Relationship of prefrontal connections to inhibitory systems in superior temporal areas in the rhesus monkey

The prefrontal cortex selects relevant signals and suppresses irrelevant signals in behavior, as exemplified by its functional interaction with superior temporal cortices. We addressed the structural basis of this process by investigating quantitatively the relationship of prefrontal pathways to inhibitory interneurons in superior temporal cortices. Pathways were labeled with neural tracers, and two neurochemical classes of inhibitory interneurons were labeled with parvalbumin (PV) and calbindin (CB), which differ in mode of inhibitory control. Both markers varied significantly and systematically across superior temporal areas. Calbindin neurons were more prevalent than PV neurons, with the highest densities found in posterior high-order auditory association cortices. Axons from anterior lateral, medial prefrontal and orbitofrontal areas terminated in the anterior half of the superior temporal gyrus, targeting mostly the superficial layers (I to upper III), where CB neurons predominated. Reciprocal projection neurons were intermingled with PV neurons, and emanated mostly from the deep part of layer III and to a lesser extent from layers V-VI, in proportions matching the laminar density of inhibitory interneurons. In marked contrast, prefrontal connections in temporal polar cortex were found mostly in the deep layers, showing mismatch with the predominant upper laminar distribution of interneurons. Differences in the relationship of connections to inhibitory neurons probably affect the dynamics in distinct superior temporal cortices. These findings may help explain the reduced efficacy of inhibitory control in superior temporal areas after prefrontal cortical damage.     

Dopamine modulates temporal dynamics of feedforward inhibition in rat prefrontal cortex in vivo

Midbrain dopamine (DA) neurons project to pyramidal cells and interneurons of the prefrontal cortex (PFC). At the microcircuit level, interneurons gate inputs to a network and regulate/pattern its outputs. Whereas several in vitro studies have examined the role of DA on PFC interneurons, few in vivo data are available. In this study, we show that DA influences the timing of interneuron firing. In particular, DA had a reductive influence on interneuron spontaneous firing, which in the context of the excitatory response of interneurons to hippocampal electrical stimulation, lead to a temporal focalization of the interneuron response. This suggests that the reductive influence of DA on interneuron excitability is responsible for filtering out weak excitatory inputs. The increase in the temporal precision of interneuron firing is a mechanism by which DA can modulate the temporal dynamics of feedforward inhibition in PFC circuits and can thereby influence cognitive information processing.     

Nutrient pathways to extensor tendons of primates

The nutrient pathways to the extensor tendon beneath the extensor retinaculum of young adult monkeys was investigated using hydrogen as tracer material. The results indicate that diffusion from the synovium is a more significant nutrient pathway than vascular perfusion from either the mesotendon or the longitudinal intratendinous vascular network.     

Activation shift from medial to lateral temporal cortex associated with recency judgements following impoverished encoding

Recency judgements can be performed on the basis of across-event relational information that directly provides temporal order among past events. Non-relational item-based information internal to individual past events, such as information retrieved through familiarity, may also contribute to recency judgements. The present functional magnetic resonance imaging study examined neural substrates for item-based processing during recency judgements as an alternative to relational recency judgements. One half of word stimuli were encoded relationally prior to recency judgements, and the relational encoding of the other half was hampered such that the words were processed relatively in an item-based manner. Brain activity in the medial temporal lobe was observed during recency judgements for words studied with relational memory processing, whereas brain activity in the lateral temporal cortex was observed during recency judgements for words studied relatively in an item-based manner. It was revealed further that recognition of individual words per se, which can also be regarded as familiarity/recency judgements but is non-relational in nature, also activated the lateral temporal region. These results indicate multiple routes for recency judgements within the temporal lobe that are recruited depending on how past episodes are represented and retrieved for judgements of their temporal order.     

