Human Lesion Studies Research Articles

Ventromedial frontoinsular connectivity is associated with long-term smoking behavior change in aging

Abstract A central question in the field of cognitive aging and behavioral neuroscience is what enables some individuals to successfully change their behavior more than others? Smoking is a significant risk factor for cognitive decline, particularly in vulnerable populations, including those who are at an elevated risk for Alzheimer’s disease (AD). Developing effective smoking reduction strategies is therefore a public health priority. The goal of the current study is to better understand the brain mechanisms underlying long-term smoking behavior change in cognitively normal, but at-risk, older adults. Neuroimaging and human lesion studies have implicated the insula and its functional network in subjective interoceptive awareness of cigarette craving and smoking-cue reactivity. We sought to characterize the extent to which anterior insular resting-state functional connectivity (RSFC) MRI predicted long-term smoking reduction (mean: 2.7 years, range 8 months–4 years) using a seed-to-voxel approach. Twenty-three (18 women; 26% APOE4 carriers; 61.5 years, SD = 3.7) cognitively unimpaired older individuals who smoked cigarettes at their baseline visit and have a first-degree family history of AD (at least one parent or multiple siblings affected) were included from a prospective longitudinal cohort, Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) in the current study. We found that reduced long-term smoking behavior was associated with enhanced antagonistic RSFC between bilateral anterior insula (aINS) and ventromedial prefrontal cortex (vmPFC). In a second pre-registered replication study within a larger, independent sample of 118 cognitively normal older adults who smoked cigarettes at baseline from the UK Biobank (73 women; 27.9% APOE4 carriers; 60.3 years, SD = 2.7), we found that baseline enhanced antagonistic RSFC between anterior insula and vmPFC predicted long-term smoking reduction (mean 5.2 years; ranging from 3 years to 7 years). To our knowledge, this is the largest study to examine the neural substrates of long-term smoking cessation in human aging. Our results suggest that antagonistic RSFC between aINS and vmPFC is a brain marker of future smoking reduction and disease prevention in older adults at risk for AD.

Functional topography of the corpus callosum as revealed by fMRI and behavioural studies of control subjects and patients with callosal resection

The concept of a topographical map of the corpus callosum (CC), the main interhemispheric commissure, has emerged from human lesion studies and from anatomical tracing investigations in other mammals. Over the last few years, a rising number of researchers have been reporting functional magnetic resonance imaging (fMRI) activation in also the CC.This short review summarizes the functional and behavioral studies performed in groups of healthy subjects and in patients undergone to partial or total callosal resection, and it is focused on the work conducted by the authors. Functional data have been collected by diffusion tensor imaging and tractography (DTI and DTT) and functional magnetic resonance imaging (fMRI), both techniques allowing to expand and refine our knowledge of the commissure. Neuropsychological test were also administered, and simple behavioral task, as imitation perspective and mental rotation ability, were analyzed. These researches added new insight on the topographic organization of the human CC. By combining DTT and fMRI it was possible to observe that the callosal crossing points of interhemispheric fibers connecting homologous primary sensory cortices, correspond to the CC sites where the fMRI activation elicited by peripheral stimulation was detected. In addition, CC activation during imitation and mental rotation performance was also reported.These studies demonstrated the presence of specific callosal fiber tracts that cross the commissure in the genu, body, and splenium, at sites showing fMRI activation, consistently with cortical activated areas. Altogether, these findings lend further support to the notion that the CC displays a functional topographic organization, also related to specific behavior.

The role of the ventromedial prefrontal cortex in moral cognition: A value-centric hypothesis

ABSTRACT Trends in moral psychology largely support the role that emotion plays in moral cognition with human lesion studies offering the most compelling evidence to date. Specifically, data from ventromedial prefrontal cortex (vmPFC) patients on moral judgment tasks has suggested the necessity of having intact emotion to behave in morally appropriate ways. However, patients with vmPFC damage also have deficits in a variety of complex judgment and decision-making tasks, regardless of whether emotion is involved. This paper argues that a basic information processing perspective of vmPFC functionality is a better interpretation of vmPFC patient deficits, specifically with the vmPFC being necessary for value assessment rather than being specific to emotion.

