requiring multiple processes and the combinations of processes recruited for different materials may vary. Using functional magnetic resonance imaging (fMRI) and simple tasks suggested by a component process approach, we found activity in left PFC when participants thought about (refreshed) a just-seen item and in right PFC when participants noted whether an item had been presented previously. Furthermore, the distribution of activation in left or right PFC varied with type of information. Thus, at the component process level, PFC shows functional organization by both process and type of information.

Adult↗

Role of the medial prefrontal cortex in N-methyl-D-aspartate receptor antagonist induced sensorimotor gating deficit in rats.

The medial prefrontal cortex (mPFC) regulates sensorimotor gating measured as prepulse inhibition (PPI) of startle. We here tested the effect of lesions of the mPFC on the PPI-disruptive effect of the non-competitive NMDA receptor antagonist dizocilpine in rats. Neurotoxic lesions of the mPFC were induced by ibotenic acid. Rats were tested for PPI after systemic injection of dizocilpine (0.15 mg/kg) and after injection of the dopamine receptor agonist apomorphine (2 mg/kg). Dizocilpine failed to disrupt PPI in rats with mPFC lesions while the PPI-disruptive effect of apomorphine was not affected. Startle response magnitude in the absence of prepulses was not affected by mPFC lesions or drugs. These data suggest that the mPFC is an important brain region within the neuronal circuit responsible for NMDA receptor antagonist induced PPI-deficits.

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rTMS of the prefrontal cortex in the treatment of chronic migraine: a pilot study.

A recent fMRI study showed that dorsolateral prefrontal cortex (DLPFC) exerts an inhibitory control on pain pathways in humans. We investigated whether high-frequency rTMS over left DLPFC could ameliorate chronic migraine. Treatment consisted of 12 rTMS sessions, delivered in alternate days over left DLPFC. Sham rTMS was used as placebo. Eleven patients were randomly assigned to the rTMS (n=6) or to the placebo (n=5) treatment. Measures of attack frequency, headache index, number of abortive medications (outcome measures) were recorded in the month before, during and in the month after treatment. Subjects treated by rTMS showed a significant reduction of the outcome measures during and in the month after the treatment as compared to the month before treatment. No significant differences in the outcome measures were observed in the placebo group. High-frequency rTMS over left DLPFC was able to ameliorate chronic migraine. This is in agreement with the suggested role of DLPFC in pain control.

Adult↗

Effects of haloperidol on behavioral responses induced by electrical stimulation of medial prefrontal cortex.

The effects of haloperidol on circling and spying behaviors induced by electrical stimulation of the medial prefrontal cortex (PFC) were evaluated. Male Wistar rats with an electrode implanted into the left medial PFC (B: 2.5 mm A, 0.6 mm L and 2.7 mm V) were electrically stimulated in a sequence of ten 30-sec trains separated by 30-sec intervals (60 Hz) in each session, and simultaneously observed in the open field. The animals with circling (CI) and spying (SP) behaviors were treated with intraperitoneal haloperidol (HAL ip, 5 mg/kg, N = 6) and saline (SAL ip, N = 7) or intracortical HAL (ic, 5 micrograms, N = 6) and SAL (ic, N = 9), 20 min before the session of electrical stimulation. HAL ic significantly decreased (P < 0.05) CI (mean frequency +/- SEM: 0.5 +/- 0.16) and nonsignificantly decreased SP behavior (0.6 +/- 0.17) compared to SAL ic (CI: 0.9 0.02, SP: 1 +/- 0). HAL ip full abolished these behaviors (P < 0.05) (CI: 0.02 +/- 0, SP: 1 +/- 0) compared to SAL ip (CI: 0.86 +/- 0.06, SP: 0:93 +/- 0.06). These results show that haloperidol, a dopaminergic antagonist and antipsychotic agent, interfered significantly with the expression of behaviors induced by electrical stimulation of the left medial PFC, suggesting that the induction of these behaviors may involve the dopaminergic neurotransmission.

Animals↗

[Neuronal activity in the prefrontal cortex in rats with various typological features during emotional affect].

