Prefrontal cortex activity is reduced in gambling and nongambling substance users during decision-making

OBJECTIVE: Poor decision-making is a hallmark of addiction, whether to substances or activities. Performance on a widely used test of decision-making, the Iowa Gambling Task (IGT), can discriminate controls from persons with ventral medial frontal lesions, substance-dependence, and pathological gambling. Positron emission tomography (PET) studies indicate that substance-dependent individuals show altered prefrontal activity on the task. Here we adapted the IGT to an fMRI setting to test the hypothesis that defects in ventral medial and prefrontal processing are associated with impaired decisions that involve risk but may differ depending on whether substance dependence is comorbid with gambling problems. METHOD: 18 controls, 14 substance-dependent individuals (SD), and 16 SD with gambling problems (SDPG) underwent fMRI while performing a modified version of the IGT. RESULT: Group differences were observed in ventral medial frontal, right frontopolar, and superior frontal cortex during decision-making. Controls showed the greatest activity, followed by SDPG, followed by SD. CONCLUSION: Our results support a hypothesis that defects in ventral medial frontal processing lead to impaired decisions that involve risk. Reductions in right prefrontal activity during decision-making appear to be modulated by the presence of gambling problems and may reflect impaired working memory, stimulus reward valuation, or cue reactivity in substance-dependent individuals.     

MRI volume of the medial frontal cortex predicts financial capacity in patients with mild Alzheimer’s disease

Persons with mild Alzheimer’s disease (AD) have significant deficits in financial abilities. This study examined the relationship between brain structure volumes, cognition, and financial capacity in patients with mild AD. Sixteen mild AD patients and 16 older adult comparisons completed the Financial Capacity Instrument (FCI), a psychometric measure of financial abilities, and also underwent magnetic resonance imaging (MRI) to obtain volumes of the bilateral hippocampi, angular gyri, precunei, and medial and dorsolateral frontal cortices. Mild AD patients performed significantly below comparisons on the FCI and had significantly smaller hippocampi. Among mild AD patients, FCI performance was moderately correlated with frontal (medial and dorsolateral frontal cortex) and posterior (angular gyri and precunei) cortical volumes. Stepwise regression demonstrated that medial frontal cortex volume predicted FCI score. The relationship between medial frontal cortex volume and overall FCI score was partially mediated by two measures of simple attention (DRS Attention, DRS Construction). The findings suggest that medial frontal cortex atrophy and associated declines in simple attention play an increasingly important role in declining financial skills in patients with mild AD.     

Medial frontal cortex lesions impair the aiming component of rat reaching

This study examined the contribution of medial frontal cortex (the medial portion of supplementary motor cortex, or Fr1) to the performance of rats on trained, or 'skilled', reaching tasks. Unilateral medial frontal cortex lesions moderately impaired reaching success on a task that demanded accuracy but they did not impair performance on a less demanding reaching task nor did they affect limb preference. Kinematic analyses indicated that the aiming component, in which the forearm of the limb is aligned along the midline of the body by adduction of the elbow, was chronically impaired. Rather than adducting the elbow to aim, the rats used a number of limb and whole body postural adjustments to compensate for incomplete or absent aiming. That medial frontal cortex is involved in the execution of at least one component of skilled reaching implies that a larger area of frontal cortex is involved in skilled limb movement than has been suggested by previous studies. The results also suggest that the different regions of frontal cortex may each have a relatively selective involvement in the execution of only a subset of the movements comprising a reach.     

Longitudinal changes in cortical thickness in children after traumatic brain injury and their relation to behavioral regulation and emotional control