A Hypothalamic Perspective of Human Socioemotional Behavior

Historical evidence from stimulation and lesion studies in animals and humans demonstrated a close association between the hypothalamus and typical and atypical socioemotional behavior. A central hypothalamic contribution to regulation of socioemotional responses was also provided indirectly by studies on oxytocin and arginine vasopressin. However, a limited number of studies have so far directly investigated the contribution of the hypothalamus in human socioemotional behavior. To reconsider the functional role of the evolutionarily conserved hypothalamic region in regulating human social behavior, here I provide a synthesis of neuroimaging investigations showing that the hypothalamus is involved in multiple and diverse facets of human socioemotional behavior through widespread functional interactions with other cortical and subcortical regions. These neuroimaging findings are then integrated with recent optogenetics studies in animals demonstrating that the hypothalamus plays a more active role in eliciting socioemotional responses and is not simply a downstream effector of higher-level brain systems. Building on the aforementioned evidence, the hypothalamus is argued to substantially contribute to a continuum of human socioemotional behaviors promoting survival and preservation of the species that extends from exploratory and approaching responses facilitating social bonding to aggressive and avoidance responses aimed to protect and defend formed relationships.

Associative recognition without hippocampal associations.

Whereas both human and animal lesion and human neuroimaging studies have implicated the hippocampus in memory for associations, some studies find preserved associative memory following hippocampal damage. Starting with a classic summed similarity model of item recognition, we can account for associative recognition without assuming a specific hippocampally-mediated associative process. We add one key assumption: that one item can influence activation of another item's features. Feature-strength patterns, evaluated for each probe item individually, are then diagnostic of whether an item was paired with one item versus another. We suggest that feature-level inference, without explicit storage of associations, may play a critical role in associative recognition tasks. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Functional Neuroimaging of Human Hypothalamus in Socioemotional Behavior: A Systematic Review.

There exist extensive animal research and lesion studies in humans demonstrating a tight association between the hypothalamus and socioemotional behavior. However, human neuroimaging literature in this direction is still rather limited. In order to reexamine the functional role of this region in regulating human social behavior, we here provided a synthesis of neuroimaging studies showing hypothalamic activation during affiliative, cooperative interactions, and in relation to ticklish laughter and humor. In addition, studies reporting involvement of the hypothalamus during aggressive and antisocial interactions were also considered. Our systematic review revealed a growing number of investigations demonstrating that the evolutionary conserved hypothalamic neural circuity is involved in multiple and diverse aspects of human socioemotional behavior. On the basis of the observed heterogeneity of hypothalamus-mediated socioemotional responses, we concluded that the hypothalamus might play an extended functional role for species survival and preservation, ranging from exploratory and approaching behaviors promoting social interactions to aggressive and avoidance responses protecting and defending the established social bonds.

The fornix supports episodic memory during childhood.

Episodic memory relies on the coordination of widespread brain regions that reconstruct spatiotemporal details of an episode. These topologically dispersed brain regions can rapidly communicate through structural pathways. Research in animal and human lesion studies implicate the fornix-the major output pathway of the hippocampus-in supporting various aspects of episodic memory. Because episodic memory undergoes marked changes in early childhood, we tested the link between the fornix and episodic memory in an age window of robust memory development (ages 4-8years). Children were tested on the stories subtest from the Children's Memory Scale, a temporal order memory task, and a source memory task. Fornix streamlines were reconstructed using probabilistic tractography to estimate fornix microstructure. In addition, we measured fornix macrostructure and computed free water. To assess selectivity of our findings, we also reconstructed the uncinate fasciculus. Findings show that children's memory increases from ages 4 to 8 and that fornix micro- and macrostructure increases between ages 4 and 8. Children's memory performance across nearly every memory task correlated with individual differences in fornix, but not uncinate fasciculus, white matter. These findings suggest that the fornix plays an important role in supporting the development of episodic memory, and potentially semantic memory, in early childhood.

Human brain activity and functional connectivity as memories age from one hour to one month

ABSTRACT Theories of memory consolidation suggest the role of brain regions and connectivity between brain regions change as memories age. Human lesion studies indicate memories become hippocampus-independent over years, whereas animal studies suggest this process occurs across relatively short intervals, from days to weeks. Human neuroimaging studies suggest that changes in hippocampal and cortical activity and connectivity can be detected over these short intervals, but many of these studies examined only two time periods. We examined memory and fMRI activity for photos of indoor and outdoor scenes across four time periods to examine these neural changes more carefully. Participants (N = 21) studied scenes 1 hour, 1 day, 1 week, or 1 month before scanning. During scanning, participants viewed scenes, made old/new recognition memory judgments, and gave confidence ratings. Memory accuracy, confidence ratings, and response times changed with memory age. Brain activity in a widespread cortical network either increased or decreased with memory age, whereas hippocampal activity was not related to memory age. These findings were almost identical when effects of behavioral changes across time periods were minimized. Functional connectivity of the ventromedial prefrontal cortex with the posterior parietal cortex increased with memory age. By contrast, functional connectivity of the hippocampus with the parahippocampal cortex and fusiform gyrus decreased with memory age. In sum, we detected changes in cortical activity and changes in hippocampal and cortical connectivity with memory age across short intervals. These findings provide support for the predictions of systems consolidation and suggest that these changes begin soon after memories are formed.

