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Human dorsal and ventral auditory streams subserve rehearsal-based and echoic processes during verbal working memory.

To hear a sequence of words and repeat them requires sensory-motor processing and something more-temporary storage. We investigated neural mechanisms of verbal memory by using fMRI and a task designed to tease apart perceptually based ("echoic") memory from phonological-articulatory memory. Sets of two- or three-word pairs were presented bimodally, followed by a cue indicating from which modality (auditory or visual) items were to be retrieved and rehearsed over a delay. Although delay-period activation in the planum temporale (PT) was insensible to the source modality and showed sustained delay-period activity, the superior temporal gyrus (STG) activated more vigorously when the retrieved items had arrived to the auditory modality and showed transient delay-period activity. Functional connectivity analysis revealed two topographically distinct fronto-temporal circuits, with STG co-activating more strongly with ventrolateral prefrontal cortex and PT co-activating more strongly with dorsolateral prefrontal cortex. These argue for separate contributions of ventral and dorsal auditory streams in verbal working memory.

Adult↗

Imaging the mental components of a planning task.

The Tower of London task (TOL) has been widely used to assess the ability to plan. We used H(2)O(15)-positron emission tomography to isolate some of the cognitive components of the task. Ten male volunteers were scanned twice in each of six conditions. In two conditions (plan) the subjects had to plan the best solution to TOL problems. In two other conditions (plan-control) the subjects were required to generate four moves without being constrained by a goal. In plan and plan-control tasks the subjects either planned the moves and then executed them (MOVE conditions) or imagined the necessary moves (IMAGINE conditions). The plan and plan-control tasks were matched for the working memory load and "initial thinking time". A visuomotor control task and rest served as baseline conditions. Performance on the plan tasks, in contrast to the baseline conditions, was associated with activation in the dorsal prefrontal cortex, premotor and parietal cortex, and cerebellum. Performance of the plan-control tasks was associated with activation of the same areas. Contrasting the plan with the plan-control tasks revealed no residual activation in the prefrontal cortex. These data show that the activity of the dorsolateral prefrontal cortex on the TOL can be accounted for by the components of generating, selecting and/or remembering mental moves. The task of relating the moves to the goal involves a comparison with a representation of the goal in posterior association areas. We did not find evidence that activation of the dorsal prefrontal cortex is specifically related to the evaluation of a path towards a specified goal, a key component of planning.

Adult↗

Magnetic fields from human prefrontal cortex differ during two recognition tasks.

The present study represents our second successful use of magnetoencephalography to identify different sources of human prefrontal activity corresponding to subjects' engagement in different tasks. We used two visual recognition tasks: a familiar person recognition and an abstract pattern recognition task in the context of a design suitable for eliciting Contingent Negative Variations (CNVs) and their concurrent slow magnetic fields in this preliminary study of 5 subjects. Each trial of either task was started by one of two specific warning symbols (S1), indicating whether a person's picture or an abstract pattern should be attended during the presentation of a second stimulus (S2), and compared to the corresponding person's picture or pattern contained in the third stimulus, (S3) that followed. The S2 and S3 stimuli were common to both tasks, and were composed of patterns made with four line traces superimposed on photographs of persons familiar to each subject. Subjects responded with a right hand button press, following S3, indicating their judgments regarding the identity of the patterns or persons' pictures contained in the S2 and the S3 stimuli, for the two tasks, respectively. Results showed that the sources of the CNV equivalent magnetic fields were localized in different cortical regions depending on the task and that this difference was consistent across all subjects. The sources were localized in the right hemisphere, in medial areas of the prefrontal cortex for the person recognition task and in the dorsolateral prefrontal cortex for the pattern recognition task. The same degree of consistency was not found for the left hemisphere sources. Moreover, as in our previous study, we found no difference between the sources active during the first and the second CNV periods (occurring during the S1-S2 and the S2-S3 intervals, respectively), within each task condition.

Adult↗

Neurocognitive measures of prefrontal cortical dysfunction in schizophrenia.

