Activation In Bilateral Prefrontal Cortex Research Articles

Distinct age-related brain activity patterns in the prefrontal cortex when increasing cognitive load: A functional near-infrared spectroscopy study

Researchers have long observed distinct brain activity patterns in older adults compared with younger adults that correlate with cognitive performance. Mainly, older adults tend to show over-recruitment of bilateral brain regions during lower task loads and improved performance interpreted as compensation, but not observed at higher loads. However, there are discrepancies about whether increases in activity are compensatory and whether older adults can show compensation at higher loads. Our aim was to examine age-related differences in prefrontal cortex (PFC) activity and cognitive performance using functional near-infrared spectroscopy (fNIRS) during single and dual N-back tasks. Twenty-seven young adults (18–27 years) and 31 older adults (64–84 yrs) took part in the study. We used a robust fNIRS data methodology consisting of channel and region of interest analyses. Results showed differences in performance between task load conditions and age-related differences in reaction times but no age-group effects for accuracy. Older adults exhibited more bilateral PFC activation compared with young adults across all tasks and showed increases in brain activity in high compared to low load conditions. Our findings further support previous reports showing that older adults use compensatory recruitment of additional brain regions in PFC to maintain cognitive performance but go against the notion that such compensation is not present at higher cognitive loads. Additionally, our results indicate that fNIRS is a sensitive tool that can characterize adaptive cortical changes in healthy aging.

Changes in prefrontal cortical activation during motor imagery of precision gait with age and task difficulty

Previous studies have shown that imagined walking ability decreases with age in a similar manner as actual walking ability; however, little is known about the neural mechanisms underlying this aging effect. The present study investigates this issue, focusing on the effect of task difficulty and the involvement of the prefrontal cortex (PFC). Twenty healthy right-handed older adults (mean age 74.5 ± 3.3 years) participated in two experiments. In Experiment 1, the time participants took for actual and imagined walking along a 5-m walkway of three different path widths (15, 25, and 50 cm) were compared. In Experiment 2, the participants imagined walking along the aforementioned paths while PFC activity was measured using functional near-infrared spectroscopy. At the behavioral level, older adults exhibited longer mental and actual walking times for narrower paths and tended to overestimate their imagined walking times over their actual ones. However, overall, the magnitude of the overestimation did not differ by task difficulty. Regarding brain activity, older adults who overestimated mental walking times to a greater degree in the narrowest path exhibited decreased activation in the bilateral PFC. Moreover, compared with young adults in our previous study (Kotegawa et al., 2020), older adults with higher gait ability exhibited the same or smaller mental/actual walking times as well as decreased bilateral PFC activation in the most difficult condition. These results suggest that older adults, especially those with higher gait ability, can utilize neural mechanisms that are different from those of young adults when generating gait motor imagery.

Relationship Between Cerebral Blood Oxygenation and Electrical Activity During Mental Stress Tasks: Simultaneous Measurements of NIRS and EEG.

The incidence of stress-induced psychological and somatic diseases has been increasing rapidly, and it is important to clarify the neurophysiological mechanisms of stress response in order to establish effective stress management methods. We previously reported that the prefrontal cortex (PFC) plays an important role in stress response. In the present study, we employed near-infrared spectroscopy (NIRS) and electroencephalography (EEG) to investigate the characteristics of PFC activity during mental arithmetic tasks. A two-channel NIRS device was used to measure hemoglobin (Hb) concentration changes in the bilateral PFC during a mental arithmetic task (2min) in normal adults. Simultaneously, EEG was used to also measure bilateral PFC activity during the same task. We evaluated concentration changes of oxy-Hb induced by the task while analyzing α wave changes using power spectrum analysis. It was observed that oxy-Hb in the bilateral PFC increased significantly during the task (p<0.05), while α wave power in the PFC decreased significantly (p<0.01). The present results indicate that mental stress tasks caused the activation of the bilateral PFC. Simultaneous measurements of NIRS and EEG are useful for evaluating the neurophysiological mechanism of stress responses in the brain.

