Event-related fMRI Research Articles

Shared subcortical arousal systems across sensory modalities during transient modulation of attention.

Subcortical arousal systems are known to play a key role in controlling sustained changes in attention and conscious awareness. Recent studies indicate that these systems have a major influence on short-term dynamic modulation of visual attention, but their role across sensory modalities is not fully understood. In this study, we investigated shared subcortical arousal systems across sensory modalities during transient changes in attention using block and event-related fMRI paradigms. We analyzed massive publicly available fMRI datasets collected while 1,561 participants performed visual, auditory, tactile, and taste perception tasks. Our analyses revealed a shared circuit of subcortical arousal systems exhibiting early transient increases in activity in midbrain reticular formation and central thalamus across perceptual modalities, as well as less consistent increases in pons, hypothalamus, basal forebrain, and basal ganglia. Identifying these networks is critical for understanding mechanisms of normal attention and consciousness and may help facilitate subcortical targeting for therapeutic neuromodulation.

A randomized proof-of-mechanism trial of TNF antagonism for motivational deficits and related corticostriatal circuitry in depressed patients with high inflammation.

Chronic, low-grade inflammation has been associated with motivational deficits in patients with major depression (MD). In turn, impaired motivation has been linked to poor quality of life across psychiatric disorders. We thus determined effects of the anti-inflammatory drug infliximab-a potent tumor necrosis factor (TNF) antagonist-on behavioral and neural measures of motivation in 42 medically stable, unmedicated MD patients with a C-reactive protein >3 mg/L. All patients underwent a double-blind, placebo-controlled, single-dose, randomized clinical trial with infliximab (5 mg/kg) versus placebo. Behavioral performance on an effort-based decision-making task, self-report questionnaires, and neural responses during event-related functional magnetic resonance imaging were assessed at baseline and 2 weeks following infusion. We found that relative to placebo, patients receiving infliximab were more willing to expend effort for rewards. Moreover, increase in effortful choices was associated with reduced TNF signaling as indexed by decreased soluble TNF receptor type 2 (sTNFR2). Changes in effort-based decision-making and sTNFR2 were also associated with changes in task-related activity in a network of brain areas, including dorsomedial prefrontal cortex (dmPFC), ventral striatum, and putamen, as well as the functional connectivity between these regions. Changes in sTNFR2 also mediated the relationships between drug condition and behavioral and neuroimaging measures. Finally, changes in self-reported anhedonia symptoms and effort-discounting behavior were associated with greater responses of an independently validated whole-brain predictive model (aka "neural signature") sensitive to monetary rewards. Taken together, these data support the use of anti-inflammatory treatment to improve effort-based decision-making and associated brain circuitry in depressed patients with high inflammation.

Differential brain activation during dream versus story recognition in the medial prefrontal cortex: An event-related functional magnetic resonance imaging study.

Differential brain activation during dream versus story recognition in the medial prefrontal cortex: An event-related functional magnetic resonance imaging study.

Reliability of task-based fMRI in the dorsal horn of the human spinal cord

Abstract The application of functional magnetic resonance imaging (fMRI) to the human spinal cord is still a relatively small field of research and faces many challenges. Here we aimed to probe the limitations of task-based spinal fMRI at 3T by investigating the reliability of spinal cord blood oxygen level dependent (BOLD) responses to repeated nociceptive stimulation across 2 consecutive days in 40 healthy volunteers. We assessed the test–retest reliability of subjective ratings, autonomic responses, and spinal cord BOLD responses to short heat-pain stimuli (1 s duration) using the intraclass correlation coefficient (ICC). At the group level, we observed robust autonomic responses as well as spatially specific spinal cord BOLD responses at the expected location, but no spatial overlap in BOLD response patterns across days. While autonomic indicators of pain processing showed good-to-excellent reliability, both β-estimates and z-scores of task-related BOLD responses showed poor reliability across days in the target region (gray matter of the ipsilateral dorsal horn). When taking into account the sensitivity of gradient-echo echo planar imaging (GE-EPI) to draining vein signals by including the venous plexus in the analysis, we observed BOLD responses with fair reliability across days. Taken together, these results demonstrate that heat-pain stimuli as short as 1 s are able to evoke a robust and spatially specific BOLD response, which is, however, strongly variable within participants across time, resulting in low reliability in the dorsal horn gray matter. Further improvements in data acquisition and analysis techniques are thus necessary before event-related spinal cord fMRI as used here can be reliably employed in longitudinal designs or clinical settings.