Frontal lobe dysfunction in individuals with schizophrenia has frequently been detected using both neuroimaging and neuropsychological testing. Results from previous studies vary in the findings of regional specificity vs. generalized frontal cortical dysfunction. We sought to examine potential regional differences in frontal cortical functioning among patients with schizophrenia vs. a comparison group using two different neurocognitive tasks: the Gambling Task (GT) and the Wisconsin Card Sorting Test (WCST). In general, the GT is thought to reflect function of the ventromedial prefrontal cortex (VMPFC), while the WCST reflects function of the dorsolateral prefrontal cortex (DLPFC). Twenty individuals with schizophrenia or schizoaffective disorder and 15 nonpsychiatrically ill comparison subjects underwent an assessment battery consisting of the GT, WCST, and positive and negative symptom ratings. Patients with schizophrenia performed worse on the GT with respect to total monetary gain (p=0.05) and total monetary loss (p<0.05). They also preferred disadvantaged vs. advantaged cards (p<0.04). Surprisingly, WCST performance was poor in both groups and was not significantly different between groups. These findings are at some variance with those in the previously reported literature, but nonetheless support the idea that prefrontal cortical areas mediating different cognitive tasks may be distinguished by specific neurocognitive assessments.

Adolescent↗

The role of prefrontal cortex in verbal episodic memory: rTMS evidence.

Long-term, episodic memory processing is supposed to involve the prefrontal cortex asymmetrically. Here we investigate the role of the dorsolateral prefrontal cortex (DLPFC) in encoding and retrieval of semantically related or unrelated word pairs. Subjects were required to perform a task consisting of two parts: a study phase (encoding), in which word pairs were presented, and a test phase (retrieval), during which stimuli previously presented had to be recognized among other stimuli. Consistently with our previous findings using pictures, repetitive transcranial magnetic stimulation (rTMS) had a significant impact on episodic memory. The performance was significantly disrupted when rTMS was applied to the left or right DLPFC during encoding, and to the right DLPFC in retrieval, but only for unrelated word pairs. These results indicate that the nature of the material to be remembered interacts with the encoding-retrieval DLPFC asymmetry; moreover, the crucial role of DLPFC is evident only for novel stimuli.

Adult↗

Interference with performance of a response selection task that has no working memory component: an rTMS comparison of the dorsolateral prefrontal and medial frontal cortex.

It has been suggested that the dorsolateral prefrontal cortex (DLPFC) is involved in free selection (FS), the process by which subjects themselves decide what action to perform. Evidence for this proposal has been provided by imaging studies showing activation of the DLPFC when subjects randomly generate responses. However, these response selection tasks have a hidden working memory element and it has been widely reported that the DLPFC is activated when subjects perform tasks which involve working memory. The primary aim of this experiment was to establish if the DLPFC is genuinely involved in response selection. We used repetitive transcranial magnetic stimulation (rTMS) to investigate whether temporary interference of the DLPFC could disrupt performance of a response selection task that had no working memory component. Subjects performed tasks in which they made bimanual sequences of eight nonrepeating finger movements. In the FS task, subjects chose their movements at random while a computer monitor displayed these moves. This visual feedback obviated the need for subjects to maintain their previous moves "on-line." No selection was required for the two control tasks as responses were cued by the visual display. The attentional demands of the control tasks varied. In the high load (HL) version, subjects had to maintain their attention throughout the sequence, but this requirement was absent in the low load (LL) task. rTMS over the DLPFC slowed response times on the FS task and at the end of the sequence on the HL task, but had no effect on the LL task. rTMS over the medial frontal cortex (MFC) slowed response times on the FS task but had no effect on the HL task. This suggests that a response selection task without a working memory load will depend on the DLPFC and the MFC. The difference appears to be that the DLPFC is important when selecting between competing responses or when concentrating if there is a high attentional demand, but that the MFC is only important during the response selection task.

Attention↗

Differentiating among prefrontal substrates in psychopathy: neuropsychological test findings.