Unit activity in the right and left prefrontal cortex was recorded in male Wistar rats after testing by the emotional resonance technique. Rats were divided in two groups by their reaction to the suffering cry of a partner. Rats from the group A ("altruists") escaped partner's crying, and those from the group E ("egoists") did not. Activity of neurons was analyzed in hungry rats, after feeding, during intracranial emotionally positive and negative stimulation, and during crying of the rat partner. Some differences in neural activity between A and E groups were revealed. In the hungry state the rate of neuronal discharges was higher in the A group. In both groups of animals the positive emotional stimulation was accompanied by more intensive neuronal reaction that the negative stimulation, but in the E group increase in the rate of neuronal discharges in both hemispheres was significantly more pronounced. Negative stimulation produced in both groups a significantly greater activation in the left hemisphere than in the right one while during the positive stimulation the neural activity was more intensive in the left hemisphere. The neuronal reaction to partner's crying was significantly higher in the A group in both hemispheres, while the neuronal activity in E group did not significantly change.

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A region of mesial prefrontal cortex tracks monetarily rewarding outcomes: characterization with rapid event-related fMRI.

The function of the mesial prefrontal cortex (MPFC: including Brodman areas 10/12/32) remains an enigma. Current theories suggest a role in representing internal information, including emotional introspection, autonomic control, and a "default state" of semantic processing. Recent evidence also suggests that parts of this region may also play a role in processing reward outcomes. In this study, we investigated the possibility that a region of the MPFC would be preferentially recruited by monetary reward outcomes using a parametric monetary incentive delay (MID) task. Twelve healthy volunteers participated in functional magnetic resonance scans while playing the MID task. Group analyses indicated that while the ventral striatum was recruited by anticipation of monetary reward, a region of the MPFC instead responded to rewarding monetary outcomes. Specifically, volume-of-interest analyses indicated that when volunteers received $5.00 after anticipating a $5.00 win, MPFC activity increased, whereas when volunteers did not receive $5.00 after anticipating a $5.00 win, MPFC activity decreased, relative to outcomes with no incentive value. These findings suggest that in the context of processing monetary rewards, a region of the MPFC preferentially tracks rewarding outcomes.

Adult↗

In vivo inhibition of neuronal activity in the rat ventromedial prefrontal cortex by midbrain-raphe nuclei: role of 5-HT1A receptors.

The ventral part of the medial prefrontal cortex (mPFC) plays an important role in mood and cognition. This study examined the effect of the 5-HT in this region by measuring the electrophysiological response of ventral mPFC neurones to electrical stimulation of the dorsal and median raphe nuclei (DRN and MRN), which are the source of the 5-HT input. DRN or MRN stimulation evoked a consistent, short-latency, post-stimulus inhibition in the majority of ventral mPFC neurones tested (DRN: 44/73 neurones; MRN: 24/31 neurones). Some neurones responded to DRN or MRN stimulation with antidromic spikes indicating that they were mPFC-raphe projection neurones. Both DRN- and MRN-evoked inhibitions were attenuated by systemic administration of the 5-HT1A antagonist WAY 100635 (0.1 mg/kg i.v.). DRN-evoked inhibition was also attenuated by iontophoretic application of WAY 100635 and by systemic administration of the 5-HT1A antagonist, NAD-299 (4 mg/kg i.v.) but not the 5-HT2 antagonist ketanserin (4 mg/kg, i.v.). These data suggest that DRN and MRN 5-HT neurones inhibit neurones in the ventral mPFC via activation of 5-HT1A receptors. Some of these mPFC neurones may be part of a 5-HT1A receptor-controlled postsynaptic feedback loop to the DRN and MRN.

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1H Magnetic resonance spectroscopy study of dorsolateral prefrontal cortex in unipolar mood disorder patients.