Brain activations elicited during task-switching generalize beyond the task: A partial least squares correlation approach to combine fMRI signals and cognition.

An underlying hypothesis for broad transfer from cognitive training is that the regional brain signals engaged during the training task are related to the transfer tasks. However, it is unclear whether the brain activations elicited from a specific cognitive task can generalize to performance of other tasks, esp. in normal aging where cognitive training holds much promise. In this large dual-site functional magnetic resonance imaging (fMRI) study, we aimed to characterize the neurobehavioral correlates of task-switching in normal aging and examine whether the task-switching-related fMRI-blood-oxygen-level-dependent (BOLD) signals, engaged during varieties of cognitive control, generalize to other tasks of executive control and general cognition. We therefore used a hybrid blocked and event-related fMRI task-switching paradigm to investigate brain regions associated with multiple types of cognitive control on 129 non-demented older adults (65-85 years). This large dataset provided a unique opportunity for a data-driven partial least squares-correlation approach to investigate the generalizability of multiple fMRI-BOLD signals associated with task-switching costs to other tasks of executive control, general cognition, and demographic characteristics. While some fMRI signals generalized beyond the scanned task, others did not. Results indicate right middle frontal brain activation as detrimental to task-switching performance, whereas inferior frontal and caudate activations were related to faster processing speed during the fMRI task-switching, but activations of these regions did not predict performance on other tasks of executive control or general cognition. However, BOLD signals from the right lateral occipital cortex engaged during the fMRI task positively predicted performance on a working memory updating task, and BOLD signals from the left post-central gyrus that were disengaged during the fMRI task were related to slower processing speed in the task as well as to lower general cognition. Together, these results suggest generalizability of these BOLD signals beyond the scanned task. The findings also provided evidence for the general slowing hypothesis of aging as most variance in the data were explained by low processing speed and global low BOLD signal in older age. As processing speed shared variance with task-switching and other executive control tasks, it might be a possible basis of generalizability between these tasks. Additional results support the dedifferentiation hypothesis of brain aging, as right middle frontal activations predicted poorer task-switching performance. Overall, we observed that the BOLD signals related to the fMRI task not only generalize to the performance of other executive control tasks, but unique brain predictors of out-of-scanner performance can be identified.

Striatal Response to Reward Anticipation as a Biomarker for Schizophrenia and Negative Symptoms: Effects, Test-Retest Reliability, and Stability Across Sites.

Ventral striatal hypoactivation during reward anticipation has consistently been observed in patients with schizophrenia. In addition, that hypoactivation has been shown to correlate negatively with negative symptoms, and in particular with apathy. However, little is known about the stability of these results over time and their reliability across different centers. In total, 67 patients with schizophrenia (15 females) and 55 healthy controls (13 females) were recruited in 2 centers in Switzerland and Germany. To assess the neural bases of reward anticipation, all participants performed a variant of the Monetary Incentive Delay task while undergoing event-related functional magnetic resonance imaging at baseline and after 3 months. Stability over time was measured using intra-class correlation (ICC(A,1)) and stability between centers was measured with mixed models. Results showed the expected ventral striatal hypoactivation in patients compared to controls during reward anticipation. We showed that these results were stable across centers. The primary analysis did not reveal an effect of time. Test-retest reliability was moderate for controls, and poor for patients. We did not find an association between ventral striatal hypoactivation and negative symptoms in patients. Our results align with the hypothesis that ventral striatal activation is related to modulation of motivational saliency during reward anticipation. They also confirm that patients with schizophrenia show impaired reward anticipation. However, the poor test-retest reliability and the absence of an association with symptoms suggests that further research is needed before ventral striatal activity can be used as a biomarker on the individual patient level.

Reliability of task-based fMRI in the dorsal horn of the human spinal cord.