Functional specializations in lateral prefrontal cortex associated with the integration and segregation of information in working memory

Control processes are thought to play an important role in working memory (WM), by enabling the coordination, transformation, and integration of stored information. Yet little is known about the neural mechanisms that subserve such control processes. This study examined whether integration operations within WM involve the activation of distinct neural mechanisms within lateral prefrontal cortex (PFC). Event-related functional magnetic resonance imaging was used to monitor brain activity while participants performed a mental arithmetic task. In the integration (IN) condition, a WM preload item had to be mentally inserted into the last step of the math problem. This contrasted with the segregation (SG) condition, which also required maintenance of the WM preload while performing mental arithmetic but had no integration requirement. Two additional control conditions involved either ignoring the preload (math only condition) or ignoring the math problem (recall only condition). Left anterior PFC (Brodmann's Area [BA] 46/10) was selectively engaged by integration demands, with activation increasing prior to, as well as during the integration period. A homologous right anterior PFC region showed selectively increased activity in the SG condition during the period in which the math problem and preload digit were reported. Left middorsolateral PFC regions (BA 9/46) showed increased, but equivalent, activity in both the SG and IN conditions relative to both control conditions. These results provide support for the selective role of lateral PFC in cognitive control over WM and suggest more specific hypotheses regarding dissociable PFC mechanisms involved during the integration and segregation of stored WM items.     

Guilt-specific processing in the prefrontal cortex

Guilt is a central moral emotion due to its inherent link to norm violations, thereby affecting both individuals and society. Furthermore, the nature and specificity of guilt is still debated in psychology and philosophy, particularly with regard to the differential involvement of self-referential representations in guilt relative to shame. Here, using functional magnetic resonance imaging (fMRI) in healthy volunteers, we identified specific brain regions associated with guilt by comparison with the 2 most closely related emotions, shame and sadness. To induce high emotional intensity, we used an autobiographical memory paradigm where participants relived during fMRI scanning situations from their own past that were associated with strong feelings of guilt, shame, or sadness. Compared with the control emotions, guilt episodes specifically recruited a region of right orbitofrontal cortex, which was also highly correlated with individual propensity to experience guilt (Trait Guilt). Guilt-specific activity was also observed in the paracingulate dorsomedial prefrontal cortex, a critical "Theory of Mind" region, which overlapped with brain areas of self-referential processing identified in an independent task. These results provide new insights on the unique nature of guilt as a "self-conscious" moral emotion and the neural bases of antisocial disorders characterized by impaired guilt processing.     

As time goes by: temporal constraints on emotional activation of inferior medial prefrontal cortex

To investigate the influence of stimulus duration on emotional processing, we measured changes of regional cerebral blood flow (rCBF) in 14 healthy subjects who viewed neutral or emotional images presented for 3 or 6 s. Presentation for 3 s reproduced the previous result of higher rCBF in inferior medial prefrontal cortex (IMPC) during neutral than emotional stimulation. Six-second presentation reverted this relationship, with activity in IMPC being higher during emotional stimulation. Prolonged stimulus presentation attenuated the rise of rCBF associated with emotions in left parietal cortex and cerebellar hemisphere. We speculate that the different rCBF during neutral and emotional stimulation for 6 s is a consequence of attention divided between the emotional stimuli and their associations. Thus, prefrontal activity rises when a cognitive task accompanies emotional stimulation because several cognitive processes compete for attention. The IMPC may serve the mechanism of attention underlying the concept of a default mode of brain function, selecting among competitive inputs from multiple brain regions rather than just processing emotions. The results emphasize the importance of implicit cognitive processing during emotional activation, however, unintended.     

Ventrolateral prefrontal neuronal activity related to active controlled memory retrieval in nonhuman primates

It is controversial whether monkeys, like human subjects, can recall, upon instruction, specific information about an event in memory. We therefore tested macaque monkeys on a task that was originally developed to study such active controlled memory retrieval in human subjects and we were able to demonstrate that monkeys, like human subjects, can retrieve, upon command, specific components of previously encoded events. Furthermore, following earlier functional neuroimaging work with human subjects showing the mid-ventrolateral prefrontal cortex to be involved in such active controlled retrieval, we recorded single-neuron activity within this region of the monkey brain while the monkeys performed the active retrieval task. Neuronal responses were related to the retrieval and the decision whether the retrieved information was the instructed one. These findings demonstrate, for the first time, an impressive capacity by macaque monkeys for controlled memory retrieval and, in addition, provide neurophysiological evidence about the role of the mid-ventrolateral prefrontal cortex in such controlled retrieval.     