Neural mechanisms necessary for empathy-related phenomena across species

The neural basis of empathy and prosociality has received much interest over the past decades. Neuroimaging studies localized a network of brain regions with activity that correlates with empathy. Here, we review how the emergence of rodent and nonhuman primate models of empathy-related phenomena supplements human lesion and neuromodulationstudies providing evidence that activity in several nodes is necessary for these phenomena to occur. We review proof that (i) affective states triggered by the emotions of others, (ii) motivations to act in ways that benefit others, and (iii) emotion recognitioncan be altered by perturbing brain activity in many nodes identified by human neuroimaging, with strongest evidence for the cingulate and the amygdala. We also include evidence that manipulations of the oxytocin system and analgesics can have such effects, the latter providing causal evidence for the recruitment of an individual's own nociceptive system to feel with the pain of others.

Network Localization of Executive Function Deficits in Patients with Focal Thalamic Lesions.

The human thalamus has been suggested to be involved in executive function, based on animal studies and correlational evidence from functional neuroimaging in humans. Human lesion studies, examining behavioral deficits associated with focal brain injuries, can directly test the necessity of the human thalamus for executive function. The goal of our study was to determine the specific lesion location within the thalamus as well as the potential disruption of specific thalamocortical functional networks, related to executive dysfunction. We assessed executive function in 15 patients with focal thalamic lesions and 34 comparison patients with lesions that spared the thalamus. We found that patients with mediodorsal thalamic lesions exhibited more severe impairment in executive function when compared to both patients with thalamic lesions that spared the mediodorsal nucleus and to comparison patients with lesions outside the thalamus. Furthermore, we employed a lesion network mapping approach to map cortical regions that show strong functional connectivity with the lesioned thalamic subregions in the normative functional connectome. We found that thalamic lesion sites associated with more severe deficits in executive function showed stronger functional connectivity with ACC, dorsomedial PFC, and frontoparietal network, compared to thalamic lesions not associated with executive dysfunction. These are brain regions and functional networks whose dysfunction could contribute to impaired executive functioning. In aggregate, our findings provide new evidence that delineates a thalamocortical network for executive function.

Ventromedial prefrontal area 14 provides opposing regulation of threat and reward-elicited responses in the common marmoset

The ventromedial prefrontal cortex (vmPFC) is a key brain structure implicated in mood and anxiety disorders, based primarily on evidence from correlational neuroimaging studies. Composed of a number of brain regions with distinct architecture and connectivity, dissecting its functional heterogeneity will provide key insights into the symptomatology of these disorders. Focusing on area 14, lying on the medial and orbital surfaces of the gyrus rectus, this study addresses a key question of causality. Do changes in area 14 activity induce changes in threat- and reward-elicited responses within the nonhuman primate, the common marmoset, similar to that seen in mood and anxiety disorders? Area 14 overactivation was found to induce heightened responsivity to uncertain, low-imminence threat while blunting cardiovascular and behavioral anticipatory arousal to high-value food reward. Conversely, inactivation enhanced the arousal to high-value reward cues while dampening the acquisition of cardiovascular and behavioral responses to a Pavlovian threat cue. Basal cardiovascular activity, including heart rate variability and sympathovagal balance, which are dysfunctional in mood and anxiety disorders, are insensitive to alterations in area 14 activity as is the extinction of conditioned threat responses. The distinct pattern of dysregulation compared to neighboring region area 25 highlights the heterogeneity of function within vmPFC and reveals how the effects of area 14 overactivation on positive and negative reactivity mirror symptoms of anhedonia and anxiety that are so often comorbid in mood disorders.

Hippocampal Representation of Threat Features and Behavior in a Human Approach-Avoidance Conflict Anxiety Task.

