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Decreased left amygdala and hippocampal volumes in young offspring at risk for schizophrenia.

Abnormalities in the structural integrity and connectivity of the medial temporal and the prefrontal cortex are well documented in schizophrenia, but it is unclear if they represent premorbid indicators of neuropathology. Studies of young relatives at high-risk for schizophrenia (HR) provide an opportunity to clarify this question. We herein provide data from a magnetic resonance imaging (MRI) study of these structures in young offspring of schizophrenia patients. A series of 17 young HR offspring of schizophrenic patients were compared with 22 healthy comparison subjects (HC). Morphometric comparisons of the right and left dorsolateral prefrontal cortex (DLPFC), and the anterior and posterior amygdala-hippocampal (A-H) complex were conducted using high-resolution whole brain T(1) weighted brain images. Compared with the HC group, HR subjects had significant decreases in intracranial volume. The volumes of the left anterior and posterior A-H complex were reduced in the HR subjects after adjusting for intracranial volume. HR subjects also showed a significant leftward (Right>Left) asymmetry of the anterior A-H complex compared to the HC subjects. No significant changes were seen in the DLPFC. Thus, lateralized alterations in the volume of the left A-H complex are evident in unaffected young offspring of schizophrenia patients and may be of neurodevelopmental origin. Follow-up studies are needed to examine the predictive value of these measures for future emergence of schizophrenia in at-risk individuals.

Adolescent↗

Wisconsin Card Sorting Test performance following head injury: dorsolateral fronto-striatal circuit activity predicts perseveration.

The Wisconsin Card Sorting Test (WCST) has been argued to be a sensitive indicator of frontal lobe function. However, several recent studies have failed to find a consistent relationship between structural damage to this cortical area and perseveration on the test. In the present study, positron emission tomography (PET) imaging with 18F-fluorodeoxyglucose was used to examine the relationship of regional brain metabolism to perseverative responding on the WCST in patients with a history of closed-head injury. An inverse relationship was found between perseverative responses and metabolism in the right, but not the left, dorsolateral prefrontal cortex and caudate nucleus. Perseverative responding was not related to metabolism in several other regions of the frontal lobes and basal ganglia, including the putamen and the frontal poles bilaterally. These data suggest that the functional integrity of the right dorsolateral frontal-subcortical circuit is critical for WCST performance.

Adult↗

Low frequency rTMS stimulation of the right frontal cortex is as effective as high frequency rTMS stimulation of the left frontal cortex for antidepressant-free, treatment-resistant depressed patients.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a promising relatively non-invasive alternative for the treatment of depression. The purpose of this study was to compare the apparent effectiveness of high frequency (20 Hertz) rTMS applied over the left dorsolateral prefrontal cortex (DLPFC) with that of low frequency (1 Hz) rTMS applied over the right DLPFC METHODS: Twenty-eight antidepressant-free adults with major depressive (n = 25) or bipolar (n = 3) disorder (not on mood stabilizers) in a current major depression (Hamilton Rating Scale for Depression [HAM-D-21] > or = 18; Mean = 24.5, SD = 5.51) were treated (14 right, 14 left) for 4 weeks. RESULTS: Overall paired t-tests revealed a significant reduction in mean HAM-D-21, Beck Depression Inventory (BDI-II), and Clinical Global Impression of Change (CGIC) scores at the end of treatment for both groups (high frequency left DLPFC and low frequency right DLPFC). The treatment response rate found (32%) was typical of other response rates reported in the literature (6,30). One-month follow-up data was obtained from 50% of participants. At 1-month follow-up no significant differences were noted as compared to patients' performance at last treatment visit, indicating moderate robustness of rTMS treatment over time. Furthermore, magnetic stimulation did not substantially alter patient memory over the course of treatment. CONCLUSION: rTMS given at low frequency over the right frontal cortex appears to be as effective treatment of refractory depression as high frequency treatment over the left frontal cortex.

Antidepressive Agents↗

RGS4 mRNA expression in postmortem human cortex is associated with COMT Val158Met genotype and COMT enzyme activity.

