Information

Endogenous Neural Activity

Endogenous Neural Activity


We are searching data for your request:

Forums and discussions:
Manuals and reference books:
Data from registers:
Wait the end of the search in all databases.
Upon completion, a link will appear to access the found materials.

Could someone explain to me what exactly is endogenous neural activity? I am reading a lot of research papers, and I want to understand things thoroughly. Thanks for the response in advance.

This is the current paper that I am reading: https://www.nature.com/articles/pr199992


Quoting from the paper you refer to:

These connections form before the retina can respond to light, but at a time when retinal ganglion cells spontaneously generate highly correlated bursts of action potentials. Blockade of this endogenous activity

By "endogenous" here they are referring to the spontaneous activity generated before sight begins mentioned in the previous sentence, which organizes the circuitry for vision. It's endogenous because it's not triggered by an external stimulus like light, it's internally generated.

More generally, people tend to refer to "endogenous" activity that is not specifically related to stimulus-evoked activity that an experimenter can manipulate. Sometimes this is also called "noise" though there is debate about whether this term should be used (not that the people using it actually think it's truly noise).


Discussion

Altered endogenous opioid activity may be a mechanism for impaired emotion regulation during social rejection and acceptance in MDD. Despite strong, sustained negative affect during rejection in both groups, MOR activation in multiple brain regions was found only in HCs, whereas MDD patients showed MOR deactivation in the amygdala and slower emotional recovery from rejection. During acceptance, both groups reported increased positive affect, with MDD patients showing greater increases from baseline compared with HCs. However, this increase returned rapidly toward baseline after acceptance trials had ended. In MDD patients, MOR deactivation during acceptance was found in the NAcc, a reward structure. MOR activation in the NAcc in HCs but not in MDD patients was positively correlated with increases in the desire for social interaction, suggesting opioid involvement in the motivation to seek out positive social interaction during acceptance in HCs, but not in MDD patients.

During social rejection, MDD patients did not show significant activation in volumes of interest, whereas in HCs, MOR activation was found in the right NAcc, left and right amygdala, midline thalamus and periaqueductal gray (Figures 2a and b, Table 1), as previously described. 29 These structures are high in MOR concentrations and part of a pathway by which stressors can influence mood and motivation 42 thus, MOR activation in these structures may reduce the negative impact of stressors. In contrast, MDD patients showed MOR deactivation in the amygdala (Figure 2c), which may contribute to blood-oxygen-level-dependent hyperactivity in the amygdala in MDD patients in response to negative social cues such as peer rejection. 43 The present study also found a strong negative correlation between MOR activation in the pgACC, an area involved in emotion regulation, 44 and increased ratings of negative affect during rejection in HCs but not in MDD patients (Figure 3e). Similarly, previous studies found a strong negative correlation between MOR activation in the pgACC and increased ratings of negative affect during self-induced sadness in HCs 40 but not in MDD patients. 45 Thus, in MDD an absence of MOR activation plus greater MOR deactivation in the amygdala, and the lack of relationship between MOR activation in the pgACC and negative affect may contribute to sustained negative affect after rejection.

Ego Resiliency is a trait conceptualized by Block 36 as the ability to psychologically adapt across situations, and has been shown to correlate with faster emotional and physiological recovery from threat. 37 Consistent with this concept, levels of Ego Resiliency were positively correlated with MOR activation in the amygdala, periaqueductal gray and sgACC in HCs during rejection, as previously described. 29 This relationship was not found in any volumes of interest in MDD patients (Figures 3a, b, and c), possibly due to significantly lower Ego Resiliency ratings in MDD patients. The positive relationship between Ego Resiliency and MOR activation in HCs suggests that MOR activation during rejection is protective or adaptive. This hypothesis is consistent with the finding that Ego Resiliency was positively correlated with changes in self-esteem in HCs but not in MDD patients during rejection (Figure 3d). Path analyses in a larger sample size may test the hypothesis that MOR activation mediates the relationship between Ego Resiliency and changes in self-esteem during rejection.