Assessing Neural Compensation With Visuospatial Working Memory Load Using Near-Infrared Imaging.

Alzheimer's disease is characterized by the progressive deterioration of cognitive abilities particularly working memory while mild cognitive impairment (MCI) represents its prodrome. It is generally believed that neural compensation is intact in MCI but absent in Alzheimer's disease. This study investigated the effects of increasing task load as a means to induce neural compensation through a novel visual working memory (VSWM) task using functional near-infrared spectroscopy (fNIRS). The bilateral prefrontal cortex (PFC) was explored due to its relevance in VSWM and neural compensation. A total of 31 healthy controls (HC), 12 patients with MCI and 18 patients with mild Alzheimer's disease (mAD) were recruited. Although all groups showed sensitivity in terms of behavioral performance (i.e. score) towards increasing task load (level 1 to 3), only in MCI load effect on cortical response (as measured by fNIRS) was significant. At lower task load, bilateral PFC activation did not differ between MCI and HC. Neural compensation in the form of hyperactivation was only noticeable in MCI with a moderate task load. Lack of hyperactivation in mAD, coupled with significantly poorer task performance across task loads, suggested the inability to compensate due to a greater degree of neurodegeneration. Our findings provided an insight into the interaction of cognitive load theory and neural compensatory mechanisms. The experiment results demonstrated the feasibility of inducing neural compensation with the proposed VSWM task at the right amount of cognitive load. This may provide a promising avenue to develop an effective cognitive training and rehabilitation for dementia population.

Pre-frontal Cortical Activity During Walking and Turning Is Reliable and Differentiates Across Young, Older Adults and People With Parkinson's Disease

Introduction: Mobility declines with age and further with neurodegenerative disorders, such as Parkinson's disease (PD). Walking and turning ability, in particular, are vital aspects of mobility that deteriorate with age and are further impaired in PD. Such deficits have been linked with reduction in automatic control of movement and the need for compensatory cognitive cortical control via the pre-frontal cortex (PFC), however the underlying neural mechanisms remain unclear. Establishing and using a robust methodology to examine PFC activity during continuous walking and turning via mobile functional near infra-red spectroscopy (fNIRS) may aid in the understanding of mobility deficits and help with development of appropriate therapeutics.This study aimed to: (1) examine test re-test reliability of PFC activity during continuous turning and walking via fNIRS measurement; and (2) compare PFC activity during continuous turning and walking in young, old and Parkinson's subjects.Methods: Twenty-five young (32.3 ± 7.5 years), nineteen older (65.4 ± 7.0 years), and twenty-four PD (69.3 ± 4.1 years) participants performed continuous walking and 360° turning-in-place tasks, each lasting 2 min. Young participants repeated the tasks a second time to allow fNIRS measurement reliability assessment. The primary outcome was PFC activity, assessed via measuring changes in oxygenated hemoglobin (HbO2) concentrations.Results: PFC activity during continuous walking and turning was moderately reproducible (Intra-class correlation coefficient = 0.67). The PD group had higher PFC activation than young and older adults during walking and turning, with significant group differences for bilateral PFC activation (p = 0.025), left PFC activation (p = 0.012), and the early period (first 40 s) of walking (p = 0.007), with greater activation required in PD. Interestingly, older adults had similar PFC activation to young adults across conditions, however older adults required greater activation than young adults during continuous turning, specifically the early period of the turning task (Cohens d = 0.86).Conclusions: PFC activity can be measured during continuous walking and turning tasks with acceptable reliability, and can differentiate young, older and PD groups. PFC activation was significantly greater in PD compared to young and older adults during walking, particularly when beginning to walk.

Working Memory, Cognitive Load andCardiorespiratory Fitness: Testing the CRUNCHModel with Near-Infrared Spectroscopy.