Linkage, association and postmortem studies have implicated regulator of G-protein signaling 4 (RGS4), which negatively modulates signal transduction at G-protein-coupled receptors, as a candidate schizophrenia susceptibility gene. We compared RGS4 mRNA expression in the dorsolateral prefrontal cortex (DLPFC), between normal controls and patients with schizophrenia in two independent cohorts (>100 subjects each) (the CBDB/NIMH Collection and the Stanley Array Collection), and in the hippocampus in the CBDB/NIMH Collection. We also examined the effects of the four previously identified putative RGS4 risk SNPs (rs10917670, rs951436, rs951439, rs2661319) on RGS4 expression levels in these cohorts. As dopamine signaling is linked to RGS4 expression and there is evidence for statistical epistasis between COMT Val158Met polymorphism and RGS4 alleles, we also examined relationships between the COMT Val158Met genotype and RGS4 expression in the DLPFC. We did not detect a difference in RGS4 expression levels between schizophrenic patients (or bipolar disorder patients in the Stanley Collection) and controls and found no significant association between any of the RGS4 risk SNPs and RGS4 expression. However, COMT Val158Met genotype was associated with prefrontal and hippocampal RGS4 mRNA expression in an allele dose-dependent manner, with carriers of the COMT Val allele showing significantly lower expression than heterozygous individuals or subjects homozygous for the Met allele. Consistent with these genotype effects, RGS4 mRNA was inversely correlated with the COMT enzyme activity in the DLPFC. These data suggest that RGS4 mRNA expression is associated with cortical dopamine signaling and illustrate the importance of genetic and/or environmental background in gene expression studies in schizophrenia.

Alleles↗

[Neuroanatomical bases of attention by means of PET-15O: the role of the prefrontal and parietal cortex in controlled processes].

AIM: The aim of this study was to investigate the changes in the cerebral blood flow that took place in normal subjects during an auditory attention paradigm which included automatic and controlled processing components. METHOD: Participants consisted in 10 normal subjects who were submitted to medical, neuropsychological and neuroimaging evaluation. PET was used to carry out an exploration of each subject in the four experimental conditions: basal, listening to clicks (A), counting while listening to clicks (C+A) and counting without listening to clicks (C). RESULTS: During the condition involving counting while listening to clicks (automatic processing) the subjects displayed a significant increase in the activation of the bilateral precentral convolutions, left dorsolateral prefrontal cortex (DLPFC), left inferior and superior frontal convolutions, left supplementary motor area and the left superior and inferior temporal convolution. During the condition involving counting without listening to clicks (controlled processing), the subjects activated the right precentral convolution, bilateral DLPFC, the right supplementary motor area, anterior cingulate and right inferior parietal convolution. DISCUSSION: The results obtained support the suggestion that regions such as the DLPFC and the inferior parietal convolution play a part in attentional tasks in which the subject is required to make an effort to carry out the controlled processing of information.

Adult↗

Interindividual differences in functional interactions among prefrontal, parietal and parahippocampal regions during working memory.

To clarify the neural systems deployed by individual subjects during working memory (WM), we collected functional neuroimaging data from healthy subjects, and constructed a model of 2-back WM using structural equation modeling (SEM). A group model was constructed, and models for each subject were validated against it. The group model consisted principally of regions in the prefrontal and parietal cortex, with considerable interindividual variance in the single-subject models. To explore this variance, subjects were split into two groups based on performance. Performance level and self-reported strategy scores were used in a correlation analysis against path weights between nodes of individual models. High performers utilized a left hemisphere sub-network involving inferior parietal lobule and Broca's area, whereas lower performers utilized a right hemisphere sub-network with interactions between inferior parietal lobule and dorsolateral prefrontal cortex. Further, we observed an interaction between the parahippocampal formation and the inferior parietal lobule that was related to the different strategies used by the individuals to perform the task. Strategy and performance level appear to be intricately related in this task, with neural systems supporting verbal processing producing better performance than those associated with spatial processing. These results demonstrate that individual behavioral characteristics are reflected in specific neurofunctional patterns at the system level and that these can be captured by analytical techniques such as SEM.

Adult↗

Executive frontal functions.