Neuroimaging and postmortem studies have suggested the involvement of the dorsolateral prefrontal cortex (DLPFC) in the pathophysioloy of unipolar disorder. We examined with in vivo 1H magnetic resonance spectroscopy (MRS) the levels of specific metabolites in the DLPFC of adult unipolar patients and the role of illness chronicity on DLPFC abnormalities. Nineteen unmedicated unipolar mood disorder patients and 19 age- and gender-matched healthy controls underwent a short echo-time 1H MRS examination localized to an 8-cm3 single voxel placed in the left DLPFC. There were no significant differences in metabolite levels, including N-acetylaspartate (NAA), phosphocreatine plus creatine (PCr+Cr) and choline-containing-compounds (GPC+PC), between the two groups. However, NAA/PCr+Cr ratios were significantly lower in the chronic than in the less chronically ill patients and healthy controls. The low levels of NAA/PCr+Cr ratios in the left DLPFC of unipolar patients who had been more chronically ill suggest a potential role for illness chronicity in neuronal abnormalities in the DLPFC in unipolar disorder. This could possibly be accounted for by neurodegenerative processes arising with the progression of the illness. Future 1H MRS investigations should longitudinally examine the role of illness chronicity on DLPFC abnormalities and their relationship with the symptoms of unipolar disorder.

Adult↗

Bilateral orbital prefrontal cortex lesions in rhesus monkeys disrupt choices guided by both reward value and reward contingency.

The orbital prefrontal cortex (PFo) operates as part of a network involved in reward-based learning and goal-directed behavior. To test whether the PFo is necessary for guiding behavior based on the value of expected reward outcomes, we compared four rhesus monkeys with two-stage bilateral PFo removals and six unoperated controls for their responses to reinforcer devaluation, a task that assesses the monkeys' abilities to alter choices of objects when the value of the underlying food has changed. For comparison, the same monkeys were tested on a standard test of flexible stimulus-reward learning, namely object reversal learning. Relative to controls, monkeys with bilateral PFo removals showed a significant attenuation of reinforcer devaluation effects on each of two separate assessments, one performed shortly after surgery and the other approximately 19 months after surgery; the operated monkeys were also impaired on object reversal learning. The same monkeys, however, were unimpaired in acquisition of object discrimination learning problems and responded like controls when allowed to choose foods alone, either on a food preference test among six different foods or after selective satiation. Thus, satiety mechanisms and the ability to assign value to familiar foods appear to be intact in monkeys with PFo lesions. The pattern of results suggests that the PFo is critical for response selection based on predicted reward outcomes, regardless of whether the value of the outcome is predicted by affective signals (reinforcer devaluation) or by visual signals conveying reward contingency (object reversal learning).

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Electrophysiological and morphological properties of layers V-VI principal pyramidal cells in rat prefrontal cortex in vitro.

This study examined the electrophysiological and morphological characteristics of layers V-VI pyramidal prefrontal cortex (PFC) neurons. In vitro intracellular recordings coupled with biocytin injections that preserved some of the PFC efferents to the nucleus accumbens (NAc) were made in brain slices. Four principal pyramidal cell types were identified and classified as regular spiking (RS) (19%), intrinsic bursting (IB) (64%), repetitive oscillatory bursting (ROB) (13%), and intermediate (IM) (4%) types. All PFC cells exhibited either subthreshold oscillation in membrane voltage or pacemaker-like rhythmic firing. IB neurons were demonstrated electrophysiologically and cytochemically to be PFC-->NAc neurons. In all IB and some RS neurons, a tetrodotoxin-sensitive, slowly inactivating Na+ current and a transient Ni(2+)-sensitive, low-threshold Ca2+ current mediated subthreshold inward rectification. During sustained membrane depolarization, the Na+ current was opposed by a 4-aminopyridine-sensitive, outwardly rectifying, slowly inactivating K+ current. Together, these three currents controlled the firing threshold of the PFC neurons. All IB and ROB cells also had postspike Ca(2+)-mediated depolarizing afterpotentials, postburst Ca(2+)-dependent after hyperpolarizations, and low- and high-threshold Ca2+ spikes. In addition, ROB cells had a hyperpolarizing "sag" mediated by the cationic conductance, Ih. IB and ROB neurons had extensive dendritic trees and radially ascending or tangentially projecting axon collaterals. RS and IM cells had comparatively simpler morphological profiles. These electrophysiological and morphological properties of the four principal pyramidal PFC cell types have provided valuable details for understanding further how PFC processes input and transmit outputs to regions such as the NAc.

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