Medial Frontal Brain Regions Research Articles

Task experience eliminates catecholaminergic effects on inhibitory control – A randomized, double-blind cross-over neurophysiological study

Catecholaminergic neural transmission plays an important role during the inhibition of prepotent responses. Methylphenidate (MPH) is an important drug that modulates the catecholaminergic system. However, theoretical considerations suggest that the effects of drugs (e.g. MPH) on cognitive control may depend on prior learning effects. Here we investigate this in a conflict-modulated Go/Nogo task and evaluate neurophysiological processes associated with this dynamic using EEG signal decomposition methods and source localization analysis. The behavioral data show that prior learning experiences eliminate effects of MPH on response inhibition processes. On a neurophysiological level, we show that MPH modulates specific processes in medial frontal brain regions. Although MPH seems to consistently modulate neurophysiological processes associated with response inhibition, this is no longer sufficient to modulate behavioral performance once learning or task familiarization processes have taken place. An important consequence of this study finding is that it may be important to adjust MPH dosage depending on learning effects in a specific setting to constantly increase cognitive control functions in that setting. This has important implications for clinical practice, since MPH is the first-line pharmacological therapy in attention-deficit hyperactivity disorder (ADHD). Cross-over study designs with constant doses of MPH can mask effects on cognitive functions. The impact of learning needs careful consideration in cross-over study designs examining catecholaminergic drug effects.

P.215 Comparing antidepressant efficacy of fluoxetine and minocycline treatment in different environmental conditions

Catecholaminergic neural transmission plays an important role during the inhibition of prepotent responses. Methylphenidate (MPH) is an important drug that modulates the catecholaminergic system. However, theoretical considerations suggest that the effects of drugs (e.g. MPH) on cognitive control may depend on prior learning effects. Here we investigate this in a conflict-modulated Go/Nogo task and evaluate neurophysiological processes associated with this dynamic using EEG signal decomposition methods and source localization analysis. The behavioral data show that prior learning experiences eliminate effects of MPH on response inhibition processes. On a neurophysiological level, we show that MPH modulates specific processes in medial frontal brain regions. Although MPH seems to consistently modulate neurophysiological processes associated with response inhibition, this is no longer sufficient to modulate behavioral performance once learning or task familiarization processes have taken place. An important consequence of this study finding is that it may be important to adjust MPH dosage depending on learning effects in a specific setting to constantly increase cognitive control functions in that setting. This has important implications for clinical practice, since MPH is the first-line pharmacological therapy in attention-deficit hyperactivity disorder (ADHD). Cross-over study designs with constant doses of MPH can mask effects on cognitive functions. The impact of learning needs careful consideration in cross-over study designs examining catecholaminergic drug effects.

Reward and empathy in the treating clinician: the neural correlates of successful doctor\u2013patient interactions

The goal of this study was to determine the neural correlates of successful doctor–patient interactions. We performed an experimental neuroimaging study where medical doctors (MDs) performed a treatment task while their brain activation pattern was measured, using functional magnetic resonance imaging (fMRI). MDs (25–37 years old) first performed a standardized clinical exam of a “professional patient”. Unbeknownst to the doctors, the professional patient was a confederate that rated the doctors’ clinical examination using the Consultation And Relational Empathy (CARE) questionnaire, a standardized protocol assessing a clinician’s social interaction during a consultation. After the clinical exam, MDs were placed inside a brain scanner and the patient was placed on a chair next to the MD. MDs performed a treatment task where an analgesic device was used to alleviate the patient’s pain (experimentally induced), while the MD’s brain activity was measured with fMRI. MDs rated their own empathic concern (equivalent of compassion) and personal distress using the Interpersonal Reactivity Index questionnaire. The patient’s rating of CARE was robustly related to the MD’s own ratings of trait empathic concern and to compassion-related and reward-related activation of medial frontal brain regions during treatment. In contrast, there was no relation with MD’s personal distress, nor with activation in regions associated with the aversive component of experiencing empathy. We conclude that a patient’s positive experience of a medical examination is reflected in doctors’ empathic concern and reward-related brain activations during treatment, suggesting that compassion and pleasure are key factors for successful doctor–patient interactions.

Offline impact of transcranial focused ultrasound on cortical activation in primates.

To understand brain circuits it is necessary both to record and manipulate their activity. Transcranial ultrasound stimulation (TUS) is a promising non-invasive brain stimulation technique. To date, investigations report short-lived neuromodulatory effects, but to deliver on its full potential for research and therapy, ultrasound protocols are required that induce longer-lasting 'offline' changes. Here, we present a TUS protocol that modulates brain activation in macaques for more than one hour after 40 s of stimulation, while circumventing auditory confounds. Normally activity in brain areas reflects activity in interconnected regions but TUS caused stimulated areas to interact more selectively with the rest of the brain. In a within-subject design, we observe regionally specific TUS effects for two medial frontal brain regions - supplementary motor area and frontal polar cortex. Independently of these site-specific effects, TUS also induced signal changes in the meningeal compartment. TUS effects were temporary and not associated with microstructural changes.

