Roles of the medial and lateral orbitofrontal cortex in major depression and its treatment.

We describe evidence for dissociable roles of the medial and lateral orbitofrontal cortex (OFC) in major depressive disorder (MDD) from structure, functional activation, functional connectivity, metabolism, and neurochemical systems. The reward-related medial orbitofrontal cortex has lower connectivity and less reward sensitivity in MDD associated with anhedonia symptoms; and the non-reward related lateral OFC has higher functional connectivity and more sensitivity to non-reward/aversive stimuli in MDD associated with negative bias symptoms. Importantly, we propose that conventional antidepressants act to normalize the hyperactive lateral (but not medial) OFC to reduce negative bias in MDD; while other treatments are needed to operate on the medial OFC to reduce anhedonia, with emerging evidence suggesting that ketamine may act in this way. The orbitofrontal cortex is the key cortical region in emotion and reward, and the current review presents much new evidence about the different ways that the medial and lateral OFC are involved in MDD.

The connectivity of the human frontal pole cortex, and a theory of its involvement in exploit versus explore.

The frontal pole is implicated in humans in whether to exploit resources versus explore alternatives. Effective connectivity, functional connectivity, and tractography were measured between six human frontal pole regions and for comparison 13 dorsolateral and dorsal prefrontal cortex regions, and the 360 cortical regions in the Human Connectome Project Multi-modal-parcellation atlas in 171 HCP participants. The frontal pole regions have effective connectivity with Dorsolateral Prefrontal Cortex regions, the Dorsal Prefrontal Cortex, both implicated in working memory; and with the orbitofrontal and anterior cingulate cortex reward/non-reward system. There is also connectivity with temporal lobe, inferior parietal, and posterior cingulate regions. Given this new connectivity evidence, and evidence from activations and damage, it is proposed that the frontal pole cortex contains autoassociation attractor networks that are normally stable in a short-term memory state, and maintain stability in the other prefrontal networks during stable exploitation of goals and strategies. However, if an input from the orbitofrontal or anterior cingulate cortex that expected reward, non-reward, or punishment is received, this destabilizes the frontal pole and thereby other prefrontal networks to enable exploration of competing alternative goals and strategies. The frontal pole connectivity with reward systems may be key in exploit versus explore.

Hierarchical organization of the human ventral visual streams revealed with magnetoencephalography.

The hierarchical organization between 25 ventral stream visual cortical regions and 180 cortical regions was measured with magnetoencephalography using the Human Connectome Project Multimodal Parcellation atlas in 83 Human Connectome Project participants performing a visual memory task. The aim was to reveal the hierarchical organization using a whole-brain model based on generative effective connectivity with this fast neuroimaging method. V1-V4 formed a first group of interconnected regions. Especially V4 had connectivity to a ventrolateral visual stream: V8, the fusiform face cortex, and posterior inferior temporal cortex PIT. These regions in turn had effectivity connectivity to inferior temporal cortex visual regions TE2p and TE1p. TE2p and TE1p then have connectivity to anterior temporal lobe regions TE1a, TE1m, TE2a, and TGv, which are multimodal. In a ventromedial visual stream, V1-V4 connect to ventromedial regions VMV1-3 and VVC. VMV1-3 and VVC connect to the medial parahippocampal gyrus PHA1-3, which, with the VMV regions, include the parahippocampal scene area. The medial parahippocampal PHA1-3 regions have connectivity to the hippocampal system regions the perirhinal cortex, entorhinal cortex, and hippocampus. These effective connectivities of two ventral visual cortical streams measured with magnetoencephalography provide support to the hierarchical organization of brain systems measured with fMRI, and new evidence on directionality.

Multiple cortical visual streams in humans.