The purpose of this study was to assess patterns of cortical development over time in children who had sustained traumatic brain injury (TBI) as compared to children with orthopedic injury (OI), and to examine how these patterns related to emotional control and behavioral dysregulation, two common post-TBI symptoms. Cortical thickness was measured at approximately 3 and 18 months post-injury in 20 children aged 8.2-17.5 years who had sustained moderate-to-severe closed head injury and 21 children aged 7.4-16.7 years who had sustained OI. At approximately 3 months post-injury, the TBI group evidenced decreased cortical thickness bilaterally in aspects of the superior frontal, dorsolateral frontal, orbital frontal, and anterior cingulate regions compared to the control cohort, areas of anticipated vulnerability to TBI-induced change. At 18 months post-injury, some of the regions previously evident at 3 months post-injury remained significantly decreased in the TBI group, including bilateral frontal, fusiform, and lingual regions. Additional regions of significant cortical thinning emerged at this time interval (bilateral frontal regions and fusiform gyrus and left parietal regions). However, differences in other regions appeared attenuated (no longer areas of significant cortical thinning) by 18 months post-injury including large bilateral regions of the medial aspects of the frontal lobes and anterior cingulate. Cortical thinning within the OI group was evident over time in dorsolateral frontal and temporal regions bilaterally and aspects of the left medial frontal and precuneus, and right inferior parietal regions. Longitudinal analyses within the TBI group revealed decreases in cortical thickness over time in numerous aspects throughout the right and left cortical surface, but with notable "sparing" of the right and left frontal and temporal poles, the medial aspects of both the frontal lobes, the left fusiform gyrus, and the cingulate bilaterally. An analysis of longitudinal changes in cortical thickness over time (18 months-3 months) in the TBI versus OI group demonstrated regions of relative cortical thinning in the TBI group in bilateral superior parietal and right paracentral regions, but relative cortical thickness increases in aspects of the medial orbital frontal lobes and bilateral cingulate and in the right lateral orbital frontal lobe. Finally, findings from analyses correlating the longitudinal cortical thickness changes in TBI with symptom report on the Emotional Control subscale of the Behavior Rating Inventory of Executive Function (BRIEF) demonstrated a region of significant correlation in the right medial frontal and right anterior cingulate gyrus. A region of significant correlation between the longitudinal cortical thickness changes in the TBI group and symptom report on the Behavioral Regulation Index was also seen in the medial aspect of the left frontal lobe. Longitudinal analyses of cortical thickness highlight an important deviation from the expected pattern of developmental change in children and adolescents with TBI, particularly in the medial frontal lobes, where typical patterns of thinning fail to occur over time. Regions which fail to undergo expected cortical thinning in the medial aspects of the frontal lobes correlate with difficulties in emotional control and behavioral regulation, common problems for youth with TBI. Examination of post-TBI brain development in children may be critical to identification of children that may be at risk for persistent problems with executive functioning deficits and the development of interventions to address these issues.     

Parietal and frontal eye field neglect in the rat

Rats were given unilateral aspiration lesions of parietal, medial frontal, or dorsolateral frontal (motor) cortex and then tested for visual, auditory and tactile neglect, and for circling. All medial frontal lesion animals showed contralateral neglect in each modality and circled ipsiversively. The parietal lesion rats initially displayed contralateral visual and auditory neglect as severe as that in the medial frontal group. Three weeks after the lesions, the parietal group had a smaller residual deficit on the visual test than the medial frontal group. In the first week, parietal animals responded less than the medial frontals to stroking the vibrissae but were more responsive to mild pinching of a toe contralateral to the lesion side. In striking contrast to the medial frontal animals, the parietal group circled strongly to the contralateral side. No rat with a motor cortex lesion neglected or circled preferentially. Like medial frontal cortex, unilateral parietal lesions also produce neglect and circling, but there are important features distinguishing unilateral lesion effects in these two regions.     

The frontal lobe role in memory: a review of convergent evidence and implications for the Wada memory test

Functional imaging studies have implicated the frontal lobe in many of the memory processes often thought to be the domain of medial temporal structures. Results from fMRI studies of normal subjects have suggested that some components of memory formation, including those components tested during the Wada memory test, may involve frontal lobe regions. Specific behavioral disruptions during carotid amytal injections support a model for frontal lobe anesthesia in explaining results of the Wada memory test. Cortical stimulation data suggest that frontal lobe disruption is sufficient to cause memory disturbances. The convergence of evidence suggests frontal lobe memory may limit the predictive value of the Wada memory test in defining the risk of memory loss following temporal lobectomy.     