The present study aimed to examine the effects of chronological age and cardiorespiratory fitness (CRF) on cognitive performance and prefrontal cortex activity, and to test the compensation-related utilization of neural circuits hypothesis (CRUNCH). A total of 19 young adults (18–22 years) and 37 older ones (60–77 years) with a high or low CRF level were recruited to perform a working memory updating task under three different cognitive load conditions. Prefrontal cortex hemodynamic responses were continuously recorded using functional near-infrared spectroscopy, and behavioral performances and perceived difficulty were measured. Results showed that chronological age had deleterious effects on both cognitive performance and prefrontal cortex activation under a higher cognitive load. In older adults, however, higher levels of CRF were related to increased bilateral prefrontal cortex activation patterns that allowed them to sustain better cognitive performances, especially under the highest cognitive load. These results are discussed in the light of the neurocognitive CRUNCH model.

Using functional near-infrared spectroscopy (fNIRS) in the assessment of cognitive motor interference in post-stroke patients

Pre-frontal cortex (PFC) activity during dual task (DT) condition in stroke patients remains unclear. Functional near-infrared spectroscopy (fNIRS) is a functional neuroimaging technique for studying cortical activity. The purpose of this study was to evaluate the hemodynamic activity of the PFC in two DT conditions in post-stroke patients. Stroke patients were instructed to perform a cognitive task (n-back test) while continuously walking. They were evaluated in DT low (n-1 back) and high (n-2 back) cognitive load. fNIRS recorded bilateral PFC activity and GAITRite measured gait parameters in these two DT conditions. Cognitive performance was evaluated by the number of answers, the number of correct answers and the error percentage. The main endpoint was the DT cost, and we compared the change in oxygenated hemoglobin (an indicator of the changes in PFC activation) between the DT high and DT low. Eleven stroke patients (8 men and 3 women; mean age, 64.2 ± 19.5 years; range, 28–87 years) were included in the study. The DT cost was higher in DT n-2 (82.1% ± 15.6) compared with DT n-1 (61.2% ± 38.6), P = 0.007. There was no decline of spatiotemporal gait parameters with the increasing of cognitive load ( P > 0.05) and no difference for the number of answers in DT high versus low cognitive load ( P > 0.05). The number of correct answers was lower during DT high (3 ± 2.4) versus DT low (7.8 ± 3.6), P = 0.0015; and the error percentage was higher during DT high (62.3 ± 23.2) versus low condition (24.4 ± 12.9), P = 0.0001. There was a greater increase bilateral PFC activity during DT high versus DT low. The increasing DT cost allowed to maintain spatiotemporal gait parameters in DT high and led to a degradation of the cognitive performance. During DT, PFC activation might prioritize gait performances in stroke patients when the cognitive load is high.

Neural correlates of response inhibition in patients with bipolar disorder during acute versus remitted phase

Objectives: Elevated behavioural impulsivity has been shown to be a core feature of bipolar disorder. However, no study has so far investigated impulsivity-related brain activation in patients with BD during acute versus remitted phase. To address the question whether elevated behavioural impulsivity and its differential neural pathways is a state or trait marker of BD, we employed a combined stop signal-go/no-go task in 30 controls, and 37 depressed and 15 remitted patients who were retested.Methods: Frontal brain activation was recorded using near-infrared spectroscopy.Results: Behaviourally, we found increased impulsivity as indexed by higher stop signal reaction time for patients in their depressed phase while remitted patients did not differ from controls in any measure. In contrast, brain activation measurements revealed an opposite pattern: compared to controls, depressed patients did not show significant differences, while the remitted group displayed significantly decreased activation in bilateral prefrontal cortex during successful inhibition. Analysis of the remaining conditions (go, no-go, unsuccessful inhibition) did not reveal significant differences.Conclusions: Therefore, behavioural impulsivity and prefrontal hypoactivation do not seem to be a trait marker of BD. As only successful inhibition differentiated between groups, a specific dysfunction of this inhibitory process and its neural pathway may be postulated in BD.

Age-specific neural strategies to maintain motor performance after an acute social stress bout.