The application of functional magnetic resonance imaging (fMRI) to the human spinal cord is still a relatively small field of research and faces many challenges. Here we aimed to probe the limitations of task-based spinal fMRI at 3T by investigating the reliability of spinal cord blood oxygen level dependent (BOLD) responses to repeated nociceptive stimulation across two consecutive days in 40 healthy volunteers. We assessed the test-retest reliability of subjective ratings, autonomic responses, and spinal cord BOLD responses to short heat pain stimuli (1s duration) using the intraclass correlation coefficient (ICC). At the group level, we observed robust autonomic responses as well as spatially specific spinal cord BOLD responses at the expected location, but no spatial overlap in BOLD response patterns across days. While autonomic indicators of pain processing showed good-to-excellent reliability, both β-estimates and z-scores of task-related BOLD responses showed poor reliability across days in the target region (gray matter of the ipsilateral dorsal horn). When taking into account the sensitivity of gradient-echo echo planar imaging (GE-EPI) to draining vein signals by including the venous plexus in the analysis, we observed BOLD responses with fair reliability across days. Taken together, these results demonstrate that heat pain stimuli as short as one second are able to evoke a robust and spatially specific BOLD response, which is however strongly variable within participants across time, resulting in low reliability in the dorsal horn gray matter. Further improvements in data acquisition and analysis techniques are thus necessary before event-related spinal cord fMRI as used here can be reliably employed in longitudinal designs or clinical settings.

Beyond faces: the contribution of the amygdala to visual processing in the macaque brain.

The amygdala is present in a diverse range of vertebrate species, such as lizards, rodents, and primates; however, its structure and connectivity differs across species. The increased connections to visual sensory areas in primate species suggests that understanding the visual selectivity of the amygdala in detail is critical to revealing the principles underlying its function in primate cognition. Therefore, we designed a high-resolution, contrast-agent enhanced, event-related fMRI experiment, and scanned 3 adult rhesus macaques, while they viewed 96 naturalistic stimuli. Half of these stimuli were social (defined by the presence of a conspecific), the other half were nonsocial. We also nested manipulations of emotional valence (positive, neutral, and negative) and visual category (faces, nonfaces, animate, and inanimate) within the stimulus set. The results reveal widespread effects of emotional valence, with the amygdala responding more on average to inanimate objects and animals than faces, bodies, or social agents in this experimental context. These findings suggest that the amygdala makes a contribution to primate vision that goes beyond an auxiliary role in face or social perception. Furthermore, the results highlight the importance of stimulus selection and experimental design when probing the function of the amygdala and other visually responsive brain regions.

Mesocorticolimbic system reactivity to alcohol use-related visual cues as a function of alcohol sensitivity phenotype: A pilot fMRI study

Low sensitivity (LS) to alcohol is a risk factor for alcohol use disorder (AUD). Compared to peers with high sensitivity (HS), LS individuals drink more, report more problems, and exhibit potentiated alcohol cue reactivity (ACR). Heightened ACR suggests LS confers AUD risk via incentive sensitization, which is thought to take place in the mesocorticolimbic system. This study examined neural ACR in LS and HS individuals. Young adults (N = 32, Mage=20.3) were recruited based on the Alcohol Sensitivity Questionnaire (HS: n = 16; LS: n = 16; 9 females/group). Participants completed an event-related fMRI ACR task. Group LS had higher ACR in left ventrolateral prefrontal cortex than group HS. In group LS, ACR in left caudomedial orbitofrontal cortex or left putamen was low at low alcohol use levels and high at heavier or more problematic alcohol use levels, whereas the opposite was true in group HS. Alcohol use level also was associated with the level of ACR in left substantia nigra among males in group LS. Taken together, results suggest elevated mesocorticolimbic ACR among LS individuals, especially those using alcohol at hazardous levels. Future studies with larger samples are warranted to determine the neurobiological loci underlying LS-based amplified ACR and AUD risk.

Encoding-related Brain Activity Predicts Subsequent Trial-level Control of Proactive Interference in Working Memory.