Entorhinal cortex structure and functional MRI response during an associative verbal memory task

Entorhinal cortex (ERC) volume in adults with mild cognitive impairment has been shown to predict prodromal Alzheimer's disease (AD). Likewise, neuronal loss in ERC has been associated with AD, but not with normal aging. Because ERC is part of a major pathway modulating input to the hippocampus, structural changes there may result in changes to cognitive performance and functional brain activity during memory tasks. In 32 cognitively intact older adults, we examined the relationship between left ERC thickness and functional magnetic resonance imaging (fMRI) activity during an associative verbal memory task. This task has been shown previously to activate regions that are sensitive to aging and AD risk. ERC was manually defined on native space, high resolution, oblique coronal MRI scans. Subjects having thicker left ERC showed greater activation in anterior cingulate and medial frontal regions during memory retrieval, but not encoding. This result was independent of hippocampal volume. Anterior cingulate cortex is directly connected to ERC, and is, along with medial frontal cortex, implicated in error detection, which is impaired in AD. Our results suggest that in healthy older adults, processes that engage frontal regions during memory retrieval are related to ERC structure. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Functional lesions and human action monitoring: combining repetitive transcranial magnetic stimulation and event-related brain potentials.

OBJECTIVE: Electrophysiological recordings of the error-related negativity (ERN) and functional imaging data point to an involvement of medial frontal cortex (including the anterior cingulate cortex, ACC) and dorsolateral prefrontal cortex (DLPFC) in the detection and correction of performance errors. Here, we studied this network by applying trains of rapid transcranial magnetic stimulation (rTMS) prior to the recording of the ERN. METHODS: Low-frequency (0.9 Hz) rTMS was applied to medial frontal or lateral frontal regions (different sessions) for 60 s immediately before each 3 min ERN recording in 11 healthy young subjects. The ERN was obtained by multichannel recordings in a typical Eriksen flanker task with instructions calling for immediate error correction in case a performance error was detected by the subject. Event-related potentials were quantified and statistically evaluated using standard methodology. RESULTS: Compared to a no-stimulation control condition, medial frontal stimulation led to a small but reliable decrease in the number of corrected errors as well as to an attenuation of the ERN and an increase of the subsequent error-positivity (Pe). No effect on these components was seen after lateral frontal stimulation. No reliable effects on the lateralized readiness potential were observed. CONCLUSIONS: Functional lesions by rTMS appear to interfere with the functions of the medial frontal cortex in error detection and correction.     

Frontal and temporal functional connections of the living human brain

Connections between human temporal and frontal cortices were investigated by intracranial electroencephalographic responses to electrical stimulation with 1-ms single pulses in 51 patients assessed for surgery for treatment of epilepsy. The areas studied were medial temporal, entorhinal, lateral temporal, medial frontal, lateral frontal and orbital frontal cortices. Findings were assumed to be representative of human brain as no differences were found between epileptogenic and non-epileptogenic hemispheres. Connections between intralobar temporal and frontal regions were common (43-95%). Connections from temporal to ipsilateral frontal regions were relatively uncommon (seen in 0-25% of hemispheres). Connections from frontal to ipsilateral temporal cortices were more common, particularly from orbital to ipsilateral medial temporal regions (40%). Contralateral temporal connections were rare (< 9%) whereas contralateral frontal connections were frequent and faster, particularly from medial frontal to contralateral medial frontal (61%) and orbital frontal cortices (57%), and between both orbital cortices (67%). Orbital cortex receives profuse connections from the ipsilateral medial (78%) and lateral (88%) frontal cortices, and from the contralateral medial (57%) and orbital (67%) frontal cortices. The high incidence of intralobar temporal connections supports the presence of temporal reverberating circuits. Frontal cortex projects within the lobe and beyond, to ipsilateral and contralateral structures.     