As with social rejection, there were marked differences between groups during social acceptance, including MOR activation/deactivation, changes in affect and relationships between those measures. HCs showed activation in the left anterior insula and right amygdala, and deactivation in the midline thalamus and sgACC, whereas MDD patients showed activation in the midline thalamus and deactivation in the left NAcc (Figures 2e, f, g, and h). In HCs, this pattern of MOR activation is consistent with increased MOR activation in the anterior insula following amphetamine administration 46 and in the amygdala during an amusing video clip, 47 suggesting that MOR activation in these areas is related to positive affect. Also in HCs, MOR deactivation during acceptance in the midline thalamus and sgACC, both of which project heavily to the NAcc, 42, 48 is a possible mechanism for facilitating positive affect. In rats, a MOR agonist injected into the medial thalamus raised the threshold for both pain and reward. 49 Similarly, MOR deactivation in the sgACC may facilitate increased NAcc activity when one is liked. 50 In contrast, MDD patients showed MOR activation in the midline thalamus, which may impede sustained positive affect. MDD patients also did not show MOR deactivation in the sgACC, a region shown to be functionally associated with anhedonia. 51, 52 Unexpectedly, MDD patients reported a greater increase in positive affect relative to baseline during acceptance compared with HCs, however this increase was short-lived (Figure 1f), consistent with a recent study showing that MDD patients can indeed experience positive affect, but with a shorter duration compared with HCs. 53 Moreover, only HCs showed significant increases in self-esteem and the desire for social interaction after acceptance (Supplementary Table 2). Thus, in response to social acceptance, MDD patients showed short-lived increases in positive affect that did not significantly increase self-esteem or social motivation.

As previously reported in HCs, increased MOR activation in the NAcc was positively correlated with an increased desire for social interaction, 29 a finding consistent with a report in rats showing that MORs in the NAcc mediate social play behavior. 28 The present study showed that after acceptance, HCs but not MDD patients reported a greater desire for social interaction, and that MOR activation in the left NAcc was positively correlated with increased desire for social interaction (Figure 3f). In contrast, MDD patients showed MOR deactivation in the left NAcc, which may contribute to abnormal NAcc activity related to anhedonia in MDD patients. 54 Thus, in addition to having short-lived positive affect, MDD patients did not show increased social motivation, which in HCs was related to MOR activation in the NAcc.

There were no significant differences in plasma cortisol levels between rejection or acceptance relative to baseline within groups, and no differences were found between groups. In HCs, a significant negative correlation was found between MOR activation in the amygdala and NAcc and changes in cortisol levels during rejection, suggesting top–down MOR regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Previous studies suggest that the MOR system has a role in dampening stress-induced HPA axis activity by inhibiting corticotropin-releasing hormone in the hypothalamus. 55, 56 Consistent with the hypothesis, MOR activation in the right amygdala was negatively correlated with cortisol levels during rejection (Figure 4a). Thus, MOR regulation of amygdala activity during rejection may dampen HPA axis activity, most likely through projections to the bed nucleus of the stria terminalis, which in turn projects to the hypothalamus. 57 MOR activation in the NAcc was also negatively correlated with cortisol (Figures 4b and c), although the pathway from the NAcc to the paraventricular nucleus of the hypothalamus is less clear and likely involves multisynaptic pathways. The inhibitory influence of MOR activation on cortisol levels has also been reported in HCs during placebo administration for pain. 58 Thus, MOR activation may dampen HPA activity during rejection, a mechanism impaired in MDD by the lack of MOR activation and/or the uncoupling of the MOR system and HPA axis.