This chapter presents a conceptual model of the representational and executive functions of the cortex of the frontal lobe derived from empirical evidence obtained principally in the monkey. According to this model, the neuronal networks of the frontal lobe that represent motor or executive memories are probably the same networks that cooperate with other cerebral structures in the temporal organization of behavior. The prefrontal cortex, at the top of the perception-action cycle, plays a critical role in the mediation of contingencies of action across time, an essential aspect of the temporal organization of behavior. That role of cross-temporal mediation is based on the interplay of two short-term cognitive functions: one retrospective, of short-term memory or sensory working memory, and the other prospective, of attentive set (or motor working memory). Both appear represented in the neuronal populations of dorsolateral prefrontal cortex. At least one of the mechanisms for the retention of working memory of either kind seems to be the reentry of excitability through recurrent cortical circuits. With those two complementary and temporally symmetrical cognitive functions of active memory for the sensory past and for the motor future, the prefrontal cortex secures the temporal closure at the top of the perception-action cycle.

Attention↗

Prefrontal activity and diagnostic monitoring of memory retrieval: FMRI of the criterial recollection task.

According to the distinctiveness heuristic, subjects rely more on detailed recollections (and less on familiarity) when memory is tested for pictures relative to words, leading to reduced false recognition. If so, then neural regions that have been implicated in effortful postretrieval monitoring (e.g., dorsolateral prefrontal cortex) might be recruited less heavily when trying to remember pictures. We tested this prediction with the criterial recollection task. Subjects studied black words, paired with either the same word in red font or a corresponding colored picture. Red words were repeated at study to equate recognition hits for red words and pictures. During fMRI scanning, alternating red word memory tests and picture memory tests were given, using only white words as test stimuli (say "yes" only if you recollect a corresponding red word or picture, respectively). These tests were designed so that subjects had to rely on memory for the criterial information. Replicating prior behavioral work, we found enhanced rejection of lures on the picture test compared to the red word test, indicating that subjects had used a distinctiveness heuristic. Critically, dorsolateral prefrontal activity was reduced when rejecting familiar lures on the picture test, relative to the red word test. These findings indicate that reducing false recognition via the distinctiveness heuristic is not heavily dependent on frontally mediated postretrieval monitoring processes.

Adolescent↗

A personalized multi-platform assessment of somatic mosaicism in the human frontal cortex.

Somatic mutations in individual cells create genomic mosaicism, influencing genetic disorders and cancers. While clonal mutations in cancers are well-studied, rarer somatic variants in normal tissues remain poorly characterized. This study systematically evaluates detection methods using a personalized donor-specific assembly (DSA) from a neurotypical individual's dorsolateral prefrontal cortex assessed with Oxford Nanopore, NovaSeq, linked-read sequencing, Cas9-targeted long-read sequencing (TEnCATS), and single-neuron MALBAC amplification. The haplotype-resolved DSA improved cross-platform analysis, dramatically increasing phasing rates. Germline SNVs, structural variations (SVs), and transposable elements (TEs) were recalled with 99.4%-99.7% accuracy in bulk tissue, and phased haplotype analysis reduced false positives by 15.4%-75.1% for putative somatic candidates. Long-read single-neuron sequencing detected nine somatic SV candidates, demonstrating enhanced sensitivity for rare variants, while TEnCATS identified eight low-frequency somatic TE candidates. These findings highlight advanced methodologies for precise somatic variant detection, critical for understanding mosaicism's role in health and disease.

Multi-platform Sequencing↗

Pilot study of functional MRI to assess cerebral activation of motor function after poststroke hemiparesis.

BACKGROUND AND PURPOSE: Studies of cerebral activation of motor function after ischemic stroke may enhance our understanding of the underlying mechanisms of motor functional recovery, including the role of the noninfarcted hemisphere. METHODS: Eight right-handed recovering hemiparetic or hemiplegic patients were studied using functional MRI. Results were evaluated for each patient to consider individual variability in original functional organization, neuroanatomy, infarct size and extent, treatment, age, and sex. The results were also pooled as a group for comparison with a control group of eight right-handed normal subjects. RESULTS: In six of eight stroke patients, extended activation in ipsilateral sensorimotor cortex was observed during paretic hand movements. Bilateral activation of the primary sensorimotor cortex was recorded in three of these six patients; ipsilateral activation alone was recorded in the remaining three patients. Only two patients had mild synkinesia. Furthermore, in two male patients, the paretic hand movements activated extended areas of ipsilateral premotor and dorsolateral prefrontal cortex, when compared with normal subjects. In two patients with left frontal infarction, profound activation in the right supramarginal gyrus and in the right premotor cortex was observed during the ipsilateral paretic hand movements. CONCLUSIONS: Synkinesia alone cannot explain the extent of ipsilateral activation in primary sensorimotor cortex. The explanation offered for our findings is that preexisting uncrossed motor neural pathways may be accessed or recruited to compensate for damage to the crossed motor pathways after ischemic stroke.