Frontal lobe and consequent executive dysfunction have long been related to psychopathy. More recently, there have been suggestions that specific regions of frontal cortex, rather than all of frontal cortex, may be implicated in psychopathy. To examine this issue, the authors presented 25 individuals with psychopathy and 30 comparison individuals with measures preferentially indexing the orbitofrontal cortex (OFC; object alternation task), dorsolateral prefrontal cortex (DLPFC; spatial alternation task), and anterior cingulate cortex (ACC; number-Stroop reading and counting tasks). The individuals with psychopathy showed significant impairment on the measure preferentially sensitive to OFC functioning. In contrast, the 2 groups did not show impairment on the measures preferentially sensitive to the functioning of the DLPFC or ACC. These results are interpreted with reference to executive dysfunction accounts of the disorder.

Antisocial Personality Disorder↗

Cross-tissue immune profiling of APOE &#x3b5;4 reveals early dysregulation in Alzheimer's disease.

INTRODUCTION: Apolipoprotein E (APOE) &#x3b5;4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), but its contribution to disease pathogenesis remains incompletely understood. METHODS: Here, we integrate proteomic profiling of plasma (n&#xa0;=&#xa0;9028), cerebrospinal fluid (n&#xa0;=&#xa0;1099), dorsolateral prefrontal cortex (n&#xa0;=&#xa0;720), and superior temporal gyrus (n&#xa0;=&#xa0;105) to define the immune phenotype associated with APOE &#x3b5;4. RESULTS: We identify a conserved, allele dose-dependent pro-inflammatory immune protein signature across peripheral and central tissues independent of AD diagnosis. This signature also emerges in patient-derived cortical organoids prior to amyloid beta and tau pathology, supporting a genotype-driven mechanism. Cross-tissue comparisons reveal shared innate and antiviral responses alongside tissue-specific immune signaling. Notably, a 12-week medical ketogenic diet partially reversed the APOE &#x3b5;4 immune signature. DISCUSSION: These findings position immune dysregulation as an early and tractable driver of AD risk in APOE &#x3b5;4 carriers with direct implications for targeted prevention strategies.

Humans↗

Continuous theta-burst stimulation over the right DLPFC modulates central executive network connectivity in depression: exploratory analysis of a randomized clinical trial.

Previous studies suggest that transcranial magnetic stimulation exerts antidepressant effects and is associated with alterations in functional connectivity (FC), but the neural correlates remain unclear. This exploratory sham-controlled trial investigated the effect of continuous theta-burst stimulation (cTBS) over the right dorsolateral prefrontal cortex (DLPFC) on FC in major depressive disorder (MDD). Seventy MDD patients were randomized to receive two-week treatment of personalized cTBS or sham stimulation. Resting-state fMRI was performed at baseline and post-treatment. Ultimately, 31 patients in the active cTBS group and 28 patients in the sham group passed imaging quality control and were included in the final analysis. To identify the FC that may have been influenced by cTBS treatment, two complementary FC analyses were conducted: (1) voxel-wise degree centrality (DC) followed by seed-based FC, and (2) an individual FC analysis based on the stimulation targets. Furthermore, correlations between FC changes and clinical symptoms improvement were examined. Both groups exhibited reductions of depression scores, with greater improvement in the active group. Compared to the sham group, active cTBS showed increased DC in the precuneus and elevated FC between the precuneus (within the para-cingulate network) and the right inferior parietal lobule (IPL) and DLPFC. Further stimulation target-based analysis revealed increased FC between stimulation targets and both the precuneus and visual regions following treatment. Our findings reveal neural changes associated with cTBS over the right DLPFC in MDD, notably involving the precuneus and its connectivity with the right IPL/DLPFC, suggesting alterations within the central executive network. TRIAL REGISTRATION: chictr.org.cn; ChiCTR2300068273.

Humans↗

The effect of tryptophan depletion on brain activation measured by functional magnetic resonance imaging during the Stroop test in healthy subjects.