In HCs, the pattern of MOR activation during rejection was similar to that found during physical pain, 30, 59 supporting the theory that the regulation of social rejection and physical pain share overlapping neural pathways. 29, 31, 32, 38, 39, 60, 61, 62 In contrast to the present findings, previous studies found opposite patterns of MOR activity in HCs and MDD patients during recall of a sad autobiographical event (death of a friend or family member, romantic break-ups or divorce). These studies found MOR deactivation in HCs (pgACC, ventral pallidum, amygdala and inferior temporal cortex) 40 and MOR activation in MDD patients (anterior insula, thalamus, ventral basal ganglia and periamygdalar cortex). 45 It is likely that different patterns of MOR activation are involved in responding to exteroceptive cues (for example, pain, rejection) vs permissive, interoceptive cues (for example, self-induced sadness). For example, in functional magnetic resonance imaging studies where subjects viewed a photo of a romantic ex-partner (exteroceptive cue), increased blood-oxygen-level-dependent signal was found in the ventral striatum, thalamus, anterior insula and ACC. 38, 63 In contrast, recalling sad thoughts about a recent romantic break-up (interoceptive cue) resulted in deactivation in similar areas. 64

The present study supports previous work in animal models and has the potential to translate into clinical applications. Interestingly, one of the earliest studies to show evidence for endogenous opioid release during social interactions was found in rats using subtractive autoradiography, 65 a method with conceptual similarities to the neuroimaging method used in the present study. This and other animal studies 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 along with the present study in humans suggest that the endogenous opioids serve similar roles in social behavior across several species, supporting future translational work. For example, animal studies may provide more detailed analysis of the genetic substrates causing altered MOR function in the social environment. Indeed, a functional variation of the MOR gene has been shown in humans to be associated with the dispositional and neural sensitivity to social rejection, 31 and may be useful in the early detection of vulnerability to MDD in the social environment. In summary, the present study supports further investigation of the interaction between the endogenous opioid system, social environment, and pathophysiology and maintenance of MDD.


Differential impact of endogenous and exogenous attention on activity in human visual cortex

How do endogenous (voluntary) and exogenous (involuntary) attention modulate activity in visual cortex? Using ROI-based fMRI analysis, we measured fMRI activity for valid and invalid trials (target at cued/un-cued location, respectively), for pre- or post-cueing in endogenous and exogenous conditions, while observers performed the same task. We found stronger modulation in contralateral than ipsilateral visual regions to the attended hemifield, and higher activity in the valid- than invalid-trials. For endogenous, modulation of stimulus-evoked activity due to a pre-cue increased along the visual hierarchy, but was constant due to a post-cue. In contrast, for exogenous, modulation of stimulus-evoked activity due to a pre-cue was constant along the visual hierarchy, but not modulated due to a post-cue. These findings reveal that endogenous and exogenous attention distinctly modulate activity in visual areas during orienting and reorienting of attention endogenous facilitates both the encoding and the readout of visual information whereas exogenous only facilitates the encoding of information.


Overt vs. Covert Attention [ edit | edit source ]

Changes in spatial attention can occur with the eyes moving, overtly, or with the eyes remaining fixated, covertly (Wright & Ward, 2008). Within the human eye only a small part, the fovea, is able to bring objects into sharp focus. However, it is this high visual acuity that is needed to perform actions such as reading words or recognizing facial features, for example. Therefore, the eyes must continually move in order to direct the fovea to the desired goal. Prior to an overt eye movement, where the eyes move to a target location, covert attention shifts to this location. ⎖] ⎗] ⎘] ⎙] However, it is important to keep in mind that attention is also able to shift covertly to objects, locations, or even thoughts while the eyes remain fixated. For example, when a person is driving and keeping their eyes on the road, but then, even though their eyes don’t move, their attention shifts from the road to thinking about what they need to get at the grocery store. The eyes may remain focused on the previous object attended to, yet attention has shifted. ⎚]

Patient studies and attention shifts [ edit | edit source ]