Adult↗

Predicted brain-regional gene expression patterns in individuals living with Alzheimer's disease.

Studying brain gene expression in Alzheimer's Disease (AD) remains difficult as postmortem brain is difficult to access, cannot be used to guide donor treatment, may be confounded by environmental factors before and after death, and is difficult to link to early AD states or disease progression. To circumvent these limitations, several studies have tested blood transcriptome biomarkers for AD. However, gene-expression levels in the blood have limited correlation with those in the brain. To evaluate the potential of monitoring Alzheimer's progression with peripheral data, we used transcriptome-imputation to identify brain-region-specific AD-associated gene-expression differences in cohorts with blood-based transcriptome data. This approach provides a high-resolution image of AD-associated molecular differences in the brains of individuals actively living with disease. We analyzed eight AD studies (777 AD cases, 779 cognitively unimpaired controls), imputing transcriptomes in 10 brain regions via the Brain Gene Expression and Network Imputation Engine (BrainGENIE). Hundreds of differentially expressed genes (DEGs) associated with AD were identified in nine brain regions, with anterior cingulate cortex and amygdala showing the most differential expression. AD-associated genes were enriched in pathways such as proteostasis, mitochondrial dysfunction, and immune activation. We observed significant yet moderate concordance between imputed AD-associated changes and those directly measured in the dorsolateral prefrontal cortex and cerebellum. These transcriptomic changes can guide future in vitro studies focused on pathogenesis or be targets of novel therapeutic development. In conclusion, we demonstrated the scope and utility of brain expression imputation from the peripheral transcriptome, laying the groundwork for biomarker discovery and prospective AD studies.

Alzheimer Disease↗

Age-related functional changes of prefrontal cortex in long-term memory: a repetitive transcranial magnetic stimulation study.

Neuroimaging findings suggest that the lateralization of prefrontal cortex activation associated with episodic memory performance is reduced by aging. It is still a matter of debate whether this loss of asymmetry during encoding and retrieval reflects compensatory mechanisms or de-differentiation processes. We addressed this issue by the transient interference produced by repetitive transcranial magnetic stimulation (rTMS), which directly assesses causal relationships between performance and stimulated regions. We compared the effects of rTMS (a rapid-rate train occurring simultaneously to the presentation of memoranda) applied to the left or right dorsolateral prefrontal cortex (DLPFC) on visuospatial recognition memory in 66 healthy subjects divided in two classes of age (<45 and >50 years). In young subjects, rTMS of the right DLPFC interfered with retrieval more than left DLPFC stimulation. The asymmetry of the effect progressively vanished with aging, as indicated by bilateral interference effects on recognition performance. Conversely, the predominance of left DLPFC effect during encoding was not abolished in elders, thus probing its causal role for encoding along the life span. Findings confirm that the neural correlates of retrieval modify along aging, suggesting that the bilateral engagement of the DLPFC has a compensatory role on the elders' episodic memory performance.

Adult↗

Painful stimuli evoke different stimulus-response functions in the amygdala, prefrontal, insula and somatosensory cortex: a single-trial fMRI study.

Only recently have neuroimaging studies moved away from describing regions activated by noxious stimuli and started to disentangle subprocesses within the nociceptive system. One approach to characterizing the role of individual regions is to record brain responses evoked by different stimulus intensities. We used such a parametric single-trial functional MRI design in combination with a thulium:yttrium-aluminium-granate infrared laser and investigated pain, stimulus intensity and stimulus awareness (i.e. pain-unrelated) responses in nine healthy volunteers. Four stimulus intensities, ranging from warm to painful (300-600 mJ), were applied in a randomized order and rated by the subjects on a five-point scale (P0-4). Regions in the dorsolateral prefrontal cortex and the intraparietal sulcus differentiated between P0 (not perceived) and P1 but exhibited no further signal increase with P2, and were related to stimulus perception and subsequent cognitive processing. Signal changes in the primary somatosensory cortex discriminated between non-painful trials (P0 and P1), linking this region to basic sensory processing. Pain-related regions in the secondary somatosensory cortex and insular cortex showed a response that did not distinguish between innocuous trials (P0 and P1) but showed a positive linear relationship with signal changes for painful trials (P2-4). This was also true for the amygdala, with the exception that, in P0 trials in which the stimulus was not perceived (i.e. 'uncertain' trials), the evoked signal changes were as great as in P3 trials, indicating that the amygdala is involved in coding 'uncertainty', as has been suggested previously in relation to classical conditioning.