We investigated the role of serotonin in cognitive activation of the frontal cortex. The serotonergic system was affected by the administration of an amino acids mixture without tryptophan (tryptophan depletion). In a placebo-controlled double-blind cross-over study with 20 healthy volunteers, we tested the hypothesis that a tryptophan (serotonin) decrease affects the activation of prefrontal cortex by the Stroop test. Cognitive brain activation was evaluated by functional magnetic resonance imaging (fMRI). Tryptophan depletion decreased the plasma tryptophan level up to 90 % for five hours after the tryptophan-free drink had been consumed when compared with the same mixture with tryptophan (p?0.0001). Tryptophan depletion did not affect the Stroop test performance. We compared fMRI activation in both conditions (tryptophan depletion and placebo) with plasma tryptophan levels as the covariates. The tryptophan depletion increased the activation (fMRI signal) in the bilateral mediofrontal cortex, anterior cingulate and left dorsolateral prefrontal cortex. The present findings allow the postulate that serotonergic medial forebrain and cingulum bundle pathways play a role in the activity of cortical structures involved in Stroop test processing.

Adult↗

Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia.

Anatomical and molecular abnormalities of excitatory neurons in the dorsolateral prefrontal cortex (DLPFC) are found in schizophrenia. We hypothesized that brain-derived neurotrophic factor (BDNF), a protein capable of increasing pyramidal neuron spine density and augmenting synaptic efficacy of glutamate, may be abnormally expressed in the DLPFC of patients with schizophrenia. Using an RNase protection assay and Western blotting, we detected a significant reduction in BDNF mRNA (mean=23%) and protein (mean=40%) in the DLPFC of patients with schizophrenia compared to normal individuals. At the cellular level, BDNF mRNA was expressed at varying intensities in pyramidal neurons throughout layers II, III, V, and VI of DLPFC. In patients with schizophrenia; neuronal BDNF expression was decreased in layers III, V and VI. Our study demonstrates a reduction in BDNF production and availability in the DLPFC of schizophrenics, and suggests that intrinsic cortical neurons, afferent neurons, and target neurons may receive less trophic support in this disorder.

Adolescent↗

Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia.

Patients with schizophrenia have reduced neurotrophin levels in their dorsolateral prefrontal cortex (DLPFC) compared to normal unaffected individuals. The tyrosine kinase-containing receptors, trkB and trkC, mediate the growth-promoting effects of neurotrophins and respond to changes in growth factor availability. We hypothesized that trkB and/or trkC expression would be altered in the DLPFC of patients with schizophrenia. We measured mRNA encoding the tyrosine kinase domain (TK+)-containing form of trkB and measured pan trkC mRNA in schizophrenics (N=14) and controls (N=15) using in situ hybridization. TrkB and trkC mRNAs were detected in large and small neurons in multiple cortical layers of the human DLPFC. We found significantly diminished expression of trkB(TK+) mRNA in large neurons in multiple cortical layers of patients as compared to controls, while small neurons also showed reductions in trkB(TK+) mRNA that did not reach statistical significance. In normals, strong positive correlations were found between trkB(TK+) mRNA levels and brain-derived neurotrophic factor (BDNF) mRNA levels among various neurons, while no correlation between BDNF and trkB(TK+) was found in patients with schizophrenia. TrkC mRNA was also reduced in the DLPFC of schizophrenics in large neurons in layers II, III, V and VI and in small neurons in layer IV. Since neurons in the DLPFC integrate and communicate signals to various cortical and subcortical regions, these reductions in growth factor receptors may compromise the function and plasticity of the DLPFC in schizophrenia.

Adolescent↗

[Research on effect of acupuncture at Sanyinjiao on brain function by means of positron emission tomographic imaging].

OBJECTIVE: To explore the mechanism of puncturing at Sanyinjiao (SP6) on modulatory function of central nerve system. METHODS: Positron emission tomography (PET) was performed, using 18F-FDG as contrast medium, in six healthy female volunteers before and after puncturing right SP6 to detect the cerebral districts with changed glucose metabolism, using statistical parametric mapping (SPM) analysis. RESULTS: Glucose metabolism was increased in contralateral primary somatosensory cortex, primary somatic motor cortex, pre-supplementary motor cortex (BA8), and medial prefrontal cortex (BA10), bilateral supplementary motor cortex (BA6), anterior cingulate gyrus (BA24, BA32), and dorsolateral prefrontal cortex (BA9), while glucose metabolism was decreased in lingual gyrus (BA17,18), hippocampus and parahippocampal gyrus (BA28, BA35, BA30). CONCLUSION: Functions of cerebral districts with changed glucose metabolism after puncturing SP6 was well parallels to the clinical effect of puncturing SP6, illustrating the brain plays a great role in the body regulation of acupuncture at SP6, which possibly was the central foundation of acupuncture therapy.