Decisions under threat are crucial to survival and require integration of distinct situational features, such as threat probability and magnitude. Recent evidence from human lesion and neuroimaging studies implicated anterior hippocampus (aHC) and amygdala in approach–avoidance decisions under threat, and linked their integrity to cautious behavior. Here we sought to elucidate how threat dimensions and behavior are represented in these structures. Twenty human participants (11 female) completed an approach–avoidance conflict task during high-resolution fMRI. Participants could gather tokens under threat of capture by a virtual predator, which would lead to token loss. Threat probability (predator wake-up rate) and magnitude (amount of token loss) varied on each trial. To disentangle effects of threat features, and ensuing behavior, we performed a multifold parametric analysis. We found that high threat probability and magnitude related to BOLD signal in left aHC/entorhinal cortex. However, BOLD signal in this region was better explained by avoidance behavior than by these threat features. A priori ROI analysis confirmed the relation of aHC BOLD response with avoidance. Exploratory subfield analysis revealed that this relation was specific to anterior CA2/3 but not CA1. Left lateral amygdala responded to low and high, but not intermediate, threat probability. Our results suggest that aHC BOLD signal is better explained by avoidance behavior than by threat features in approach–avoidance conflict. Rather than representing threat features in a monotonic manner, it appears that aHC may compute approach–avoidance decisions based on integration of situational threat features represented in other neural structures.SIGNIFICANCE STATEMENT An effective threat anticipation system is crucial to survival across species. Natural threats, however, are diverse and have distinct features. To be able to adapt to different modes of danger, the brain needs to recognize these features, integrate them, and use them to modify behavior. Our results disclose the human anterior hippocampus as a likely arbiter of approach–avoidance decisions harnessing compound environmental information while partially replicating previous findings and blending into recent efforts to illuminate the neural basis of approach–avoidance conflict in humans.

Recent advances in neuroimaging of bladder, bowel and sexual function

In this review, we summarize recent advances in the understanding of the neural control of the bladder, bowel and sexual function, in both men and women. Evidence of supraspinal areas controlling the storage of urine and micturition in animals, such as the pontine micturition centre, emerged in the early 20th century. Neurological stimulation and lesion studies in humans provided additional indirect evidence for additional bladder-related brain areas. Thereafter, functional neuroimaging in humans with PET and fMRI provided more direct evidence of the involvement of these brain areas. The areas involved in the storage and expulsion of urine also seem to be involved in the central control of storage and expulsion of feces. Furthermore, most knowledge on the brain control of sexual function is obtained from dynamic imaging in human volunteers. Relatively little is known about the dysfunctional central circuits in patients with pelvic organ dysfunction. fMRI has been the most widely used functional neuroimaging technique in the last decade to study the central control of bladder function, anorectal function and sexual function. The studies described in this review show which sensory and motor areas are involved, including cortical and subcortical areas. We propose the existence of a switch-like phenomenon located in the pons controlling micturition, defecation and orgasm.

Neural Representation of Threat Features and Behavior in a Human Approach-Avoidance Conflict Anxiety Task

Decisions under threat are crucial to survival and require integration of distinct situational features such as threat probability and magnitude. Recent evidence from human lesion and neuroimaging studies implicated anterior hippocampus (aHC) and amygdala in approach/avoidance decisions under predation and linked their integrity to cautious behavior. Here we sought to elucidate how threat dimensions and behavior are represented in these structures.

Damage to the right insula disrupts the perception of affective touch.

Specific, peripheral C-tactile afferents contribute to the perception of tactile pleasure, but the brain areas involved in their processing remain debated. We report the first human lesion study on the perception of C-tactile touch in right hemisphere stroke patients (N = 59), revealing that right posterior and anterior insula lesions reduce tactile, contralateral and ipsilateral pleasantness sensitivity, respectively. These findings corroborate previous imaging studies regarding the role of the posterior insula in the perception of affective touch. However, our findings about the crucial role of the anterior insula for ipsilateral affective touch perception open new avenues of enquiry regarding the cortical organization of this tactile system.

Oral and written narrative comprehension in left-brain damaged individuals and brain volumes correlates

Oral and written narrative comprehension in left-brain damaged individuals and brain volumes correlates

Causal Evidence from Humans for the Role of Mediodorsal Nucleus of the Thalamus in Working Memory.