Some of the first research into the neurology behind attention shifts came from examining brain damaged patients. First, Posner et al., studied persons affected by progressive supranuclear palsy, a condition wherein it is difficult to exert eye movements voluntarily, particularly vertical movements. Patients were found to have damage present in the mid-brain area and associated cortical areas. Although patients were not able to move their eyes, they were still able to shift attention covertly. However, there was a slowing of the process of shifting attention in these patients, suggesting that the mid-brain and cortical areas must be associated with covert attention shifts. Additionally, previous research has shown support for covert attention shifts being associated with activity in the parietal lobe. On the other hand, research seems to indicate differences in brain areas activated for overt attention shifts, as compared to covert shifts. Previous evidence has shown that the superior colliculus is associated with eye movements, or overt attention shifts. ⎛] Additionally, the medial cerebellum has shown activation only during eye movements. ⎜]

Neural overlap for overt and covert attention [ edit | edit source ]

Although, after reviewing Posner’s research, it may seem logical to conclude that covert and overt attention shifts utilize different neural mechanisms, other more recent studies have shown more overlap than not. Multiple studies have shown activity evident in the frontal cortex, concentrating in the precentral sulcus, the parietal cortex, specifically in the intraparietal sulcus, and in the lateral occipital cortex for both overt and covert attention shifts. ⎝] This is in support of the premotor theory of attention. While these studies may agree on the areas, they are not always in agreement on whether an overt or covert attentional shift causes more activation. Utilizing functional magnetic resonance imaging (fMRI) technology, Corbetta et al., found that overt and covert attention shift tasks showed activation within the same areas, namely, the frontal, parietal and temporal lobes. Additionally, this study reported that covert shifts of attention showed greater activity levels than in the overt attention condition. However, it is important to note that different tasks were used for the covert versus the overt condition. One task involved a probe being flashed to the subject’s fovea, while another task showed the probe in the participant’s peripheral vision, making it questionable whether these results can be directly compared. ⎜] Nobre et al. also sought to determine whether covert and overt attention shifts revealed activation in the same brain areas. Once again fMRI technology was utilized, as well as, two separate tasks, one for covert attention and one for overt attention. Results showed overlap in activated areas for overt and covert attention shifts, mainly in the parietal and frontal lobes. However, one area was shown to be specific to covert attention, which was the right dorsolateral cortex typically associated with voluntary attention shifts and working memory. One should question whether this additional activation has to do with the selected task for the covert condition, or rather if it is specific to a covert shift of attention. ⎞]

Beauchamp et al. more recently attempted to reproduce these same results by performing a study utilizing the same task for both conditions, as well as across multiple shift rates. Results were in agreement that covert and overt attentional shifts engage the same neural mechanisms. However, this study differed in that overt shifts of attention showed greater activation in these neural areas, and this occurred even at multiple shift rates. Once again, the neural regions implicated in this study included the intraparietal sulcus, the precentral sulcus, and the lateral occipital cortex. This larger activation evident with overt attention shifts was attributed to the added involvement of eye movements. ⎝]


Discussion

These results demonstrate that pre-stimulus activity modulates the degree of category tuning on the trial-by-trial basis in category-selective areas of the cortex. Previous studies have mainly focused on the overall correlation between the pre-stimulus activity and the evoked response in features including phase and oscillatory power of the event-related response 23,24,25 , often not definitively localized to the regions that process the stimulus class being presented 41 . The results here demonstrate that pre-stimulus activity modulates the post-stimulus activity in the regions that are selective for the stimulus being viewed.

The results also show that the degree of influence on the neural classification accuracy from the pre-stimulus activity correlates with behavioral reaction time specifically for the category of stimulus that a particular region processes. Prior work has shown that different aspects of the pre-stimulus activity, including phase and amplitude of the event-related response/field 7,42 , as well as BOLD signal 8,43 , correlate to behavioral performance. However, prior studies leave unclear whether the same aspects of pre-stimulus activity that modulate category-tuning also give rise to the influence on behavior as these two different effects have mostly not been linked to one another. The results here demonstrate that the two processes can be attributed to the same aspects of pre-stimulus activity in the same local category-sensitive circuit. The results demonstrated a significant relationship between the MI and the reaction time in detecting repetitions in the category that the electrode is selective for. Furthermore, no significant correlation was found between the MI and the reaction time with respect to categories that the electrode is not selective for, suggesting that this effect is not global and non-specific, such as reflecting arousal or alertness, but restricted to specific functional neural circuits.