Risk and resilience markers in bipolar disorder: brain responses to emotional challenge in bipolar patients and their healthy siblings

OBJECTIVE: The authors previously identified depression-specific differences in brain responses to an emotional challenge in patients with bipolar and unipolar mood disorder. In this study, potential markers of bipolar risk and resilience were examined in a new cohort of lithium-responsive bipolar patients and their healthy siblings. METHOD: Changes in regional cerebral blood flow (rCBF) were measured with [(15)O]water positron emission tomography after induction of transient sadness in nine euthymic lithium responders and nine healthy siblings. The patterns of change in these groups were compared, and then they were contrasted with previous findings on bipolar responders to valproate. RESULTS: Common to all three groups with induced sadness were rCBF increases in the dorsal/rostral anterior cingulate and anterior insula and decreases in the orbitofrontal and inferior temporal cortices. Distinguishing the groups were decreases in the medial frontal cortex in the patients but an increase in this region in the siblings. DISCUSSION: Common changes with emotional challenge were identified in bipolar patients and their healthy siblings. These were not seen previously in healthy subjects without a family history of mood disorder, suggesting a potential marker of bipolar risk. The siblings' unique increases in the medial frontal cortex appear to identify a compensatory response in this at-risk group, as this pattern was not seen previously in healthy subjects without depression risk factors. This differential change pattern in patients and their siblings highlights the role of the anterior cingulate and medial frontal regions in mediating resiliency and vulnerability in bipolar disorder families.     

Metabolite changes with age measured by proton magnetic resonance spectroscopy in normal subjects

Abstract  To determine whether there are metabolite changes in the left medial temporal and frontal lobes with aging, we performed proton magnetic resonance spectroscopy in 36 normal subjects. The N-acetylaspartate/creatine-phosphocreatine ratio in the medial temporal lobe tended to be decreased in subjects over 60 years of age. The ratio decrease in the frontal lobe related to aging was lower than that in the medial temporal lobe. There were no significant differences in the metabolite ratios between males and females. These findings suggest that structures in the medial temporal lobe may be more susceptible to neuronal dysfunction associated with aging than those in the frontal lobe.     

Immediate and delayed effects of risperidone on cerebral metabolism in neuroleptic naïve schizophrenic patients: correlations with symptom change

OBJECTIVE: Different symptom patterns have been shown to be associated with specific patterns of cerebral metabolic activity in schizophrenia. Treatment with various neuroleptic drugs results in decreased metabolism in frontal cortical regions. The temporal and regional relation between changes in metabolism and symptom improvement after treatment with risperidone was studied in eight previously unmedicated schizophrenic patients. METHOD: Cerebral metabolic activity was measured using PET before neuroleptic exposure, after the first dose of risperidone, and after 6 weeks of treatment. Pearson correlations were calculated for regions of significant change in metabolism and symptom change. RESULTS: After 6 weeks of treatment significant deactivations were seen in the left lateral cortical frontal region and medial frontal cortex. Significant changes were detectable in the medial frontal region 90 minutes after the first dose of risperidone. Patients with higher baseline activity in the identified medial frontal cluster had higher baseline positive symptom scores and reduction in medial frontal metabolism was correlated with reduction in positive symptom score. CONCLUSION: The evidence suggests that the reduction in medial-frontal activity after treatment with risperidone is a direct effect of risperidone and not a consequence of symptom improvement. Reduction of medial frontal metabolism may be one of the physiological mechanisms by which risperidone alleviates symptoms of psychosis in schizophrenia.     

Topographic organization of efferent projections of medial frontal cortex

By using fluorescent retrograde tracers, we compared efferent projections of the medial frontal cortex to two subcortical areas: the superior colliculus, a somatic motor area, and the laterodorsal tegmental nucleus, a visceral motor area. Neurons projecting to the superior colliculus originated in layer V of the cingulate (Cg1 area) and medial agranular cortex, while neurons projecting to the laterodorsal tegmental nucleus originated in layers V and VI of the cingulate (Cg3 area) and infralimbic cortex. Thus, within the medial frontal cortex, the ventral portion (the Cg3 and infralimbic areas) may be a visceral motor area while the dorsal portion is a somatic motor region.     