The effective connectivity between 55 visual cortical regions and 360 cortical regions was measured in 171 HCP participants using the HCP-MMP atlas, and complemented with functional connectivity and diffusion tractography. A Ventrolateral Visual "What" Stream for object and face recognition projects hierarchically to the inferior temporal visual cortex, which projects to the orbitofrontal cortex for reward value and emotion, and to the hippocampal memory system. A Ventromedial Visual "Where" Stream for scene representations connects to the parahippocampal gyrus and hippocampus. An Inferior STS (superior temporal sulcus) cortex Semantic Stream receives from the Ventrolateral Visual Stream, from visual inferior parietal PGi, and from the ventromedial-prefrontal reward system and connects to language systems. A Dorsal Visual Stream connects via V2 and V3A to MT+ Complex regions (including MT and MST), which connect to intraparietal regions (including LIP, VIP and MIP) involved in visual motion and actions in space. It performs coordinate transforms for idiothetic update of Ventromedial Stream scene representations. A Superior STS cortex Semantic Stream receives visual inputs from the Inferior STS Visual Stream, PGi, and STV, and auditory inputs from A5, is activated by face expression, motion and vocalization, and is important in social behaviour, and connects to language systems.

The human posterior parietal cortex: effective connectome, and its relation to function.

The effective connectivity between 21 regions in the human posterior parietal cortex, and 360 cortical regions was measured in 171 Human Connectome Project (HCP) participants using the HCP atlas, and complemented with functional connectivity and diffusion tractography. Intraparietal areas LIP, VIP, MIP, and AIP have connectivity from early cortical visual regions, and to visuomotor regions such as the frontal eye fields, consistent with functions in eye saccades and tracking. Five superior parietal area 7 regions receive from similar areas and from the intraparietal areas, but also receive somatosensory inputs and connect with premotor areas including area 6, consistent with functions in performing actions to reach for, grasp, and manipulate objects. In the anterior inferior parietal cortex, PFop, PFt, and PFcm are mainly somatosensory, and PF in addition receives visuo-motor and visual object information, and is implicated in multimodal shape and body image representations. In the posterior inferior parietal cortex, PFm and PGs combine visuo-motor, visual object, and reward input and connect with the hippocampal system. PGi in addition provides a route to motion-related superior temporal sulcus regions involved in social interactions. PGp has connectivity with intraparietal regions involved in coordinate transforms and may be involved in idiothetic update of hippocampal visual scene representations.

Auditory cortical connectivity in humans.

To understand auditory cortical processing, the effective connectivity between 15 auditory cortical regions and 360 cortical regions was measured in 171 Human Connectome Project participants, and complemented with functional connectivity and diffusion tractography. 1. A hierarchy of auditory cortical processing was identified from Core regions (including A1) to Belt regions LBelt, MBelt, and 52; then to PBelt; and then to HCP A4. 2. A4 has connectivity to anterior temporal lobe TA2, and to HCP A5, which connects to dorsal-bank superior temporal sulcus (STS) regions STGa, STSda, and STSdp. These STS regions also receive visual inputs about moving faces and objects, which are combined with auditory information to help implement multimodal object identification, such as who is speaking, and what is being said. Consistent with this being a "what" ventral auditory stream, these STS regions then have effective connectivity to TPOJ1, STV, PSL, TGv, TGd, and PGi, which are language-related semantic regions connecting to Broca's area, especially BA45. 3. A4 and A5 also have effective connectivity to MT and MST, which connect to superior parietal regions forming a dorsal auditory "where" stream involved in actions in space. Connections of PBelt, A4, and A5 with BA44 may form a language-related dorsal stream.

Prefrontal and somatosensory-motor cortex effective connectivity in humans.

Effective connectivity, functional connectivity, and tractography were measured between 57 cortical frontal and somatosensory regions and the 360 cortical regions in the Human Connectome Project (HCP) multimodal parcellation atlas for 171 HCP participants. A ventral somatosensory stream connects from 3b and 3a via 1 and 2 and then via opercular and frontal opercular regions to the insula, which then connects to inferior parietal PF regions. This stream is implicated in "what"-related somatosensory processing of objects and of the body and in combining with visual inputs in PF. A dorsal "action" somatosensory stream connects from 3b and 3a via 1 and 2 to parietal area 5 and then 7. Inferior prefrontal regions have connectivity with the inferior temporal visual cortex and orbitofrontal cortex, are implicated in working memory for "what" processing streams, and provide connectivity to language systems, including 44, 45, 47l, TPOJ1, and superior temporal visual area. The dorsolateral prefrontal cortex regions that include area 46 have connectivity with parietal area 7 and somatosensory inferior parietal regions and are implicated in working memory for actions and planning. The dorsal prefrontal regions, including 8Ad and 8Av, have connectivity with visual regions of the inferior parietal cortex, including PGs and PGi, and are implicated in visual and auditory top-down attention.