Taken together these results suggest a model for how endogenous states can influence neural activity to modulate the perception of specific visual stimuli. If the stimulus is presented when endogenous activity in regions selective to that type of stimulus is relatively low, as indicated by lower pre-stimulus mean and variance, and when the phases of endogenous oscillations in the alpha/beta frequency range are optimal, then neural tuning will be stronger and perceptual behavior will be facilitated. The size of the behavioral modulation with endogenous activity (

20 ms) is on par with the magnitude of the behavioral facilitation seen with certain kinds of visual priming 44 and endogenous visual attention 45 , suggesting that while the effect may be relatively small, it may play an important role in perception. The results of the present study cannot completely exclude the possibility that the behavioral correlation seen is due to endogenous activity modulating decision processes rather than perceptual processes. However, most of the electrodes examined were located in VTC regions associated with visual perception. Furthermore, the multivariate pattern of activity in VTC, which is the same aspect of the signal that pre-stimulus activity modulates in this study, has previously been linked to the subjective perceptual representation 46 . The location of the electrodes and the aspects of the neural signals examined suggest that the perceptual rather than decision processes were influenced by endogenous activity here.

Given the random stimulus presentation in the present study, facilitating one stimulus over another on a trial-by-trial basis does not provide a behavioral advantage. Therefore, it is unclear if the endogenous activity seen here reflects stochastic dynamics in brain circuits, such a fluctuations of neurotransmitter levels 47 , or strategic processes, such as fluctuations in stimulus-specific attention or preference 48 , that may reflect pattern detection and strategies primates adopt even when stimuli are presented randomly 49 . While in the present study a strategic process would not provide a behavioral advantage, for example visual perception in familiar environments that one commonly finds oneself in, such as one’s house or office, facilitating the processing of particular stimuli may be advantageous. In these contexts, the stimulus-specificity of endogenous optimization may reflect a prediction of the next stimulus viewed based on internal models of the environment 22 . The magnitude of the effects seen here may be larger in cases where facilitating a particular stimulus over another was behaviorally useful. Active sensing in natural settings may organize the processes that underlie this optimization 50 and/or these active processes may synchronize to fluctuations in endogenous activity so that deployment of overt and covert attention occurs at temporally optimal times for information gathering 51 .

One hypothesis about how endogenous fluctuations modulate neural responses and behavior is that they may reflect a priming-like pre-activation of a predicted stimulus 22 , for example a prior in the Bayesian sense 52 . However, pre-activation would likely correspond to a higher pre-stimulus response in regions that process a particular stimulus type, not lower as was seen here. Without single unit recording we cannot fully exclude the alternative possibility that the reduced mean and variance of the pre-stimulus activity could be a result of desynchronization that can go along with enhanced frequency of action potentials 53,54 . However, prior studies in early visual cortex in monkeys also showed that lower pre-stimulus activity is associated with improved tuning and behavior, though in a non-specific manner associated with attentiveness 19,20,55 . The results of the present study suggest that the effects seen in early visual cortex in single units in monkeys may also occur in a stimulus- and circuit-specific manner in higher-level visual regions and in regions outside of visual cortex in humans. Lower pre-stimulus mean and variance may reflect an optimization of the dynamic range or gain 55 , potentially through normalization 56 in neural circuits responsible for processing particular stimulus types to enhance information pick-up for those stimuli 57 . While reduced pre-stimulus activity and variance is not consistent with a priming-like prior, the results here do provide a potential foundation for endogenous activity to reflect predictive processing 21 , though through a non-priming mechanism, such as circuit-specific optimization of processing. Note that while these results are not sufficient evidence of predictive processing, for the hypothesis that endogenous activity is a signature of predictive coding to be correct 22 , stimulus and circuit level modulation of tuning is a necessary feature of endogenous activity. The results here provide evidence of this necessary (though not fully sufficient) feature of endogenous activity needed for this activity to reflect predictive processes.