Proactive interference (PI) appears when familiar information interferes with newly acquired information and is a major cause of forgetting in working memory. It has been proposed that encoding of item-context associations might help mitigate familiarity-based PI. Here, we investigate whether encoding-related brain activation could predict subsequent level of PI at retrieval using trial-specific parametric modulation. Participants were scanned with event-related fMRI while performing a 2-back working memory task with embedded 3-back lures designed to induce PI. We found that the ability to control interference in working memory was modulated by level of activation in the left inferior frontal gyrus, left hippocampus, and bilateral caudate nucleus during encoding. These results provide insight to the processes underlying control of PI in working memory and suggest that encoding of temporal context details support subsequent interference control.

Brain morphological changes and functional neuroanatomy related to cognitive and emotional distractors during working memory maintenance in post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is associated with abnormalities in the processing and regulation of emotion as well as cognitive deficits. This study evaluated the differential brain activation patterns associated with cognitive and emotional distractors during working memory (WM) maintenance for human faces between patients with PTSD and healthy controls (HCs) and assessed the relationship between changes in the activation patterns by the opposing effects of distraction types and gray matter volume (GMV). Twenty-two patients with PTSD and twenty-two HCs underwent T1-weighted magnetic resonance imaging (MRI) and event-related functional MRI (fMRI), respectively. Event-related fMRI data were recorded while subjects performed a delayed-response WM task with human face and trauma-related distractors. Compared to the HCs, the patients with PTSD showed significantly reduced GMV of the inferior frontal gyrus (IFG) (p < 0.05, FWE-corrected). For the human face distractor trial, the patients showed significantly decreased activities in the superior frontal gyrus and IFG compared with HCs (p < 0.05, FWE-corrected). The patients showed lower accuracy scores and slower reaction times for the face recognition task with trauma-related distractors compared with HCs as well as significantly increased brain activity in the STG during the trauma-related distractor trial was observed (p < 0.05, FWE-corrected). Such differential brain activation patterns associated with the effects of distraction in PTSD patients may be linked to neural mechanisms associated with impairments in both cognitive control for confusable distractors and the ability to control emotional distraction.

The neural representations of valence transformation in indole processing.

Indole is often associated with a sweet and floral odor typical of jasmine flowers at low concentrations and an unpleasant, animal-like odor at high concentrations. However, the mechanism whereby the brain processes this opposite valence of indole is not fully understood yet. In this study, we aimed to investigate the neural mechanisms underlying indole valence encoding in conversion and nonconversion groups using the smelling task to arouse pleasantness. For this purpose, 12 conversion individuals and 15 nonconversion individuals participated in an event-related functional magnetic resonance imaging paradigm with low (low-indole) and high (high-indole) indole concentrations in which valence was manipulated independent of intensity. The results of this experiment showed that neural activity in the right amygdala, orbitofrontal cortex and insula was associated with valence independent of intensity. Furthermore, activation in the right orbitofrontal cortex in response to low-indole was positively associated with subjective pleasantness ratings. Conversely, activation in the right insula and amygdala in response to low-indole was positively correlated with anticipatory hedonic traits. Interestingly, while amygdala activation in response to high-indole also showed a positive correlation with these hedonic traits, such correlation was observed solely with right insula activation in response to high-indole. Additionally, activation in the right amygdala in response to low-indole was positively correlated with consummatory pleasure and hedonic traits. Regarding olfactory function, only activation in the right orbitofrontal cortex in response to high-indole was positively correlated with olfactory identification, whereas activation in the insula in response to low-indole was negatively correlated with the level of self-reported olfactory dysfunction. Based on these findings, valence transformation of indole processing in the right orbitofrontal cortex, insula, and amygdala may be associated with individual hedonic traits and perceptual differences.

Reprint of Altered corollary discharge in the auditory cortex could reflect louder inner voice experience in patients with verbal hallucinations, a pilot fMRI study