Odor encoding by signals in the olfactory bulb.

To understand the operation of the olfactory system, it is essential to know how information is encoded in the olfactory bulb. We applied Shannon information theoretic methods to address this, with signals from up to 57 glomeruli simultaneously optically imaged from presynaptic inputs in glomeruli in the mouse dorsal (dOB) and lateral (lOB) olfactory bulb, in response to six exemplar pure chemical odors. We discovered that, first, the tuning of these signals from glomeruli to a set of odors is remarkably broad, with a mean sparseness of 0.83 and a mean signal correlation of 0.64. Second, both of these factors contribute to the low information that is available from the responses of even populations of many tens of glomeruli, which was only 1.35 bits across 33 glomeruli on average, compared with the 2.58 bits required to perfectly encode these six odors. Third, although there is considerable interest in the possibility of temporal encoding of stimulus including odor identity, the amount of information in the temporal aspects of the presynaptic glomerular responses was low (mean 0.11 bits) and, importantly, was redundant with respect to the information available from the rates. Fourth, the information from simultaneously recorded glomeruli asymptotes very gradually and nonlinearly, showing that glomeruli do not have independent responses. Fifth, the information from a population became available quite rapidly, within 100 ms of sniff onset, and the peak of the glomerular response was at 200 ms. Sixth, the information from the lOB was not additive with that of the dOB.NEW & NOTEWORTHY We report broad tuning and low odor information available across the lateral and dorsal bulb populations of glomeruli. Even though response latencies can be significantly predictive of stimulus identity, such contained very little information and none that was not redundant with information based on rate coding alone. Last, in line with the emerging notion of the important role of earliest stages of responses ("primacy"), we report a very rapid rise in information after each inhalation.

Hippocampal spatial view cells for memory and navigation, and their underlying connectivity in humans.

Hippocampal and parahippocampal gyrus spatial view neurons in primates respond to the spatial location being looked at. The representation is allocentric, in that the responses are to locations "out there" in the world, and are relatively invariant with respect to retinal position, eye position, head direction, and the place where the individual is located. The underlying connectivity in humans is from ventromedial visual cortical regions to the parahippocampal scene area, leading to the theory that spatial view cells are formed by combinations of overlapping feature inputs self-organized based on their closeness in space. Thus, although spatial view cells represent "where" for episodic memory and navigation, they are formed by ventral visual stream feature inputs in the parahippocampal gyrus in what is the parahippocampal scene area. A second "where" driver of spatial view cells are parietal inputs, which it is proposed provide the idiothetic update for spatial view cells, used for memory recall and navigation when the spatial view details are obscured. Inferior temporal object "what" inputs and orbitofrontal cortex reward inputs connect to the human hippocampal system, and in macaques can be associated in the hippocampus with spatial view cell "where" representations to implement episodic memory. Hippocampal spatial view cells also provide a basis for navigation to a series of viewed landmarks, with the orbitofrontal cortex reward inputs to the hippocampus providing the goals for navigation, which can then be implemented by hippocampal connectivity in humans to parietal cortex regions involved in visuomotor actions in space. The presence of foveate vision and the highly developed temporal lobe for object and scene processing in primates including humans provide a basis for hippocampal spatial view cells to be key to understanding episodic memory in the primate and human hippocampus, and the roles of this system in primate including human navigation.

Hippocampal spatial view cells, place cells, and concept cells: View representations.