Stress due to cognitive demands and fatigue have shown to impair motor performance in older adults; however, the effect of social stress and its influence on prefrontal cortex (PFC) functioning in older adults during upper extremity motor performance tasks is not known. The present study explored the after-effects of an acute social stress bout on neural strategies, measured using PFC and hand/arm muscle activation, and adopted by younger and older adults to maintain handgrip force control. Nine older [74.1 (6.5) years; three men, six women] and ten younger [24.2 (5.0) years, four men, six women] adults performed handgrip force control trials at 30% maximum voluntary contractions before and after the Trier Social Stress Test (TSST). PFC activity was measured using functional near infrared spectroscopy and muscle activity from the flexor and extensor carpi radialis (FCR/ECR) was measured using electromyography. In general, aging was associated with decreased force steadiness and force complexity with a concomitant increase in bilateral PFC activity. While motor performance remained comparable before and after the TSST stress session in both age groups, the associated neural strategies differed between groups. While the stress condition was associated with lower FCR and ECR activity in younger adults despite no change in the PFC activation, stress was associated with increases in FCR activity in older adults. This stress-related compensatory neural strategy of increasing hand/arm muscle activation, potentially via the additional recruitment of the stress-motor neural circuitry, may have played a role in maintaining motor performance in older adults.

Cortical and Autonomic Stress Responses in Adults with High Versus Low Levels of Trait Anxiety: A Pilot Study.

Stress responses are mediated by complex patterns of cortical and autonomic activity. Earlier studies showed increased recruitment of the right prefrontal cortex (PFC) and parasympathetic withdrawal during a stress task; however, it remains unclear whether these responses change in relation to different levels of psychopathological symptoms, such as trait anxiety. The present study examines the effect of a mathematical task (with a control condition and a stressful/experimental condition) on the PFC and autonomic activity, using a two-channel near infrared spectroscopy (NIRS) and an ECG monitoring system. After a preliminary screening of 65 subjects, a sample of 12 individuals (6 with the highest and 6 with the lowest scores on an anxiety questionnaire, i.e. the STAI trait) was selected. The two groups were similar regarding demographic variables (age, sex, body mass index) and baseline STAI-state scores. Repeated measures ANOVAs were used to compare changes from baseline in oxyhemoglobin (oxy-Hb), heart rate (HR) and root mean square of successive differences (RMSSD) between the two groups. Individuals affected by high levels of trait anxiety showed a reduced bilateral PFC activity during the entire experimental procedure compared to those with low anxiety. No differences in NIRS channels were found between the two groups. During both conditions, RMSSD was lower among individuals affected by high levels of anxious symptoms. Finally, throughout the procedure, changes in HR were higher in the anxious group. Overall, these findings suggest a reduced PFC activity and a larger parasympathetic withdrawal during a stress task in individuals with high levels of trait anxiety compared to those with low anxiety. These results could represent a starting point for future NIRS and ECG studies on the relationship between mental disorders and acute stress responses.

Comparison of associative recognition versus source recognition

The importance of the medial temporal lobe (MTL) for memory of arbitrary associations has been well established. However, the contribution of the MTL in concurrent retrieval of different classes of associations remains unclear. The present fMRI study investigated neural correlates of concurrent retrieval of associative and source memories. Participants studied a list of object pairs with two study tasks and judged the status and context of the pair during test. Associative retrieval was supported by neural activity in bilateral prefrontal cortex and left ventral occipito-temporal cortex, while source recognition was linked to activity in the right caudate. Both the hippocampus and MTL cortex showed retrieval activity for associative and source memory. Importantly, greater brain activity for successful associative recognition accompanied with successful source recognition was evident in left perirhinal and anterior hippocampal regions. These results indicate that the MTL is critical in the retrieval of different classes of associations.

Crack cocaine use impairs anterior cingulate and prefrontal cortex function in women with HIV infection.