Keeping time: effects of focal frontal lesions

This study examined the performance of 32 normal subjects and 39 patients with focal lesions of the frontal lobes on two simple timing tasks-responding in time with a tone that regularly repeated at a rate of once every 1.5s, and then maintaining the same regular response rhythm without any external stimulus. The hypothesis was that lesions to the right prefrontal cortex would disrupt timing performance. The two main findings were (1) an abnormally high variability in the timing performance (both self-timed and tone-timed) of patients with lesions to the right lateral frontal lobe, particularly involving Brodmann area 45 and subjacent regions of the basal ganglia; (2) an increase in the variability of timing performance as the task continued in patients with lesions to the superior medial regions of the frontal lobe. These findings indicate that the right lateral frontal lobe is crucially involved in the ongoing control of timed behavior, either because of its role in generating time intervals or in monitoring the passage of these intervals. In contrast, the superior medial regions of the frontal lobe are necessary to maintain consistent timing performance over prolonged periods of time.     

Do forebrain structures compete for behavioral expression? Evidence from amphetamine-induced behavior, microdialysis, and caudate-accumbens lesions in medial frontal cortex damaged rats.

The neurochemical basis of behavioral changes following medial frontal cortex damage were investigated. Experiment 1 examined locomotion in response to D-amphetamine (1.5 and 5 mg/kg) in rats that had received bilateral aspirative lesions of the medial frontal cortex alone or in combination with 6-hydroxydopamine (6-OHDA) lesions of the nucleus accumbens or caudate-putamen. Relative to controls, medial frontal cortex rats were initially hypoactive (day 1 postoperative) but rapidly became hyperactive (days 5-15 postoperative). Locomotor-time profiles and stereotypy ratings showed that amphetamine produced a selective enhancement of locomotion at the expense of stereotyped behavior. Nucleus accumbens lesions blocked the locomotion but enhanced stereotyped behavior in the medial frontal cortex damaged rats, suggesting that amphetamine-enhanced locomotion is dependent upon the integrity of the nucleus accumbens. In Experiment 2, intracerebral microdialysis was used to examine whether alterations in dopamine (DA) or monoamine metabolites in the nucleus accumbens or caudate-putamen accompanied the lesion-induced changes in locomotion. There were no differences in extracellular DA or monoamine levels between control rats and medial frontal cortex rats when tested on day 1 or day 15 postsurgery, either when they were at rest, while they walked on a motor-driven belt, or after amphetamine treatment. Therefore, it seems unlikely that changes in amphetamine-induced locomotion following medial frontal cortex lesions are related to underlying modifications in dopaminergic activity in the nucleus accumbens. It is suggested that neural structures compete for behavioral expression and that postlesion behavioral alterations reveal the competitive advantage of remaining intact neural systems.     

Impairments in proverb interpretation following focal frontal lobe lesions

The proverb interpretation task (PIT) is often used in clinical settings to evaluate frontal “executive” dysfunction. However, only a relatively small number of studies have investigated the relationship between frontal lobe lesions and performance on the PIT. We compared 52 patients with unselected focal frontal lobe lesions with 52 closely matched healthy controls on a proverb interpretation task. Participants also completed a battery of neuropsychological tests, including a fluid intelligence task (Raven’s Advanced Progressive Matrices). Lesions were firstly analysed according to a standard left/right sub-division. Secondly, a finer-grained analysis compared the performance of patients with medial, left lateral and right lateral lesions with healthy controls. Thirdly, a contrast of specific frontal subgroups compared the performance of patients with medial lesions with patients with lateral frontal lesions. The results showed that patients with left frontal lesions were significantly impaired on the PIT, while in patients with right frontal lesions the impairments approached significance. Medial frontal patients were the only frontal subgroup impaired on the PIT, relative to healthy controls and lateral frontal patients. Interestingly, an error analysis indicated that a significantly higher number of concrete responses were found in the left lateral subgroup compared to healthy controls. We found no correlation between scores on the PIT and on the fluid intelligence task. Overall our results suggest that specific regions of the frontal lobes contribute to the performance on the PIT.     