A commentary is provided on issues raised in the Special Issue of Hippocampus (2023) on hippocampal system view representations. First, the evidence for hippocampal and parahippocampal spatial view cells in primates including humans shows that the allocentric representations provided by at least some of these cells are very useful for human memory in that where objects and rewards are seen in the world "out there" is a key component of episodic memory and navigation. Spatial view cell representations provide for memory and navigation to be independent of the place where the individual is currently located and of the egocentric coordinates of the viewed location and the facing direction of the individual. Second, memory and navigation in humans are normally related to the visual cues encoded by spatial view cells that define a location "out there" such as a building, hill, and so forth, not to an unmarked place without local cues and identified only by distant environmental/room cues. Third, "mixed" representations, for example of particular combinations of spatial view and place, can arise if the training has been for only some combinations of place and view, for that is what can then be learned by the hippocampus. Fourth, rodents, with their much less good visual acuity (~1 cycle/° in rats, compared with ~60 cycles/° for the human fovea), and rodents' very wide viewing angle for the world (~270°) might be expected, when using the same computational mechanisms as in primates, to use widely spaced environmental cues to define a place where the rodent is located, supported by inputs about place using local olfactory and tactile cues. Fifth, it is shown how view-point dependent allocentric representations could form a view-point independent allocentric representation for memory and navigation. Sixth, concept cells in humans and primates with connectivity to the hippocampus are compared.

Lifestyle risks associated with brain functional connectivity and structure.

Some lifestyle factors are related to health and brain function and structure, but the brain systems involved are incompletely understood. A general linear model was used to test the associations of the combined and separate lifestyle risk measures of alcohol use, smoking, diet, amounts of physical activity, leisure activity, and mobile phone use, with brain functional connectivity with the high resolution Human Connectome Project (HCP) atlas in 19,415 participants aged 45-78 from the UK Biobank, with replication with HCP data. Higher combined lifestyle risk scores were associated with lower functional connectivity across the whole brain, but especially of three brain systems. Low physical, and leisure and social, activity were associated with low connectivities of the somatosensory/motor cortical regions and of hippocampal memory-related regions. Low mobile phone use, perhaps indicative of poor social communication channels, was associated with low functional connectivity of brain regions in and related to the superior temporal sulcus that are involved in social behavior and face processing. Smoking was associated with lower functional connectivity of especially frontal regions involved in attention. Lower cortical thickness in some of these regions, and also lower subcortical volume of the hippocampus, amygdala, and globus pallidus, were also associated with the sum of the poor lifestyle scores. This very large scale analysis emphasizes how the lifestyle of humans relates to their brain structure and function, and provides a foundation for understanding the causalities that relate to the differences found here in the brains of different individuals.

The human posterior cingulate, retrosplenial, and medial parietal cortex effective connectome, and implications for memory and navigation.

The human posterior cingulate, retrosplenial, and medial parietal cortex are involved in memory and navigation. The functional anatomy underlying these cognitive functions was investigated by measuring the effective connectivity of these Posterior Cingulate Division (PCD) regions in the Human Connectome Project-MMP1 atlas in 171 HCP participants, and complemented with functional connectivity and diffusion tractography. First, the postero-ventral parts of the PCD (31pd, 31pv, 7m, d23ab, and v23ab) have effective connectivity with the temporal pole, inferior temporal visual cortex, cortex in the superior temporal sulcus implicated in auditory and semantic processing, with the reward-related vmPFC and pregenual anterior cingulate cortex, with the inferior parietal cortex, and with the hippocampal system. This connectivity implicates it in hippocampal episodic memory, providing routes for "what," reward and semantic schema-related information to access the hippocampus. Second, the antero-dorsal parts of the PCD (especially 31a and 23d, PCV, and also RSC) have connectivity with early visual cortical areas including those that represent spatial scenes, with the superior parietal cortex, with the pregenual anterior cingulate cortex, and with the hippocampal system. This connectivity implicates it in the "where" component for hippocampal episodic memory and for spatial navigation. The dorsal-transitional-visual (DVT) and ProStriate regions where the retrosplenial scene area is located have connectivity from early visual cortical areas to the parahippocampal scene area, providing a ventromedial route for spatial scene information to reach the hippocampus. These connectivities provide important routes for "what," reward, and "where" scene-related information for human hippocampal episodic memory and navigation. The midcingulate cortex provides a route from the anterior dorsal parts of the PCD and the supracallosal part of the anterior cingulate cortex to premotor regions.