A Network for Computing Value Equilibrium in the Human Medial Prefrontal Cortex

Humans and other animals make decisions in order to satisfy their goals. However, it remains unknown how neural circuits compute which of multiple possible goals should be pursued (e.g., when balancing hunger and thirst) and how to combine these signals with estimates of available reward alternatives. Here, humans undergoing fMRI accumulated two distinct assets over a sequence of trials.Financial outcomes depended on the minimum cumulate of either asset, creating a need to maintain "value equilibrium" by redressing any imbalance among the assets. Blood-oxygen-level-dependent (BOLD) signals in the rostral anterior cingulate cortex (rACC) tracked the level of imbalance among goals, whereas the ventromedial prefrontal cortex (vmPFC) signaled the level of redress incurred by a choice rather than the overall amount received. These results suggest that a network of medial frontal brain regions compute a value signal that maintains value equilibrium among internal goals.

Human ventromedial prefrontal lesions alter incentivisation by reward

Although medial frontal brain regions are implicated in valuation of rewards, evidence from focal lesions to these areas is scant, with many conflicting results regarding motivation and affect, and no human studies specifically examining incentivisation by reward. Here, 19 patients with isolated, focal damage in ventral and medial prefrontal cortex were selected from a database of 453 individuals with subarachnoid haemorrhage. Using a speeded saccadic task based on the oculomotor capture paradigm, we manipulated the maximum reward available on each trial using an auditory incentive cue. Modulation of behaviour by motivation permitted quantification of reward sensitivity. At the group level, medial frontal damage was overall associated with significantly reduced effects of reward on invigorating saccadic velocity and autonomic (pupil) responses compared to age-matched, healthy controls. Crucially, however, some individuals instead showed abnormally strong incentivisation effects for vigour. Increased sensitivity to rewards within the lesion group correlated with damage in subgenual ventromedial prefrontal cortex (vmPFC) areas, which have recently become the target for deep brain stimulation (DBS) in depression. Lesion correlations with clinical apathy suggested that the apathy associated with prefrontal damage is in fact reduced by damage at those coordinates. Reduced reward sensitivity showed a trend to correlate with damage near nucleus accumbens. Lesions did not, on the other hand, influence reward sensitivity of cognitive control, as measured by distractibility. Thus, although medial frontal lesions may generally reduce reward sensitivity, damage to key subregions paradoxically protect from this effect.

Connectivity reveals relationship of brain areas for reward-guided learning and decision making in human and monkey frontal cortex

Reward-guided decision-making depends on a network of brain regions. Among these are the orbitofrontal and the anterior cingulate cortex. However, it is difficult to ascertain if these areas constitute anatomical and functional unities, and how these areas correspond between monkeys and humans. To address these questions we looked at connectivity profiles of these areas using resting-state functional MRI in 38 humans and 25 macaque monkeys. We sought brain regions in the macaque that resembled 10 human areas identified with decision making and brain regions in the human that resembled six macaque areas identified with decision making. We also used diffusion-weighted MRI to delineate key human orbital and medial frontal brain regions. We identified 21 different regions, many of which could be linked to particular aspects of reward-guided learning, valuation, and decision making, and in many cases we identified areas in the macaque with similar coupling profiles.

Neural substrates of normal and impaired preattentive sensory discrimination in large cohorts of nonpsychiatric subjects and schizophrenia patients as indexed by MMN and P3a change detection responses

Schizophrenia (SZ) patients have information processing deficits, spanning from low level sensory processing to higher-order cognitive functions. Mismatch negativity (MMN) and P3a are event-related potential (ERP) components that are automatically elicited in response to unattended changes in ongoing, repetitive stimuli that provide a window into abnormal information processing in SZ. MMN and P3a are among the most robust and consistently identified deficits in SZ, yet the neural substrates of these responses and their associated deficits in SZ are not fully understood. This study examined the neural sources of MMN and P3a components in a large cohort of SZ and nonpsychiatric control subjects (NCS) using Exact Low Resolution Electromagnetic Tomography Analyses (eLORETA) in order to identify the neural sources of MMN and P3a as well as the brain regions associated with deficits commonly observed among SZ patients. 410 SZ and 247 NCS underwent EEG testing using a duration-deviant auditory oddball paradigm (1-kHz tones, 500ms SOA; standard p=0.90, 50-ms duration; deviant tones P=0.10, 100-ms duration) while passively watching a silent video. Voxel-by-voxel within- (MMN vs. P3a) and between-group (SZ vs. NCS) comparisons were performed using eLORETA. SZ had robust deficits in MMN and P3a responses measured at scalp electrodes consistent with other studies. These components mapped onto neural sources broadly distributed across temporal, frontal, and parietal regions. MMN deficits in SZ were associated with reduced activations in discrete medial frontal brain regions, including the anterior-posterior cingulate and medial frontal gyri. These early sensory discriminatory MMN impairments were followed by P3a deficits associated with widespread reductions in the activation of attentional networks (frontal, temporal, parietal regions), reflecting impaired orienting or shifts of attention to the infrequent stimuli. MMN and P3a are dissociable responses associated with broadly distributed patterns of neural activation. MMN deficits among SZ patients appear to be primarily accounted for by reductions in medial prefrontal brain regions that are followed by widespread dysfunction across cortical networks associated with P3a in a manner that is consistent with hierarchical information processing models of cognitive deficits in SZ patients. Impairments in automatic stimulus discrimination may contribute to higher-order cognitive and psychosocial deficits in SZ.