Frontal eye field as defined by intracortical microstimulation in squirrel monkeys, owl monkeys, and macaque monkeys: I. Subcortical connections

Intracortical microstimulation was used to define the borders of the frontal eye fields in squirrel, owl, and macaque monkeys. The borders were marked with electrolytic lesions, and horseradish peroxidase conjugated to wheat germ agglutinin was injected within the field. Following tetramethyl benzidine histochemistry, afferent and efferent connections of the frontal eye field with subcortical structures were studied. Most connections were ipsilateral and were similar in all primates studied. These include reciprocal connections with the following nuclei: medial dorsal (lateral parts), ventral anterior (especially with pars magnocellularis), central lateral, paracentral, ventral lateral, parafascicular, medial pulvinar, limitans, and suprageniculate. The frontal eye field also projects to the ipsilateral pretectal nuclei, subthalamic nucleus, nucleus of the posterior commissure, superior colliculus (especially layer four), zona incerta, rostral interstitial nucleus of the medial longitudinal fasciculus, nucleus Darkschewitsch, dorsomedial parvocellular red nucleus, interstitial nucleus of Cajal, basilar pontine nuclei, and bilaterally to the paramedian pontine reticular formation and the nucleus reticularis tegmenti pontis. Many of these structures also receive input from deeper layers of the superior colliculus and are known to participate in visuomotor function. These results reveal connections that account for the parallel influence of the superior colliculus and the frontal eye field on visuomotor function; suggest that there has been little evolutionary change in subcortical connections, and therefore function, of the frontal eye fields since the time that these lines of primates diverged; and support the conclusion that the frontal eye fields are homologous in New and Old World monkeys.     

Amnesia following left medial frontal subcortical hemorrhage: a case report]

There has been a controversy as to the contribution of the frontal lobe to human memory function. We describe a 49-year-old right-handed patient with memory disturbance following a left medial frontal subcortical hematoma. Her amnesia was characterized by (1) predominant anterograde amnesia, (2) difficulty in both voluntary recall and recognition tasks, (3) a great number of false-alarm responses in a recognition task, and (4) no confabulation. An MRI demonstrated that her lesion was restricted to the left medial frontal area and anterior cingulate gyrus. This case represents a rare instance of amnesia following damage to the frontal lobe. We speculated that the unique feature of her memory impairment resulted from combined lesions in the medial frontal subcortical white matter and anterior cingulate gyrus. It seems that Papez's circuite participated in the development of these symptoms.     

Septum and medial frontal cortex contribution to spatial problem-solving

An attempt was made to contrast the effects of lesions to the medial frontal cortex and septum in two spatial tasks. In the fixed-goal (FG) task, the food was located on the same table throughout testing, and the start table was randomly varied from day to day. In the variable-goal (VG) task, the start table remained constant but the food was randomly distributed on one or the other of the two remaining tables. In both tasks, normal animals performed better than frontal and septal rats whose performance, however, improved over days in the FG, but not in the VG, task. In both tasks, significant improvement within days was found in medial frontal animals, but not in septal animals. Additional analyses revealed that septal animals had a general pattern of disrupted exploration and a tendency to use a response strategy (i.e. to repeat the same response both within and between days) which decreased over days in the FG task. In contrast, medial frontal animals did not demonstrate disrupted exploration nor any response tendency. It is concluded that both septal and medial frontal cortical damage produce a common spatial working memory impairment. However, there is some evidence to suggest that this common memory impairment could result from disruption of distinct mechanisms in septal and frontal animals. It is proposed that medial frontal lesions could affect some specific mechanism related either to attentional processes or to the ability to anticipate future events, whereas septal damage would interfere with the building of comprehensive and flexible spatial memories.     

General and task-specific frontal lobe recruitment in older adults during executive processes: a fMRI investigation of task-switching.

Performance deteriorates when subjects must shift between two different tasks relative to performing either task separately. This switching cost is thought to result from executive processes that are not inherent to the component operations of either task when performed alone. Medial and dorsolateral frontal cortices are theorized to subserve these executive processes. Here we show that larger areas of activation were seen in dorsolateral and medial frontal cortex in both younger and older adults during switching than repeating conditions, confirming the role of these frontal brain regions in executive processes. Younger subjects activated these medial and dorsolateral frontal cortices only when switching between tasks; in contrast, older subjects recruited similar frontal regions while performing the tasks in isolation as well as alternating between them. Older adults recruit medial and dorsolateral frontal areas, and the processes computed by these areas, even when no such demands are intrinsic to the current task conditions. This neural recruitment may be useful in offsetting the declines in cognitive function associated with ageing.