Adult↗

Midazolam decreases cerebral blood flow in the left prefrontal cortex in a dose-dependent fashion.

Midazolam, a short-lived benzodiazepine producing sedation and reversible anterograde amnesia, was administered intravenously to 14 healthy male volunteers. Regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET) with intravenous H2 15O at either a 'high' midazolam EEG effect (EEG signs of stage 2 sleep), or 'low' midazolam EEG effect (increase in EEG beta power only). Memory tests administered following PET scans showed significant drug-induced impairment in learning and retrieval at the same drug concentration at which PET images were acquired. Statistical parametric mapping was used to identify regions where rCBF changes after drug administration were significantly different in the high- vs. low- effect groups. Dosexcondition interactions were found in the left dorsolateral prefrontal cortex [Brodmann's areas (BA) 9 and 46], bilateral orbital-frontal cortex (BA 47), the left middle temporal gyrus (BA 22) and the right hippocampus. The predominantly left frontal rCBF decreases occur in a region associated with semantic processing, working memory, and encoding of verbal material, a process preferentially affected by midazolam. Our interpretation is that rCBF changes in the hippocampus are unlikely to mediate the anterograde amnesia produced by midazolam. Although in the present study PET images were acquired during the resting state rather than during memory processing, these results underscore the need for further investigation relating to the interaction of midazolam with specific cognitive operations in these brain regions.

Journal Article↗

5-HT6 receptor binding sites in schizophrenia and following antipsychotic drug administration: autoradiographic studies with [125I]SB-258585.

The 5-hydroxytryptamine (5-HT; serotonin)-6 receptor (5-HT6R) is a putative target of atypical antipsychotic drugs and its mRNA expression is altered in schizophrenia. [125I]SB-258585 is a selective 5-HT6R antagonist which has been well characterized for use in the rat brain. The present study evaluated its suitability for receptor autoradiography in the human brain and its application to quantitative studies. The affinity (K(d) approximately 1.2 nM) and relative distribution of binding sites (striatum >> cortex approximately hippocampus) were similar to the rat. The distribution of [125I]SB-258585 binding in these regions was also consistent with that of 5-HT6R mRNA, determined in parallel using in situ hybridization. [125I]SB-258585 binding site densities were measured in dorsolateral prefrontal cortex of 20 patients with chronic schizophrenia and compared with 17 normal subjects. No differences were seen between groups. Neither were [125I]SB-258585 binding site densities affected in the frontal cortex or striatum of rats following 2 weeks' administration of the antipsychotic drugs haloperidol, chlorpromazine, olanzapine, risperidone, or clozapine. In summary, [125I]SB-258585 is a suitable radioligand for studies of human brain 5-HT6R binding sites and shows that their distribution is broadly similar to that of the rodent. The lack of effect of schizophrenia or antipsychotic drug administration on [125I]SB-258585 binding suggests that an altered receptor density does not contribute to any involvement which the 5-HT6R may have in the disease or its treatment.

Adult↗

Effect of repetitive transcranial magnetic stimulation on saccades in depression: a pilot study.