IntroductionWide range of evidence associates auditory verbal hallucinations (AVH) with frontotemporal corollary discharge deficit. AVH likely reflect altered experiences of the inner voice and are phenomenologically diverse. The aspects of hallucinations (and related inner voice experiences) that could be explained by this deficit remain unclear. To address this important subject, we examined the temporal cortex activity during two tasks with and without corollary discharge. MethodsWe carried out an event-related BOLD fMRI study to examine temporal cortex activity in seven patients and eight healthy controls during two tasks with and without corollary discharge: reading aloud and hearing, respectively. Data were denoised by removing independent components related to head movement and subsequently processed using finite impulse response basis function to address hemodynamic response variations. To mitigate the small sample size, final analyses were carried out using permutation-based analysis of variance. ResultsThere was a significant group interaction in the Read relative to Hear condition during the early post-stimulus stage in the left Heschl's Gyrus (p<0.01, corrected for multiple comparisons, at peak voxel [−72,53,41]). This effect was driven by a higher activity in the Read relative to the Hear condition in the same area in the patients (p<0.02, corrected). ConclusionsOur results are consistent with prior literature indicating abnormal frontotemporal disconnection in participants with hallucinations. The functional repercussions of this deficit were limited to the primary auditory cortex in early post-stimulus stage, which suggests louder experience of the inner voice in patients and could account for the loudness of their hallucinations.

Functional reorganization of memory processing in the hippocampus is associated with neuroprotector GLP-1 levels in type 2 diabetes

Type 2 diabetes (T2D) often impairs memory functions, suggesting specific vulnerability of the hippocampus. In vivo neuroimaging studies relating encoding and retrieval of memory information with endogenous neuroprotection are lacking. The neuroprotector glucagon-like peptide (GLP-1) has a high receptor density in anterior/ventral hippocampus, as shown by animal models. Using an innovative event-related fMRI design in 34 participants we investigated patterns of hippocampal activity in T2D (n = 17) without mild cognitive impairment (MCI) versus healthy controls (n = 17) during an episodic memory task. We directly measured neurovascular coupling by estimating the hemodynamic response function using event-related analysis related to encoding and retrieval of episodic information in the hippocampus. We applied a mixed-effects general linear model analysis and a two-factor ANOVA to test for group differences. Significant between-group differences were found for memory encoding, showing evidence for functional reorganization: T2D patients showed an augmented activation in the posterior hippocampus while anterior activation was reduced. The latter was negatively correlated with both GLP-1 pre- and post-breakfast levels, in the absence of grey matter changes. These results suggest that patients with T2D without MCI have pre-symptomatic functional reorganization in brain regions underlying episodic memory, as a function of the concentration of the neuroprotective neuropeptide GLP-1.

Top-down modulation of DLPFC in visual search: a study based on fMRI and TMS.

Effective visual search is essential for daily life, and attention orientation as well as inhibition of return play a significant role in visual search. Researches have established the involvement of dorsolateral prefrontal cortex in cognitive control during selective attention. However, neural evidence regarding dorsolateral prefrontal cortex modulates inhibition of return in visual search is still insufficient. In this study, we employed event-related functional magnetic resonance imaging and dynamic causal modeling to develop modulation models for two types of visual search tasks. In the region of interest analyses, we found that the right dorsolateral prefrontal cortex and temporoparietal junction were selectively activated in the main effect of search type. Dynamic causal modeling results indicated that temporoparietal junction received sensory inputs and only dorsolateral prefrontal cortex →temporoparietal junction connection was modulated in serial search. Such neural modulation presents a significant positive correlation with behavioral reaction time. Furthermore, theta burst stimulation via transcranial magnetic stimulation was utilized to modulate the dorsolateral prefrontal cortex region, resulting in the disappearance of the inhibition of return effect during serial search after receiving continuous theta burst stimulation. Our findings provide a new line of causal evidence that the top-down modulation by dorsolateral prefrontal cortex influences the inhibition of return effect during serial search possibly through the retention of inhibitory tagging via working memory storage.

The hemodynamic response function as a type 2 diabetes biomarker: a data-driven approach.