Crack cocaine use is associated with impaired verbal memory in HIV-infected women more than uninfected women. To understand the neural basis for this impairment, this study examined the effects of crack cocaine use on activation of the prefrontal cortex (PFC) and strategic encoding during a verbal memory task in HIV-infected women. Three groups of HIV-infected women from the Chicago Consortium of the Women's Interagency HIV Study were compared: current users of crack cocaine (n = 10), former users of cocaine (n = 11), and women who had never used cocaine (n = 9). Participants underwent functional magnetic resonance imaging during a verbal memory task and completed a neuropsychological test of verbal memory. On the neuropsychological test, current crack users performed significantly worse than other groups on semantic clustering, a measure of strategic encoding, p < 0.05. During encoding, activation in left anterior cingulate cortex (ACC) was lower in current and former cocaine users compared to never users. During recognition, activation in bilateral PFC, specifically left dorsal medial PFC and bilateral dorsolateral PFC, was lower in current and former users compared to women who had never used cocaine. Lower activation in left dorsolateral PFC was correlated with worse performance on the recognition task, p < 0.05. The verbal learning and memory deficits associated with cocaine use in women with HIV may be partially accounted for by alterations in ACC and PFC function.

Transition to Psychosis Associated With Prefrontal and Subcortical Dysfunction in Ultra High-Risk Individuals

People at ultra high risk (UHR) of psychosis have an elevated risk of developing a psychotic disorder, but it is difficult to predict which individuals will make a transition to frank illness. We investigated whether functional magnetic resonance imaging (fMRI) in conjunction with a phonological fluency task at presentation could distinguish subjects who subsequently developed psychosis from those who did not. Sixty-five subjects (41 with an UHR and 24 healthy controls) were assessed at clinical presentation using fMRI, in conjunction with a verbal fluency task. [18F]-DOPA positron emission tomography (PET) data were also available in a subgroup of 21 UHR and 14 healthy controls subjects. UHR subjects were followed clinically for at least 2 years. Compared with UHR subjects who did not become psychotic, UHR subjects who subsequently developed psychosis showed increased activation in bilateral prefrontal cortex (PFC), brainstem (midbrain/basilar pons), the left hippocampus, and greater midbrain-PFC connectivity. Furthermore, exploratory analysis of [18F]-DOPA PET data showed that transition to psychosis was associated with elevated dopaminergic function in the brainstem region. In people at high risk of psychosis, increased activation in a network of cortical and subcortical regions may predict the subsequent onset of illness. Functional neuroimaging, in conjunction with clinical assessment and other investigations, may facilitate the prediction of outcome in subjects who are vulnerable to psychosis.

Serotonin Transporter Polymorphism Modulates N-Back Task Performance and fMRI BOLD Signal Intensity in Healthy Women

ContextExploring intermediate phenotypes within the human brain's functional and structural circuitry is a promising approach to explain the relative contributions of genetics, complex behaviors and neural mechanisms in the development of major depressive disorder (MDD). The polymorphic region 5-HTTLPR in the serotonin transporter gene (SLC6A4) has been shown to modulate MDD risk, but the neural underpinnings are incompletely understood.Objective37 right handed healthy women between 21 and 61 years of age were invited to participate in an fMRI modified n-back study. The functional polymorphism 5-HTTLPR located in the promoter region of the SLC6A4 gene was genotyped using polymerase chain reaction (PCR).ResultsShort 5-HTTLPR allele carriers showed more blood-oxygen-level-dependent (BOLD) bilateral prefrontal cortex activation in the right [F(2, 30) = 4.8, η2 = .25, p = .026] and left [F(2, 30) = 4.1, η2 = .22, p = .015] inferior frontal gyrus pars triangularis with increasing n-back task difficulty relative to long 5-HTTLPR allele carriers. Short 5-HTTLPR allele carriers had inferior task performance on the most difficult n-back condition [F(2, 30) = 4.9, η2 = .26, p = .014].ConclusionsThis activation pattern found in healthy at risk individuals resembles an activation pattern that is typically found in patients suffering from acute MDD. Altered function in these areas may reflect intermediate phenotypes and may help explain the increased risk of depression in short 5-HTTLPR allele carriers.