The mediodorsal nucleus of the thalamus (MD), with its extensive connections to the lateral pFC, has been implicated in human working memory and executive functions. However, this understanding is based solely on indirect evidence from human lesion and imaging studies and animal studies. Direct, causal evidence from humans is missing. To obtain direct evidence for MD's role in humans, we studied patients treated with deep brain stimulation (DBS) for refractory epilepsy. This treatment is thought to prevent the generalization of a seizure by disrupting the functioning of the patient's anterior nuclei of the thalamus (ANT) with high-frequency electric stimulation. This structure is located superior and anterior to MD, and when the DBS lead is implanted in ANT, tip contacts of the lead typically penetrate through ANT into the adjoining MD. To study the role of MD in human executive functions and working memory, we periodically disrupted and recovered MD's function with high-frequency electric stimulation using DBS contacts reaching MD while participants performed a cognitive task engaging several aspects of executive functions. We hypothesized that the efficacy of executive functions, specifically working memory, is impaired when the functioning of MD is perturbed by high-frequency stimulation. Eight participants treated with ANT-DBS for refractory epilepsy performed a computer-based test of executive functions while DBS was repeatedly switched ON and OFF at MD and at the control location (ANT). In comparison to stimulation of the control location, when MD was stimulated, participants committed 2.26 times more errors in general (total errors; OR = 2.26, 95% CI [1.69, 3.01]) and 2.86 times more working memory-related errors specifically (incorrect button presses; OR = 2.88, CI [1.95, 4.24]). Similarly, participants committed 1.81 more errors in general ( OR = 1.81, CI [1.45, 2.24]) and 2.08 times more working memory-related errors ( OR = 2.08, CI [1.57, 2.75]) in comparison to no stimulation condition. "Total errors" is a composite score consisting of basic error types and was mostly driven by working memory-related errors. The facts that MD and a control location, ANT, are only few millimeters away from each other and that their stimulation produces very different results highlight the location-specific effect of DBS rather than regionally unspecific general effect. In conclusion, disrupting and recovering MD's function with high-frequency electric stimulation modulated participants' online working memory performance providing causal, in vivo evidence from humans for the role of MD in human working memory.

New Perspectives on the Brain Lesion Approach – Implications for Theoretical Models of Human Memory

Human lesion studies represent the cornerstone of modern day neuropsychology and provide an important adjunct to functional neuroimaging methods. The study of human lesion groups with damage to distinct regions of the brain permits the identification of underlying mechanisms and structures not only associated with, but essential for, complex cognitive processes. Here, we consider a recent review by McCormick et al., 2018 in which the power of the lesion model approach is elegantly presented with respect to a host of sophisticated cognitive endeavors, including autobiographical memory, future thinking, spatial navigation, and decision-making. By comparing profiles of loss and sparing in hippocampal (HC) and ventromedial prefrontal cortex (vmPFC) lesion groups, the authors provide new insights into the underlying neuroarchitecture of these diverse cognitive functions. Building on this framework, we consider how vmPFC and HC degeneration, in the context of large-scale network dysfunction in dementia, impacts discrete facets of memory and social cognition. Notably, we find remarkable concordance between the available evidence in dementia and that of the HC and vmPFC lesion literature. We further assess the role of the prefrontal cortex in modulating aspects of spatial navigation and discuss the role of schema-related processing in the service of memory more broadly. Far from being obsolete, we contend that human lesion work occupies a crucial position in cognitive neuroscience and offers an array of exciting areas for future study within this field.

Insula : neuropsychologie du cinquième lobe du cerveau

The insula, considered as the fifth lobe of the human brain, is one of the least understood areas of the brain, and its role in neuropsychological functioning remains enigmatic for many. In recent years, electrocortical stimulation, lesion, and neuroimaging studies in humans have shed light on several functions of this brain region. However, these functions are often looked at separately. This review article aims to summarize the current knowledge about the functions of the insula in humans. After a brief description of the anatomy and connectivity of the insula, we review its role in three main domains of neuropsychological function: (1) sensorimotor processing (viscerosensory and visceromotor function, interoception, somatosensory processing, and chemosensation); (2) emotion processing (emotional experience, empathy, and risky decision-making); and (3) cognitive functions (salience processing and speech). Broad anatomo-functional subdivisions within the insular lobe itself are presented. Finally, the insula’s potential involvement in psychopathology, especially anxiety, schizophrenia, autism, and addiction, are discussed. The insula's contribution to these many functions and pathologies may largely be attributable to its role in the subjective representation of body states. This article provides clinical neuropsychologists and researchers with a global and exhaustive portrait of the insula's role in neuropsychological functioning.

Roles of the Declive, Folium, and Tuber Cerebellar Vermian Lobules in Sportspeople.

The cerebellum plays vital roles in balance control and motor learning, including in saccadic adaptation and coordination. It consists of the vermis and two hemispheres and is anatomically separated into ten lobules that are designated as I–X. Although neuroimaging and clinical studies suggest that functions are compartmentalized within the cerebellum, the function of each cerebellar lobule is not fully understood. Electrophysiological and lesion studies in animals as well as neuroimaging and lesion studies in humans have revealed that vermian lobules VI and VII (declive, folium, and tuber) are critical for controlling postural balance, saccadic eye movements, and coordination. In addition, recent structural magnetic resonance imaging studies have revealed that these lobules are larger in elite basketball and short-track speed skaters. Furthermore, in female short-track speed skaters, the volume of this region is significantly correlated with static balance. This article reviews the function of vermian lobules VI and VII, focusing on the control of balance, eye movements, and coordination including coordination between the eyes and hands and bimanual coordination.