Therapeutic repetitive transcranial magnetic stimulation (rTMS) in depression is applied over the prefrontal cortex. This brain region is known to play an important role in the control of saccades. We wanted to investigate whether the fast rTMS procedure affected saccadic activity in depression. Reflexive saccades (RS) and voluntary saccades were studied in 11 patients before and after therapeutic rTMS for depression. Two types of voluntary saccade tasks were used: a voluntary prosaccade (VpS) task and an antisaccade (AS) task. Eye movements were registered by infrared oculography. Latency and directional error rate were analyzed. rTMS was applied over the left dorsolateral prefrontal cortex (DLPFC). RS and VpS parameters were unchanged after 10 sessions of rTMS. However, the latency of antisaccades (AS) was significantly shorter after rTMS than before rTMS. It can be concluded that rTMS over the left DLPFC cortex in depression seems to have no important effect on reflexive saccades, while antisaccade activity is clearly favored by shortening of latency. As voluntary prosaccades were not significantly influenced, our findings may indicate that not merely the voluntary triggering of saccades but the inhibition of unwanted reflexive saccades is influenced by fast rTMS delivered over the DLPFC. These results suggest the intriguing possibility that rTMS might differentially affect specific aspects of saccade behavior.

Adult↗

Pre-frontal executive committee for perception, working memory, attention, long-term memory, motor control, and thinking: a tutorial review.

As an explicit organizing metaphor, memory aid, and conceptual framework, the prefrontal cortex may be viewed as a five-member 'Executive Committee,' as the prefrontal-control extensions of five sub-and-posterior-cortical systems: (1) the 'Perceiver' (dominant-right-hemisphere ventral-lateral prefrontal cortex--VL/PERC-PFC) is the frontal extension of the ventral perceptual stream (the VL/PERC system) which represents the world and self in object coordinates; (2) the 'Verbalizer' (dominant-left-hemisphere ventral-lateral prefrontal cortex system--VL/VERB-PFC) is the frontal extension of the language stream (the VL/VERB system) which represents the world and self in language coordinates; (3) the 'Motivator' (ventral/medial-orbital pre-frontal cortex--VMO-PFC) is the frontal cortical extension of a subcortical extended-amygdala stream (the VMO system) which represents the world and self in motivational/emotional coordinates; (4) the 'Attender' (dorsal-medial/anterior cingulate--DM/AC-PFC) is the frontal cortical extension of a subcortical extended-hippocampal stream (the DM/AC system) which represents the world and self in spatiotemporal coordinates and directs attention to internal and external events; and (5) the 'Coordinator' (the dorsolateral prefrontal cortex--DL-PFC) is the frontal extension of the dorsal perceptual stream (the DL system) which represents the world and self in body- and eye-coordinates and controls willed action and working memory. This tutorial review examines the interacting roles of these five systems in perception, working memory, attention, long-term memory, motor control, and thinking.

Attention↗

Prefrontal cortex involvement in processing incorrect arithmetic equations: evidence from event-related fMRI.

The main aim of this study was to investigate the differential processing of correct and incorrect equations to gain further insight into the neural processes involved in arithmetic reasoning. Electrophysiological studies in humans have demonstrated that processing incorrect arithmetic equations (e.g., 2 + 2 = 5) elicits a prominent event-related potential (ERP) compared to processing correct equations (e.g., 2 + 2 = 4). In the present study, we investigated the neural substrates of this process using event-related functional magnetic resonance imaging (fMRI). Subjects were presented with arithmetic equations and asked to indicate whether the solution displayed was correct or incorrect. We found greater activation to incorrect, compared to correct equations, in the left dorsolateral prefrontal cortex (DLPFC, BA 46) and the left ventrolateral prefrontal cortex (VLPFC, BA 47). Our results provide the first brain imaging evidence for differential processing of incorrect vs. correct equations. The prefrontal cortex activation observed in processing incorrect equations overlaps with brain areas known to be involved in working memory and interference processing. The DLPFC region differentially activated by incorrect equations was also involved in overall arithmetic processing, whereas the VLPFC was activated only during the differential processing of incorrect equations. Differential response to correct and incorrect arithmetic equations was not observed in parietal cortex regions such as the angular gyrus and intra-parietal sulcus, which are known to play a specific role in performing arithmetic computations. The pattern of brain response observed is consistent with the hypothesis that processing incorrect equations involves detection of an incorrect answer and resolution of the interference between the internally computed and externally presented incorrect answer. More specifically, greater activation during processing of incorrect equations appears to reflect additional operations involved in maintaining the results in working memory, while subjects attempt to resolve the conflict and select a response. These findings allow us to further delineate and dissociate the contributions of prefrontal and parietal cortices to arithmetic reasoning.

Adolescent↗