Modulatory Effects of Levodopa on Cognitive Control in Young but not in Older Subjects: A Pharmacological fMRI Study

Older individuals show decline of prefrontal cortex (PFC) functions which may be related to altered dopaminergic neurotransmission. We investigated the effects of aging and dopaminergic stimulation in 15 young and 13 older healthy subjects on the neural correlates of interference control using fMRI. In a double-blind, placebo-controlled within-subject design, subjects were measured after levodopa (100 mg) or placebo administration. In each session, subjects performed a visual-spatial interference task based on a Stroop/Simon-like paradigm. Across age groups, interference (incongruent relative to congruent trials) was associated with activations in the presupplementary motor area, ACC, and intraparietal cortex. Increased interference was found behaviorally in older volunteers. Differential activation in left dorsolateral PFC in young subjects and bilateral PFC activity in older subjects was observed to be associated with interference control. Performance deteriorated under levodopa only in young subjects. This was accompanied by an increase of neural activity in ACC (p < .05; small-volume correction for multiple comparisons). Worsening of performance under levodopa in young subjects and the associated effect on ACC may indicate that overstimulation of the dopaminergic system compromises interference control. This supports the inverted-U-shaped model of neurotransmitter action.

Exercise improves executive function and achievement and alters brain activation in overweight children: A randomized, controlled trial.

This experiment tested the hypothesis that exercise would improve executive function. Sedentary, overweight 7- to 11-year-old children (N = 171, 56% girls, 61% Black, M ± SD age = 9.3 ± 1.0 years, body mass index [BMI] = 26 ± 4.6 kg/m², BMI z-score = 2.1 ± 0.4) were randomized to 13 ± 1.6 weeks of an exercise program (20 or 40 min/day), or a control condition. Blinded, standardized psychological evaluations (Cognitive Assessment System and Woodcock-Johnson Tests of Achievement III) assessed cognition and academic achievement. Functional MRI measured brain activity during executive function tasks. Intent to treat analysis revealed dose-response benefits of exercise on executive function and mathematics achievement. Preliminary evidence of increased bilateral prefrontal cortex activity and reduced bilateral posterior parietal cortex activity attributable to exercise was also observed. Consistent with results obtained in older adults, a specific improvement on executive function and brain activation changes attributable to exercise were observed. The cognitive and achievement results add evidence of dose-response and extend experimental evidence into childhood. This study provides information on an educational outcome. Besides its importance for maintaining weight and reducing health risks during a childhood obesity epidemic, physical activity may prove to be a simple, important method of enhancing aspects of children's mental functioning that are central to cognitive development. This information may persuade educators to implement vigorous physical activity.

Neural Mechanisms of Interference Control in Working Memory: Effects of Interference Expectancy and Fluid Intelligence

BackgroundA critical aspect of executive control is the ability to limit the adverse effects of interference. Previous studies have shown activation of left ventrolateral prefrontal cortex after the onset of interference, suggesting that interference may be resolved in a reactive manner. However, we suggest that interference control may also operate in a proactive manner to prevent effects of interference. The current study investigated the temporal dynamics of interference control by varying two factors – interference expectancy and fluid intelligence (gF) – that could influence whether interference control operates proactively versus reactively.Methodology/Principal FindingsA modified version of the recent negatives task was utilized. Interference expectancy was manipulated across task blocks by changing the proportion of recent negative (interference) trials versus recent positive (facilitation) trials. Furthermore, we explored whether gF affected the tendency to utilize specific interference control mechanisms. When interference expectancy was low, activity in lateral prefrontal cortex replicated prior results showing a reactive control pattern (i.e., interference-sensitivity during probe period). In contrast, when interference expectancy was high, bilateral prefrontal cortex activation was more indicative of proactive control mechanisms (interference-related effects prior to the probe period). Additional results suggested that the proactive control pattern was more evident in high gF individuals, whereas the reactive control pattern was more evident in low gF individuals.Conclusions/SignificanceThe results suggest the presence of two neural mechanisms of interference control, with the differential expression of these mechanisms modulated by both experimental (e.g., expectancy effects) and individual difference (e.g., gF) factors.