The cortical regions and white matter tracts underlying auditory comprehension in patients with primary brain tumor.

The comprehension of spoken language is one of the most essential language functions in humans. However, the neurological underpinnings of auditory comprehension remain under debate. Here we used multi-modal neuroimaging analyses on a group of patients with low-grade gliomas to localize cortical regions and white matter tracts responsible for auditory language comprehension. Region-of-interests and voxel-level whole-brain analyses showed that cortical areas in the posterior temporal lobe are crucial for language comprehension. The fiber integrity assessed with diffusion tensor imaging of the arcuate fasciculus and the inferior longitudinal fasciculus was strongly correlated with both auditory comprehension and the grey matter volume of the inferior temporal and middle temporal gyri. Together, our findings provide direct evidence for an integrated network of auditory comprehension whereby the superior temporal gyrus and sulcus, the posterior parts of the middle and inferior temporal gyri serve as auditory comprehension cortex, and the arcuate fasciculus and the inferior longitudinal fasciculus subserve as crucial structural connectivity. These findings provide critical evidence on the neural underpinnings of language comprehension.

Association between parental age, brain structure, and behavioral and cognitive problems in children.

OBJECTIVE: To investigate the relation between parental age, and behavioral, cognitive and brain differences in the children. METHOD: Data with children aged 9-11 of 8709 mothers with parental age 15-45 years were analyzed from the Adolescent Brain Cognitive Development (ABCD) study. A general linear model was used to test the associations of the parental age with brain structure, and behavioral and cognitive problems scores. RESULTS: Behavioral and cognitive problems were greater in the children of the younger mothers, and were associated with lower volumes of cortical regions in the children. There was a linear correlation between the behavioral and cognitive problems scores, and the lower brain volumes (r > 0.6), which was evident when parental age was included as a stratification factor. The regions with lower volume included the anterior cingulate cortex, medial and lateral orbitofrontal cortex and amygdala, parahippocampal gyrus and hippocampus, and temporal lobe (FDR corrected p < 0.01). The lower cortical volumes and areas in the children significantly mediated the association between the parental age and the behavioral and cognitive problems in the children (all p < 10-4). The effects were large, such as the 71.4% higher depressive problems score, and 27.5% higher rule-breaking score, in the children of mothers aged 15-19 than the mothers aged 34-35. CONCLUSIONS: Lower parental age is associated with behavioral problems and reduced cognitive performance in the children, and these differences are related to lower volumes and areas of some cortical regions which mediate the effects in the children. The findings are relevant to psychiatric understanding and assessment.

Sleep, physical activity, sedentary behavior, and risk of incident dementia: a prospective cohort study of 431,924 UK Biobank participants.

Although sleep, physical activity and sedentary behavior have been found to be associated with dementia risk, findings are inconsistent and their joint relationship remains unclear. This study aimed to investigate independent and joint associations of these three modifiable behaviors with dementia risks. A total of 431,924 participants (median follow-up 9.0 years) without dementia from UK Biobank were included. Multiple Cox regressions were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Models fitted with restricted cubic spline were conducted to test for linear and nonlinear shapes of each association. Sleep duration, leisure-time physical activity (LTPA), and screen-based sedentary behavior individually associated with dementia risks in different non-linear patterns. Sleep duration associated with dementia in a U-shape with a nadir at 7 h/day. LTPA revealed a curvilinear relationship with dementia in diminishing tendency, while sedentary behavior revealed a J-shaped relationship. The dementia risk was 17% lower in the high LTPA group (HR[95%CI]: 0.83[0.76-0.91]) and 22% higher in the high sedentary behavior group (1.22[1.10-1.35]) compared to the corresponding low-level group, respectively. A combination of seven-hour/day sleep, moderate-to-high LTPA, and low-to-moderate sedentary behavior showed the lowest dementia risk (0.59[0.50-0.69]) compared to the referent group (longer or shorter sleep/low LTPA/high sedentary behavior). Notably, each behavior was non-linearly associated with brain structures in a pattern similar to its association with dementia, suggesting they may affect dementia risk by affecting brain structures. Our findings highlight the potential to change these three daily behaviors individually and simultaneously to reduce the risk of dementia.