Acupuncture↗

Prefrontal cortex function, quasi-physiological stimuli, and synaptic plasticity.

The prelimbic area of rat medial frontal cortex may be functionally analogous to human/primate dorsolateral prefrontal cortex. This area may be involved in selective attention to the external stimuli and the coupling of the attention to a repertory of actions. It was suggested that this function may rely on a form of long-term memory [Biol. Rev. 77 (2002) 563]. Indeed, during learning of this type of behavior, a portion of prelimbic neurons persistently change their firing characteristics [Prog. Brain Res. 126 (2000) 287]. It is therefore important to study long-term potentiation (LTP) and depression (LTD) in rat prelimbic neurons. In this article, the author first briefly reviews recent findings on the prefrontal cortex function and discusses that the prefrontal cortex may be involved in long-term memory. Second, the author will show some new results which indicate that quasi-physiological patterns of stimuli mimicking prelimbic neuronal activity during behavior can induce LTP in prelimbic pyramidal neuron synapses. These results suggest that prelimbic neuronal activity during behavior may lastingly modify prelimbic synaptic efficacy.

Animals↗

Effects of treatment with the atypical neuroleptic quetiapine on working memory function: a functional MRI follow-up investigation.

BACKGROUND: Working memory as a part of higher-order executive functions is defined by the parallel storage and processing of information. Recent functional fMRI studies have revealed a functional, interregional disintegration of a neuronal network connecting cortical, subcortical and cerebellar regions in schizophrenic patients (SZ). Cognitive impairment in working memory is a core psychopathological correlate of schizophrenic symptoms. Atypical neuroleptics such as quetiapine have shown good efficacy in treating positive and negative symptoms. The presented study evaluated the impact of a neuroleptic steady state treatment with quetiapine on the altered working memory activation patterns in schizophrenia. METHODS: Patients were examined by fMRI at baseline and after 12 weeks of steady state treatment with quetiapine. Matched healthy controls (HC) underwent baseline examination. In the scanner, stimuli were presented in a 2-back and 0-back condition of a working memory (wm) paradigm, whereby a degraded and a non-degraded version were used each time. Additionally, behavioural responses (reaction time to target stimuli and error ratio) were measured. RESULTS: At baseline, healthy controls revealed increased activity in the frontal lobe, especially in regions of the prefrontal cortex. Compared to HC, SZ showed hypoactivation in the right dorsolateral prefrontal cortex (DLPFC) and the ventrolateral prefrontal cortex (VLPFC) bilaterally for the 2-back condition. In the 2-back degraded condition there was a hypoactivation in both, the right DLPFC and the VLPFC. Additionally, patients showed bilaterally decreased activation in the basalganglia in the 2-back and in the right caudatus in the 2-back degraded condition compared to healthy controls. After treatment with quetiapine, patients activations patterns were increased. The pre-post comparison of the 2-back condition revealed a significant increase of activation in the left VLPFC at a significance level of 0.001 (uncorrected). The 2-back degraded condition led to a significant activation pattern in the lingual gyrus and the right precuneus. In both wm conditions, at baseline there were no differences in reaction time but only a worse performance in SZ. After treatment, behavioural measurement of responses, including reaction time and performance, showed slight improvements in SZ, although these did not reach statistical significance. CONCLUSIONS: The neuronal networks underlying working memory are clearly altered in schizophrenia. After 12 weeks of treatment with quetiapine monotherapy, patients showed significant clinical improvement and revealed increased BOLD activity in the VLPFC during a working memory task, although there was no improvement of cognitive performance.

Adult↗

Brain activation of spider phobics towards disorder-relevant, generally disgust- and fear-inducing pictures.