Depressive symptoms and baseline prefrontal EEG alpha activity: A study utilizing Ecological Momentary Assessment

Prefrontal cortex (PFC) electroencephalography (EEG) alpha asymmetry has been found in individuals with major depression. However, EEG activity has never been examined in regard to specific depressive symptoms. We examine the relationship between resting baseline PFC alpha activity and both rumination and self-esteem in a depressed outpatient group ( N = 6) and a healthy control group ( N = 7) using high-density EEG sampling and multiple longitudinal self report measures, i.e. Ecological Momentary Assessment (EMA). Symptom measures were collected five times daily for 7 days, i.e. 35 assessments. Using a mixed-level analysis, significant Group × Hemisphere interactions for PFC sites and both rumination and self-esteem were found. Within the depressed group, lower bilateral PFC activity predicted higher levels of rumination, and lower right PFC activity predicted higher levels of self-esteem. There were no significant effects for the control group. Results indicate that specific symptoms of depression are uniquely associated with patterns of PFC EEG alpha activity.

Intramuscular Testosterone Treatment in Elderly Men: Evidence of Memory Decline and Altered Brain Function

Recent clinical trials of im testosterone in eugonadal men suggest positive effects on verbal memory, but other studies find no effect. Our objective was to determine whether supraphysiological testosterone influences verbal memory and brain function during a verbal memory task in healthy eugonadal older men. Fifteen cognitively normal men, aged 66-86 yr, participated in a randomized, double-blind, placebo-controlled crossover trial involving 9 months of participation per participant at a hospital-based research facility. We used testosterone enanthate (200 mg im every other week for 90 d) crossed over with placebo (sesame oil vehicle im) with a 90-d washout between treatments. Performance was assessed on a standardized verbal memory test, and brain activity (relative glucose metabolic rates) in medial temporal and frontal regions was measured with positron emission tomography during a verbal memory task. Treatment increased total testosterone by 241%. Behavioral results showed a significant decrease in short-delay verbal memory with treatment (P < 0.05, effect size = 0.59 sd) and a nonsignificant decrease on a composite verbal memory measure (P = 0.09, effect size = 0.48 sd). Positron emission tomography scans revealed decreased relative activity in ventromedial temporal cortex (i.e. right amygdala/entorhinal cortex) and increased relative activity in bilateral prefrontal cortex with treatment. Decreased verbal memory and altered relative activity in medial temporal and prefrontal regions suggest possible detrimental effects of supraphysiological testosterone supplementation in elderly men. The results do not rule out potential benefits with other regimens, cognitive tests, or populations.

Failure to Regulate: Counterproductive Recruitment of Top-Down Prefrontal-Subcortical Circuitry in Major Depression

Although depressed mood is a normal occurrence in response to adversity in all individuals, what distinguishes those who are vulnerable to major depressive disorder (MDD) is their inability to effectively regulate negative mood when it arises. Investigating the neural underpinnings of adaptive emotion regulation and the extent to which such processes are compromised in MDD may be helpful in understanding the pathophysiology of depression. We report results from a functional magnetic resonance imaging study demonstrating left-lateralized activation in the prefrontal cortex (PFC) when downregulating negative affect in nondepressed individuals, whereas depressed individuals showed bilateral PFC activation. Furthermore, during an effortful affective reappraisal task, nondepressed individuals showed an inverse relationship between activation in left ventrolateral PFC and the amygdala that is mediated by the ventromedial PFC (VMPFC). No such relationship was found for depressed individuals, who instead show a positive association between VMPFC and amygdala. Pupil dilation data suggest that those depressed patients who expend more effort to reappraise negative stimuli are characterized by accentuated activation in the amygdala, insula, and thalamus, whereas nondepressed individuals exhibit the opposite pattern. These findings indicate that a key feature underlying the pathophysiology of major depression is the counterproductive engagement of right prefrontal cortex and the lack of engagement of left lateral-ventromedial prefrontal circuitry important for the downregulation of amygdala responses to negative stimuli.