One methodological note about this work is that the two-stage statistical model described here has potential applications beyond examining the effects of pre-stimulus activity on discriminant information. Specifically, this method can be used to examine the effects of any multivariate signal on local discriminant information on a trial-by-trial basis. For example, this algorithm could be used to examine how activity in one region modulates discriminant information in another region, a form of multivariate functional connectivity 58,59 . Much like MI here, using this method for multivariate functional connectivity would yield a trail-by-trial measure of how much one region influences the representation in another region. That trial-by-trial measure of interregional influence could then be correlated to external variables, such as behavior, as was done in the present study between MI and reaction time.

Taken together, our results provide empirical support for a mechanism in which the present neural state influences the perception of sensory input in a stimulus-specific manner by modulating the tuning properties of neural circuits selective for those stimuli.


The Involvement of Endogenous Neural Oscillations in the Processing of Rhythmic Input: More Than a Regular Repetition of Evoked Neural Responses

It is undisputed that presenting a rhythmic stimulus leads to a measurable brain response that follows the rhythmic structure of this stimulus. What is still debated, however, is the question whether this brain response exclusively reflects a regular repetition of evoked responses, or whether it also includes entrained oscillatory activity. Here we systematically present evidence in favor of an involvement of entrained neural oscillations in the processing of rhythmic input while critically pointing out which questions still need to be addressed before this evidence could be considered conclusive. In this context, we also explicitly discuss the potential functional role of such entrained oscillations, suggesting that these stimulus-aligned oscillations reflect, and serve as, predictive processes, an idea often only implicitly assumed in the literature.

Keywords: ERP endogenous entrainment evoked response oscillation phase power.

Figures

It has often been reported…

It has often been reported that neural oscillations can align to a rhythmic…

Overview of selected studies that…

Overview of selected studies that show endogenous oscillatory activity in the absence of…

Overview of selected studies providing…

Overview of selected studies providing evidence from signal properties and cognitive effects that…


REVIEW article

  • 1 MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, United Kingdom
  • 2 Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, Netherlands

It is undisputed that presenting a rhythmic stimulus leads to a measurable brain response that follows the rhythmic structure of this stimulus. What is still debated, however, is the question whether this brain response exclusively reflects a regular repetition of evoked responses, or whether it also includes entrained oscillatory activity. Here we systematically present evidence in favor of an involvement of entrained neural oscillations in the processing of rhythmic input while critically pointing out which questions still need to be addressed before this evidence could be considered conclusive. In this context, we also explicitly discuss the potential functional role of such entrained oscillations, suggesting that these stimulus-aligned oscillations reflect, and serve as, predictive processes, an idea often only implicitly assumed in the literature.


Brain Repair: The Role of Endogenous and Transplanted Neural Stem Cells

Inflammation and degeneration are typical pathological processes occurring in the central nervous system (CNS) of patients with chronic irreversible neurological conditions. They are only apparently separate processes because, as soon as the pathological process becomes chronic, they have the tendency to become strictly interrelated (Martino et al. , 2002, 2011 Martino, 2004). Therefore, primary neurodegeneration triggers secondary inflammatory reactions, while primary inflammatory reactions lead to secondary neurodegeneration.