Learning-related neuronal responses in prefrontal cortex studied with functional neuroimaging

We assessed time-dependent neuronal activity accompanying learning using functional magnetic resonance imaging (fMRI). An artificial grammar learning paradigm enabled us to dissociate activations associated with individual item learning from those involved in learning the underlying grammar system. We show that a localized region of right prefrontal cortex (PFC) is preferentially sensitive to individual item learning during the early stages of the experiment, while the left PFC region is sensitive to grammar learning which occurred across the entire course of the experiment. In addition to dissociating these two types of learning, we were able to characterize the effect of rule acquisition on neuronal responses associated with explicit learning of individual items. This effect was expressed as modulation of the time-dependent right PFC activations such that the early increase in activation associated with item learning was attenuated as the experiment progressed. In a further analysis we used structural equation modelling to explore time-dependent changes in inter-regional connectivity as a function of both item and grammar rule learning. Although there were no significant effects of item learning on the measured path strengths, rule learning was associated with a decrease in right fronto-parietal connectivity and an increase in connectivity between left and right PFC. Further fronto-parietal path strengths were observed to change, with an increase in left fronto-parietal and a decrease in right fronto-parietal connectivity path strength from right PFC to left parietal cortex. We interpret our findings in terms of a left frontal system mediating the semantic analysis of study items and directly influencing a right fronto-parietal system associated with episodic memory retrieval.     

Basal-ganglia 'projections' to the prefrontal cortex of the primate

We used retrograde transneuronal transport of the McIntyre-B strain of herpes simplex virus type 1 to examine the extent and organization of basal-ganglia-thalamocortical projections to five regions of prefrontal cortex in the cebus monkey (Cebus apella): medial and lateral area 9 (9m and 9l), dorsal and ventral area 46 (46d and 46v) and lateral area 12 (12l). All of these prefrontal areas were found to be targets of basal-ganglia output that originated in the internal segment of the globus pallidus (GPi) and/or the pars reticulata of the substantia nigra (SNpr). Approximately one-third of the total volume of these nuclei was directed toward prefrontal cortex, a volume comparable to that directed at the cortical motor areas. The origins of the outputs to different prefrontal areas were topographically organized. Different portions of SNpr (the rostral and caudal thirds) projected to areas 9m and 12l. Similarly, different output nuclei (GPi and SNpr) projected to adjacent portions of the same cytoarchitectonic field (46d and 46v). Furthermore, the outputs to prefrontal areas were segregated from those to motor areas of cortex. Thus, basal-ganglia outputs to prefrontal cortex are both extensive and topographically organized, forming a rich anatomical substrate for basal-ganglia influences on the cognitive operations of the frontal lobe.     

Role of the prefrontal cortex in the foreperiod effect: TMS evidence for dual mechanisms in temporal preparation

The involvement of right dorsolateral prefrontal cortex (rDLPFC) in explicit temporal processing is well documented. Conversely, the role of this area in implicit temporal processing (e.g., foreperiod [FP] effect) is still poorly understood. The FP effect, usually observed when a range of variable FPs occur randomly and equiprobably, consists of reaction times (RTs) decreasing as the FP increases. Moreover, in such paradigms, RTs increase as a function of the preceding FP (i.e., sequential effects). Patients with lesions of the rDLPFC do not show the typical FP effect. The present study aimed to replicate these results in healthy adults using transcranial magnetic stimulation (TMS) and to further investigate whether any change of sequential effects follows a reduction of the FP effect. The results of 2 experiments (with simple and choice RT tasks, respectively) indicate that the FP effect was significantly reduced after TMS over the rDLPFC, whereas no effect was observed after stimulation of a left contralateral site and the right angular gyrus. Conversely, sequential effects were not influenced by TMS. A dual-process model of the FP phenomena is proposed to interpret the dissociation found between the 2 effects.     