Separating distinct aspects of the voluntary selection between response alternatives: N2- and P3-related BOLD responses

Voluntary selection between response alternatives belongs to cognitive abilities controlling and regulating goal-directed behaviour. Voluntary selection processes are associated with increased neural activity, especially in medial and lateral frontal brain regions as well as the inferior parietal gyrus. However, the precise function of each brain region as well as the spatiotemporal characteristic of the brain regions involved is not yet clear. The aim of the present study was to disentangle distinct aspects of voluntary selection and their underlying neural processes. Hence, event-related potentials (ERPs) and functional MRI data were acquired simultaneously. Brain regions modulated by the task-induced amplitude variation of ERPs (N2, P3) were identified. The results showed N2-related hemodynamic responses, especially in medial and lateral frontal brain regions. Among other things, medial frontal brain regions are related to conflict monitoring, control of voluntary action and decision making. By contrast, the P3-amplitude proved to be predominantly related to increased BOLD responses in the temporo-parietal junction and lateral frontal brain regions. These brain regions are thought to play a decisive role in an attentional network involved in detecting auditory and visual stimuli. Overall, the results of the study indicated a whole network of brain regions to be associated with voluntary selection processes. In addition, at least some frontal brain regions seemed to be involved at an earlier stage than temporo-parietal regions, probably indicating a top-down process.

PW01-143 - Separating distinct aspects of the voluntary selection between response alternatives: N2 and P3 related bold responses

Voluntary selection between response alternatives belong to cognitive abilities controlling and regulating goal-directed behaviour. Voluntary selection processes are associated with increased neural activity, especially in medial and lateral frontal brain regions as well as the inferior parietal gyrus. However, the precise function of each brain region as well as the spatiotemporal characteristic of the brain regions involved is not yet clear. The aim of the present study was to disentangle distinct aspects of voluntary selection and their underlying neural processes. Hence, event-related potentials (ERPs) and functional MRI data were acquired simultaneously. Brain regions modulated by the task-induced amplitude variation of ERPs (N2, P3) were indentified. The results showed N2-related hemodynamic responses, especially in medial and lateral frontal brain regions. Among other things, medial frontal brain regions are related to conflict monitoring, control of voluntary action and decision making. By contrast, the P3-amplitude proved to be predominantly related to increased BOLD responses in the temporo-parietal junction [TPJ] and lateral frontal brain regions. These brain regions are thought to play a decisive role in an attentional network involved in detecting auditory and visual stimuli.Overall, the results of the study indicated a whole network of brain regions to be associated with voluntary selection processes. In addition, at least some frontal brain regions seemed to be involved at an earlier stage than temporo-parietal regions, probably indicating a top-down process.

Brain mechanisms associated with background monitoring of the environment for potentially significant sensory events

Background monitoring is a necessary prerequisite to detect unexpected changes in the environment, while being involved in a primary task. Here, we used fMRI to investigate the neural mechanisms that underlie adaptive goal-directed behavior in a cued task switching paradigm during real response conflict or, more generally, when expectations on the repetitive features of the environment were violated. Unexpected changes in sensory stimulus attributes in the currently unattended stimulus dimension thereby led to activations in a bilateral network comprising inferior lateral frontal, intraparietal, and posterior medial frontal brain regions, independent of whether these attributes elicited a factual response conflict or not. This fronto-parietal network may thus play an important role in adaptive responding to potentially significant events outside the current focus of attention.

Temporal lobe interictal epileptic discharges affect cerebral activity in “default mode” brain regions

A cerebral network comprising precuneus, medial frontal, and temporoparietal cortices is less active both during goal‐directed behavior and states of reduced consciousness than during conscious rest. We tested the hypothesis that the interictal epileptic discharges affect activity in these brain regions in patients with temporal lobe epilepsy who have complex partial seizures. At the group level, using electroencephalography‐correlated functional magnetic resonance imaging in 19 consecutive patients with focal epilepsy, we found common decreases of resting state activity in 9 patients with temporal lobe epilepsy (TLE) but not in 10 patients with extra‐TLE. We infer that the functional consequences of TLE interictal epileptic discharges are different from those in extra‐TLE and affect ongoing brain function. Activity increases were detected in the ipsilateral hippocampus in patients with TLE, and in subthalamic, bilateral superior temporal and medial frontal brain regions in patients with extra‐TLE, possibly indicating effects of different interictal epileptic discharge propagation. Hum Brain Mapp 2006. © 2006 Wiley‐Liss, Inc.