There is a need to better understand the neurophysiological changes associated with early brain dysfunction in Type 2 diabetes mellitus (T2DM) before vascular or structural lesions. Our aim was to use a novel unbiased data-driven approach to detect and characterize hemodynamic response function (HRF) alterations in T2DM patients, focusing on their potential as biomarkers. We meshed task-based event-related (visual speed discrimination) functional magnetic resonance imaging with DL to show, from an unbiased perspective, that T2DM patients' blood-oxygen-level dependent response is altered. Relevance analysis determined which brain regions were more important for discrimination. We combined explainability with deconvolution generalized linear model to provide a more accurate picture of the nature of the neural changes. The proposed approach to discriminate T2DM patients achieved up to 95% accuracy. Higher performance was achieved at higher stimulus (speed) contrast, showing a direct relationship with stimulus properties, and in the hemispherically dominant left visual hemifield, demonstrating biological interpretability. Differences are explained by physiological asymmetries in cortical spatial processing (right hemisphere dominance) and larger neural signal-to-noise ratios related to stimulus contrast. Relevance analysis revealed the most important regions for discrimination, such as extrastriate visual cortex, parietal cortex, and insula. These are disease/task related, providing additional evidence for pathophysiological significance. Our data-driven design allowed us to compute the unbiased HRF without assumptions. We can accurately differentiate T2DM patients using a data-driven classification of the HRF. HRF differences hold promise as biomarkers and could contribute to a deeper understanding of neurophysiological changes associated with T2DM.

Insights from simultaneous EEG-fMRI and patient data illuminate the role of the anterior medial temporal lobe in N400 generation

The N400, a negative event-related potential (ERP) peaking approximately 400 ms after stimulus onset, is known to reflect the processing of semantic information. While scalp recordings have contributed to understanding the psychological processes underlying the N400, they have been limited in identifying its neural basis. However, recent intracranial ERP recordings and fMRI studies have shed light on the crucial role of the anterior medial temporal lobe (AMTL) in semantic information processing. These findings suggest that the N400 partially represents activity in the AMTL structures. To investigate the neural underpinnings of the N400 effect, we simultaneously recorded ERPs and event-related fMRI during a semantic priming paradigm in a sample of 12 young, healthy subjects. Additionally, we collected ERPs and structural brain data from older healthy adults and patients with amnestic mild cognitive impairment (aMCI), a population characterized by neurodegenerative changes in the AMTL. In our fMRI results, we identified bilateral loci in the AMTL as the global maxima. Employing an EEG-informed fMRI analysis, we explored trial-to-trial fluctuations in semantic processing by linking single-trial N400 amplitudes to the Blood Oxygen Level Dependent (BOLD) signal. This approach provided the first direct evidence linking the N400 recorded at the scalp level to the corresponding BOLD signal in the AMTL. Consistent with these findings, patients with aMCI exhibited a diminished N400 effect compared to healthy older adults. Furthermore, voxel-based morphometry analysis revealed a correlation between the magnitude of the N400 effect and the integrity of the AMTL. By integrating data from simultaneous EEG-fMRI, and patient studies, our research advances our understanding of the neural substrate of the N400 and highlights the critical involvement of the AMTL in semantic processing.

Reduced neural responses to pleasant odor stimuli after acute psychological stress is associated with cortisol reactivity

Acute stress alters olfactory perception. However, little is known about the neural processing of olfactory stimuli after acute stress exposure and the role of cortisol in such an effect. Here, we used an event-related olfactory fMRI paradigm to investigate brain responses to odors of different valence (unpleasant, pleasant, or neutral) in healthy young adults following an acute stress (Trier Social Stress Test, TSST) induction (N = 22) or a non-stressful resting condition (N = 22). We obtained the odor pleasantness, intensity, and familiarity ratings after the acute stress induction or resting condition. We also measured the participants' perceived stress and salivary cortisol at four time points during the procedure. We found a stress-related decrease in brain activation in response to the pleasant, but not to the neutral or unpleasant odor stimuli in the right piriform cortex extending to the right amygdala, the right orbitofrontal cortex, and the right insula. In addition, activation of clusters within the regions of interest were negatively associated with individual baseline-to-peak increase in salivary cortisol levels after stress. We also found increased functional connectivity between the right piriform cortex and the right insula after stress when the pleasant odor was presented. The strength of the connectivity was positively correlated with increased perceived stress levels immediately after stress exposure. These results provide novel evidence for the effects of acute stress in attenuating the neural processing of a pleasant olfactory stimulus. Together with previous findings, the effect of acute stress on human olfactory perception appears to depend on both the valence and the concentration (e.g., peri-threshold or suprathreshold levels) of odor stimuli.