Dynamic signals related to choices and outcomes in the dorsolateral prefrontal cortex

Although economic theories based on utility maximization account for a range of choice behaviors, utilities must be estimated through experience. Dynamics of this learning process may account for certain discrepancies between the predictions of economic theories and real choice behaviors of humans and other animals. To understand the neural mechanisms responsible for such adaptive decision making, we trained rhesus monkeys to play a simulated matching pennies game. Small but systematic deviations of the animal's behavior from the optimal strategy were consistent with the predictions of reinforcement learning theory. In addition, individual neurons in the dorsolateral prefrontal cortex (DLPFC) encoded 3 different types of signals that can potentially influence the animal's future choices. First, activity modulated by the animal's previous choices might provide the eligibility trace that can be used to attribute a particular outcome to its causative action. Second, activity related to the animal's rewards in the previous trials might be used to compute an average reward rate. Finally, activity of some neurons was modulated by the computer's choices in the previous trials and may reflect the process of updating the value functions. These results suggest that the DLPFC might be an important node in the cortical network of decision making.     

Task-specific repetition priming in left inferior prefrontal cortex

Previous neuroimaging studies have shown that activation in left inferior prefrontal cortices (LIPC) is reduced during repeated (primed) relative to initial (unprimed) stimulus processing. These reductions in anterior (approximately BA 45/47) and posterior (approximately BA 44/6) LIPC activation have been interpreted as reflecting implicit memory for initial semantic or phonological processing. However, prior studies do not unambiguously indicate that LIPC priming effects are specific to the recapitulation of higher-level (semantic and/or phonological), rather than lower-level (perceptual), processes. Moreover, no prior study has shown that the patterns of priming in anterior and posterior LIPC regions are dissociable. To address these issues, the present fMRI study examined the nature of priming in LIPC by examining the task-specificity of these effects. Participants initially processed words in either a semantic or a nonsemantic manner. Subsequently, participants were scanned while they made semantic decisions about words that had been previously processed in a semantic manner (within-task repetition), words that had been previously processed in a nonsemantic manner (across-task repetition), and words that had not been previously processed (novel words). Behaviorally, task-specific priming was observed: reaction times to make the semantic decision declined following prior semantic processing but not following prior nonsemantic processing of a word. Priming in anterior LIPC paralleled these results with signal reductions being observed following within-task, but not following across-task, repetition. Importantly, neural priming in posterior LIPC demonstrated a different pattern: priming was observed following both within-task and across-task repetition, with the magnitude of priming tending to be greater in the within-task condition. Direct comparison between anterior and posterior LIPC regions revealed a significant interaction. These findings indicate that anterior and posterior LIPC demonstrate distinct patterns of priming, with priming in the anterior region being task-specific, suggesting that this facilitation derives from repeated semantic processing of a stimulus.     

Anterior prefrontal cortex mediates rule learning in humans

Despite a need for rule learning in everyday life, the brain regions involved in explicit rule induction remain undetermined. Here we use event-related functional magnetic resonance imaging to measure learning-dependent neuronal responses during an explicit categorization task. Subjects made category decisions, with feedback, to exemplar letter strings for which the rule governing category membership was periodically changed. Bilateral fronto-polar prefrontal cortices were selectively engaged following rule change. This activation pattern declined with improving task performance reflecting rule acquisition. The vocabulary of letters comprising the exemplars was also periodically changed, independently of rule changes. This exemplar change modulated activation in left anterior hippocampus. Our finding that fronto-polar cortex mediates rule learning supports a functional contribution of this region to generic reasoning and problem-solving behaviours.     

Synaptic distinction of laminar-specific prefrontal-temporal pathways in primates

Prefrontal pathways exert diverse effects in widespread cortical areas, issuing projections both to the middle layers and to layer I, which are anatomically and functionally distinct. Here we addressed the still unanswered question of whether cortical pathways that terminate in different layers are distinct at the synaptic level. We addressed this issue using as a model system the robust and functionally significant pathways from prefrontal areas 10 and 32 to superior temporal areas in rhesus monkeys. Boutons from prefrontal axons synapsing in the middle layers of superior temporal cortex were significantly larger than boutons synapsing in layer I. Most synapses were on spines in both layers, which are found on dendrites of excitatory neurons. The less prevalent synapses on smooth dendrites, characteristic of inhibitory interneurons, were more common in the middle cortical layers than in layer I. Bouton volume was linearly related to vesicular and mitochondrial content in both layers, though a subset of small boutons, found mostly in layer I, contained no mitochondria. The systematic laminar-specific presynaptic differences in stable cortical synapses in adult primates were independent of their origin in the functionally distinct prefrontal areas 10 and 32, or their destination in architectonically distinct superior temporal areas. This synaptic distinction suggests differences in efficacy of synaptic transmission and metabolic demands in laminar-specific pathways that may be selectively recruited in behavior.     