The effective connectivity of the human hippocampal memory system.

Effective connectivity measurements in the human hippocampal memory system based on the resting-state blood oxygenation-level dependent signal were made in 172 participants in the Human Connectome Project to reveal the directionality and strength of the connectivity. A ventral "what" hippocampal stream involves the temporal lobe cortex, perirhinal and parahippocampal TF cortex, and entorhinal cortex. A dorsal "where" hippocampal stream connects parietal cortex with posterior and retrosplenial cingulate cortex, and with parahippocampal TH cortex, which, in turn, project to the presubiculum, which connects to the hippocampus. A third stream involves the orbitofrontal and ventromedial-prefrontal cortex with effective connectivity with the hippocampal, entorhinal, and perirhinal cortex. There is generally stronger forward connectivity to the hippocampus than backward. Thus separate "what," "where," and "reward" streams can converge in the hippocampus, from which back projections return to the sources. However, unlike the simple dual stream hippocampal model, there is a third stream related to reward value; there is some cross-connectivity between these systems before the hippocampus is reached; and the hippocampus has some effective connectivity with earlier stages of processing than the entorhinal cortex and presubiculum. These findings complement diffusion tractography and provide a foundation for new concepts on the operation of the human hippocampal memory system.

The human orbitofrontal cortex, vmPFC, and anterior cingulate cortex effective connectome: emotion, memory, and action.

The human orbitofrontal cortex, ventromedial prefrontal cortex (vmPFC), and anterior cingulate cortex are involved in reward processing and thereby in emotion but are also implicated in episodic memory. To understand these regions better, the effective connectivity between 360 cortical regions and 24 subcortical regions was measured in 172 humans from the Human Connectome Project and complemented with functional connectivity and diffusion tractography. The orbitofrontal cortex has effective connectivity from gustatory, olfactory, and temporal visual, auditory, and pole cortical areas. The orbitofrontal cortex has connectivity to the pregenual anterior and posterior cingulate cortex and hippocampal system and provides for rewards to be used in memory and navigation to goals. The orbitofrontal and pregenual anterior cortex have connectivity to the supracallosal anterior cingulate cortex, which projects to midcingulate and other premotor cortical areas and provides for action-outcome learning including limb withdrawal or flight or fight to aversive and nonreward stimuli. The lateral orbitofrontal cortex has outputs to language systems in the inferior frontal gyrus. The medial orbitofrontal cortex connects to the nucleus basalis of Meynert and the pregenual cingulate to the septum, and damage to these cortical regions may contribute to memory impairments by disrupting cholinergic influences on the neocortex and hippocampus.

The human language effective connectome.

To advance understanding of brain networks involved in language, the effective connectivity between 26 cortical regions implicated in language by a community analysis and 360 cortical regions was measured in 171 humans from the Human Connectome Project, and complemented with functional connectivity and diffusion tractography, all using the HCP multimodal parcellation atlas. A (semantic) network (Group 1) involving inferior cortical regions of the superior temporal sulcus cortex (STS) with the adjacent inferior temporal visual cortex TE1a and temporal pole TG, and the connected parietal PGi region, has effective connectivity with inferior temporal visual cortex (TE) regions; with parietal PFm which also has visual connectivity; with posterior cingulate cortex memory-related regions; with the frontal pole, orbitofrontal cortex, and medial prefrontal cortex; with the dorsolateral prefrontal cortex; and with 44 and 45 for output regions. It is proposed that this system can build in its temporal lobe (STS and TG) and parietal parts (PGi and PGs) semantic representations of objects incorporating especially their visual and reward properties. Another (semantic) network (Group 3) involving superior regions of the superior temporal sulcus cortex and more superior temporal lobe regions including STGa, auditory A5, TPOJ1, the STV and the Peri-Sylvian Language area (PSL) has effective connectivity with auditory areas (A1, A4, A5, Pbelt); with relatively early visual areas involved in motion, e.g., MT and MST, and faces/words (FFC); with somatosensory regions (frontal opercular FOP, insula and parietal PF); with other TPOJ regions; and with the inferior frontal gyrus regions (IFJa and IFSp). It is proposed that this system builds semantic representations specialising in auditory and related facial motion information useful in theory of mind and somatosensory / body image information, with outputs directed not only to regions 44 and 45, but also to premotor 55b and midcingulate premotor cortex. Both semantic networks (Groups 1 and 3) have access to the hippocampal episodic memory system via parahippocampal TF. A third largely frontal network (Group 2) (44, 45, 47l; 55b; the Superior Frontal Language region SFL; and including temporal pole TGv) receives effective connectivity from the two semantic systems, and is implicated in syntax and speech output.