The functional organization of skilled actions in the adextral and atypical brain

When planning functional grasps of tools, right-handed individuals (dextrals) show mostly left-lateralized neural activity in the praxis representation network (PRN), regardless of the used hand. Here we studied whether or not similar cerebral asymmetries are evident in non-righthanded individuals (adextrals). Sixty two participants, 28 righthanders and 34 non-righthanders (21 lefthanders, 13 mixedhanders), planned functional grasps of tools vs. grasps of control objects, and subsequently performed their pantomimed executions, in an event-related functional magnetic resonance imaging (fMRI) project. Both hands were tested, separately in two different sessions, counterbalanced across participants. After accounting for non-functional components of the prospective grasp, planning functional grasps of tools was associated with greater engagement of the same, left-hemisphere occipito-temporal, parietal and frontal areas of PRN, regardless of hand and handedness. Only when the analyses involved signal changes referenced to resting baseline intervals, differences between adextrals and dextrals emerged. Whereas in the left hemisphere the neural activity was equivalent in both groups (except for the occipito-temporo-parietal junction), its increases in the right occipito-temporal cortex, medial intraparietal sulcus (area MIP), the supramarginal gyrus (area PFt/PF), and middle frontal gyrus (area p9-46v) were significantly greater in adextrals. The inverse contrast was empty. Notably, when individuals with atypical and typical hemispheric phenotypes were directly compared, planning functional (vs. control) grasps invoked, instead, significant clusters located nearly exclusively in the left hemisphere of the typical phenotype. Previous studies interpret similar right-sided vs. left-sided increases in neural activity for skilled actions as handedness dependent, i.e., located in the hemisphere dominant for manual skills. Yet, none of the effects observed here can be purely handedness dependent because there were mixed-handed individuals among adextrals, and numerous mixed-handed and left-handed individuals possess the typical phenotype. Thus, our results clearly show that hand dominance has limited power in driving the cerebral organization of motor cognitive functions.

Menopause Status and Within-Group Differences in Chronological Age Affect the Functional Neural Correlates of Spatial Context Memory in Middle-Aged Females.

Reductions in the ability to encode and retrieve past experiences in rich spatial contextual detail (episodic memory) are apparent by midlife-a time when most females experience spontaneous menopause. Yet, little is known about how menopause status affects episodic memory-related brain activity at encoding and retrieval in middle-aged premenopausal and postmenopausal females, and whether any observed group differences in brain activity and memory performance correlate with chronological age within group. We conducted an event-related task fMRI study of episodic memory for spatial context to address this knowledge gap. Multivariate behavioral partial least squares was used to investigate how chronological age and retrieval accuracy correlated with brain activity in 31 premenopausal females (age range, 39.55-53.30 years; mean age, 44.28 years; SD age, 3.12 years) and 41 postmenopausal females (age range, 46.70-65.14 years; mean age, 57.56 years; SD age, 3.93 years). We found that postmenopausal status, and advanced age within postmenopause, was associated with lower spatial context memory. The fMRI analysis showed that only in postmenopausal females, advanced age was correlated with decreased activity in occipitotemporal, parahippocampal, and inferior parietal cortices during encoding and retrieval, and poorer spatial context memory performance. In contrast, only premenopausal females exhibited an overlap in encoding and retrieval activity in angular gyrus, midline cortical regions, and prefrontal cortex, which correlated with better spatial context retrieval accuracy. These results highlight how menopause status and chronological age, nested within menopause group, affect episodic memory and its neural correlates at midlife.SIGNIFICANCE STATEMENT This is the first fMRI study to examine how premenopause and postmenopause status affect the neural correlates of episodic memory encoding and retrieval, and how chronological age contributes to any observed group similarities and differences. We found that both menopause status (endocrine age) and chronological age affect spatial context memory and its neural correlates. Menopause status directly affected the direction of age-related and performance-related correlations with brain activity in inferior parietal, parahippocampal, and occipitotemporal cortices across encoding and retrieval. Moreover, we found that only premenopausal females exhibited cortical reinstatement of encoding-related activity in midline cortical, prefrontal, and angular gyrus, at retrieval. This suggests that spatial context memory abilities may rely on distinct brain systems at premenopause compared with postmenopause.