Compositionality of rule representations in human prefrontal cortex

Rules are widely used in everyday life to organize actions and thoughts in accordance with our internal goals. At the simplest level, single rules can be used to link individual sensory stimuli to their appropriate responses. However, most tasks are more complex and require the concurrent application of multiple rules. Experiments on humans and monkeys have shown the involvement of a frontoparietal network in rule representation. Yet, a fundamental issue still needs to be clarified: Is the neural representation of multiple rules compositional, that is, built on the neural representation of their simple constituent rules? Subjects were asked to remember and apply either simple or compound rules. Multivariate decoding analyses were applied to functional magnetic resonance imaging data. Both ventrolateral frontal and lateral parietal cortex were involved in compound representation. Most importantly, we were able to decode the compound rules by training classifiers only on the simple rules they were composed of. This shows that the code used to store rule information in prefrontal cortex is compositional. Compositional coding in rule representation suggests that it might be possible to decode other complex action plans by learning the neural patterns of the known composing elements.     

Lie-specific involvement of dorsolateral prefrontal cortex in deception

Lies are intentional distortions of event knowledge. No experimental data are available on manipulating lying processes. To address this issue, we stimulated the dorsolateral prefrontal cortex (DLPFC) using transcranial direct current stimulation (tDCS). Fifteen healthy volunteers were tested before and after tDCS (anodal, cathodal, and sham). Two types of truthful (truthful selected: TS; truthful unselected: TU) and deceptive (lie selected: LS; lie unselected: LU) responses were evaluated using a computer-controlled task. Reaction times (RTs) and accuracy were collected and used as dependent variables. In the baseline task, the RT was significantly longer for lie responses than for true responses ([mean +/- standard error] 1153.4 +/- 42.0 ms vs. 1039.6 +/- 36.6 ms; F(1,14) = 27.25, P = 0.00013). At baseline, RT for selected pictures was significantly shorter than RT for unselected pictures (1051.26 +/- 39.0 ms vs. 1141.76 +/- 41.1 ms; F(1,14) = 34.85, P = 0.00004). Whereas after cathodal and sham stimulation, lie responses remained unchanged (cathodal 5.26 +/- 2.7%; sham 5.66 +/- 3.6%), after anodal tDCS, RTs significantly increased but did so only for LS responses (16.86 +/- 5.0%; P = 0.002). These findings show that manipulation of brain function with DLPFC tDCS specifically influences experimental deception and that distinctive neural mechanisms underlie different types of lies.     

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.     

Reduced N-acetylaspartate in prefrontal cortex of adult rats with neonatal hippocampal damage

Previous studies in animals suggested that neonatal lesions of the ventral hippocampus disrupt development of prefrontal cortex and its regulation of dopaminergic activity. In the present study, we assayed an in vivo chemical marker of neuronal integrity (proton magnetic resonance spectroscopy signal of N-acetylaspartate, NAA) in prefrontal cortex and striatum of rats with neonatal excitotoxic lesions of the ventral hippocampus. We also measured in post-mortem tissue expression of EAAC1 mRNA, a molecular marker of intrinsic neurons. In the cohort studied at juvenile age and again at young adulthood [postnatal day (PD) 37 and 71], we found selective reductions of NAA in the prefrontal cortex only at PD 71. Emergence of neuronal pathology was temporally associated with emergence of amphetamine-induced hyperlocomotion. Reduced prefrontal NAA was confirmed in the second cohort studied at an older age (PD 120). Expression of EAAC1 mRNA was significantly reduced in prefrontal cortex of the lesioned rats. No changes in NAA were found in the striatum in either cohort and cortical area size was not changed. These results suggest that early ventral hippocampal lesions produce developmental neuronal pathology in prefrontal cortex that is temporally associated with dysregulation of dopamine behaviors and is reminiscent of the temporal profile of the onset of schizophrenia.