Risk-taking in humans and the medial orbitofrontal cortex reward system.

Risk-taking differs between humans, and is associated with the personality measures of impulsivity and sensation-seeking. To analyse the brain systems involved, self-report risk-taking, resting state functional connectivity, and related behavioral measures were analyzed in 18,740 participants of both sexes from the UK Biobank. Functional connectivities of the medial orbitofrontal cortex, ventromedial prefrontal cortex (VMPFC), and the parahippocampal areas were significantly higher in the risk-taking group (p < 0.001, FDR corrected). The risk-taking measure was validated in that it was significantly associated with alcohol drinking amount (r = 0.08, p = 5.1×10-28), cannabis use (r = 0.12, p = 6.0×10-66), and anxious feelings (r = -0.12, p = 7.6×-98). The functional connectivity findings were cross-validated in two independent datasets. The higher functional connectivity of the medial orbitofrontal cortex and VMPFC included higher connectivity with the anterior cingulate cortex, which provides a route for these reward-related regions to have a greater influence on action in risk-taking individuals. In conclusion, the medial orbitofrontal cortex, which is involved in reward value and pleasure, was found to be related to risk-taking, which is associated with impulsivity. An implication is that risk-taking is driven by specific orbitofrontal cortex reward systems, and is different for different rewards which are represented differently in the brains of different individuals. This is an advance in understanding the bases and mechanisms of risk-taking in humans, given that the orbitofrontal cortex, VMPFC and anterior cingulate cortex are highly developed in humans, and that risk-taking can be reported in humans.

Dopamine depletion and subcortical dysfunction disrupt cortical synchronization and metastability affecting cognitive function in Parkinson's disease.

Parkinson's disease (PD) is primarily characterized by the loss of dopaminergic cells and atrophy in subcortical regions. However, the impact of these pathological changes on large-scale dynamic integration and segregation of the cortex are not well understood. In this study, we investigated the effect of subcortical dysfunction on cortical dynamics and cognition in PD. Spatiotemporal dynamics of the phase interactions of resting-state blood-oxygen-level-dependent signals in 159 PD patients and 152 normal control (NC) individuals were estimated. The relationships between subcortical atrophy, subcortical-cortical fiber connectivity impairment, cortical synchronization/metastability, and cognitive performance were then assessed. We found that cortical synchronization and metastability in PD patients were significantly decreased. To examine whether this is an effect of dopamine depletion, we investigated 45 PD patients both ON and OFF dopamine replacement therapy, and found that cortical synchronization and metastability are significantly increased in the ON state. The extent of cortical synchronization and metastability in the OFF state reflected cognitive performance and mediates the difference in cognitive performance between the PD and NC groups. Furthermore, both the thalamic volume and thalamocortical fiber connectivity had positive relationships with cortical synchronization and metastability in the dopaminergic OFF state, and mediate the difference in cortical synchronization between the PD and NC groups. In addition, thalamic volume also reflected cognitive performance, and cortical synchronization/metastability mediated the relationship between thalamic volume and cognitive performance in PD patients. Together, these results highlight that subcortical dysfunction and reduced dopamine levels are responsible for decreased cortical synchronization and metastability, further affecting cognitive performance in PD. This might lead to biomarkers being identified that can predict if a patient is at risk of developing dementia.