The present functional magnetic resonance imaging study investigated the fear and disgust reactivity of patients suffering from spider phobia. Ten phobics and 13 control subjects were scanned while viewing alternating blocks of phobia-relevant, generally fear-inducing, disgust-inducing and affectively neutral pictures. The patient group rated the spider pictures as being more disgust and fear evoking than the control group, and showed greater activation of the visual association cortex, the amygdalae, the right dorsolateral prefrontal cortex and the right hippocampus. Specific phobia-related activation occurred in the supplementary motor area. The patients also showed greater amygdala activation during the presentation of generally disgust- and fear-inducing pictures. This points to an elevated sensitivity to repulsive and threatening stimuli in spider phobics and implicates the amygdala as a crucial neural substrate.

Adult↗

Neural substrates of faulty decision-making in abstinent marijuana users.

Persistent dose-related cognitive decrements have been reported in 28-day abstinent heavy marijuana (MJ) users. However, the neural substrates of these decrements in cognitive performance are not known. This study aimed to determine if 25-day abstinent MJ users show persistent dose-related alterations in performance and brain activity using PET H(2)(15)O during the Iowa Gambling Task-IGT (a decision-making task). Eleven heavy MJ users and 11 non-drug users participated. The MJ group resided in an inpatient research unit at the NIH/NIDA-IRP for 25 days prior to testing to ensure abstinence. A dose-related association was found between increased MJ use and lower IGT performance and alterations in brain activity. The MJ group showed greater activation in the left cerebellum and less activation in the right lateral orbitofrontal cortex (OFC) and the right dorsolateral prefrontal cortex (DLPFC) than the Control group. When the MJ group was divided into Moderate (8-35 joints/week) and Heavy users (53-84 joints/week), the Heavy MJ group showed less activation in the left medial OFC and greater activation in the left cerebellum than the Moderate group. However, brain activity and task performance were similar between the Moderate MJ users and the Control group, suggesting a "threshold effect". These preliminary findings indicate that very heavy users of MJ have persistent decision-making deficits and alterations in brain activity. Specifically, the Heavy MJ users may focus on only the immediate reinforcing aspects of a situation (i.e., getting high) while ignoring the negative consequences. Thus, faulty decision-making could make an individual more prone to addictive behavior and more resistant to treatment. Finally, it is unclear if these neurologic findings will become progressively worse with continued heavy MJ use or if they will resolve with abstinence from MJ use.

Adult↗

Brain activity correlates differentially with increasing temporal complexity of rhythms during initialisation, synchronisation, and continuation phases of paced finger tapping.

Activity in parts of the human motor system has been shown to correlate with the complexity of performed motor sequences in terms of the number of limbs moved, number of movements, and number of trajectories. Here, we searched for activity correlating with temporal complexity, in terms of the number of different intervals produced in the sequence, using an overlearned tapping task. Our task was divided into three phases: movement selection and initiation (initiate), synchronisation of finger tapping with an external auditory cue (synchronise), and continued tapping in absence of the auditory pacer (continue). Comparisons between synchronisation and continuation showed a pattern in keeping with prior neuroimaging studies of paced finger tapping. Thus, activation of bilateral SMA and basal ganglia was greater in continuation tapping than in synchronisation tapping. Parametric analysis revealed activity correlating with temporal complexity during initiate in bilateral supplementary and pre-supplementary motor cortex (SMA and preSMA), rostral dorsal premotor cortex (PMC), basal ganglia, and dorsolateral prefrontal cortex (DLPFC), among other areas. During synchronise, correlated activity was observed in bilateral SMA, more caudal dorsal and ventral PMC, right DLPFC and right primary motor cortex. No correlated activity was observed during continue at P<0.01 (corrected, cluster level), though left angular gyrus was active at P<0.05. We suggest that the preSMA and rostral dorsal PMC activities during initiate may be associated with selection of timing parameters, while activation in centromedial prefrontal cortex during both initiate and synchronise may be associated with temporal error monitoring or correction. The absence of activity significantly correlated with temporal complexity during continue suggests that, once an overlearned timed movement sequence has been selected and initiated, there is no further adjustment of the timing control processes related to its continued production in absence of external cues.

Adult↗