In the last 50 years, it has become clear that the CNS displays intrinsic ‘constitutive’ tissue repair ability to prevent the irreversible tissue damage occurring as a consequence of chronic inflammatory and/or degenerative processes. Several molecular and cellular events sustaining innate brain repair mechanisms have been described. On one hand, humoral and cellular inflammatory components shift their function over time, from a tissue-damaging mode to one promoting tissue repair. Not only pro-inflammatory cytokines may, under certain circumstances, act as anti-inflammatory molecules, but also pro-inflammatory mononuclear cells may promote neuroprotection by secreting neurotrophic factors (Martino et al. , 2002). On the other hand, the recruitment of alternative ‘non-damaged’ functioning neuronal pathways – occurring also via axonal sprouting and synaptogenesis – takes place as a consequence of brain damage. Whether or not this process is paralleled by central axon regeneration (i.e. an axon growing back along the distal stump of a crushed or transected nerve to re-innervate its normal target) is still a matter of intense debate (Tuszynski and Steward, 2012). Finally, endogenous neural stem and precursor cells – the self-renewing and multipotent cells of the CNS capable of driving neurogenesis and gliogenesis in adult life – may adapt targeted migration into damaged areas, to promote tissue repair and regeneration via cell replacement and/or the so-called bystander (paracrine) effect, which is due to the capacity of such cells to constitutively secrete neurotrophic and anti-inflammatory molecules (Martino et al. , 2011). However, ‘protective’ mechanisms reactive to CNS damage are not strong enough to promote the full recovery of cyto-architecture in most of the chronic inflammatory and degenerative neurological disorders. This evidence supports the ensuing view that irreversible neurodegeneration might be a consequence of the failure of CNS intrinsic repair mechanisms. Thus, it is believed that fostering and/or resetting ‘spontaneous’ regenerative process may lead to more efficacious, and less toxic, therapies.

Given that stem cells are an integral part of the mechanisms sustaining CNS tissue repair processes, strategies that mobilize neural progenitor cells (NPCs) or in vivo transplantation of NPCs might represent promising therapeutic approaches to foster intrinsic repair mechanisms and promote neuroprotection (Martino et al. , 2010 Pera and Tam, 2010). In this chapter, we will focus our attention on the self-renewal and differentiation potential and on the recently discovered homeostatic constitutive functions of endogenous NPCs as prerequisites to develop NPC-based transplantation strategies aimed at promoting CNS repair. At the same time, we will also discuss the ability of transplanted NPCs to adapt behaviour and fate in response to the CNS microenvironment and how this behaviour culminates in protection of the CNS from pathogenic signals, the concept of ‘therapeutic plasticity’.

In the adult rodent CNS, neurogenesis continues for the rodent’s entire life mainly in two regions, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus (Alvarez-Buylla and Lim, 2004 Zhao et al. , 2008). Newly formed adult NPCs of the SGZ migrate short distances and differentiate into dentate granule cells (DGCs) within the dentate granule cell layer (Kallur et al. , 2011). These newly formed DGCs migrate into the granule cell layer to become indistinguishable from pre-existing cells and are necessary for modulating and refining the existing neuronal circuits involved in hippocampus-dependent memory processing and behaviour (Imayoshi et al. , 2008 Kitamura et al. , 2009 Singer et al. , 2011). In the rodent, however, SVZ NPCs migrate along the rostral migratory stream (RMS) to the olfactory bulb where they integrate within the granule and glomerular cell layer in order to maintain and reorganize the olfactory bulb system (Imayoshi et al. , 2008).

However, recent evidence challenges the sole and exclusive view that the neurogenic CNS areas mainly act as a source of newly formed neurons, able to replace neuronal cells in the hippocampus and in the olfactory bulb (Imayoshi et al. , 2008). As a matter of fact, adult NPCs residing within germinal niches might exert other ‘non-neurogenic’ homeostatic regulatory functions alternative to cell replacement during either a healthy state or pathology.

Apart from a recent report showing that neurogenesis in the SGZ exerts an antidepressant activity by regulating (via glucocorticoid release buffering) the hypothalamus–pituitary axis (Snyder et al. , 2011), evidence collected so far suggests that SVZ represents the more ‘strategic’ area where NPCs might exert a homeostatic role in addition to neurogenesis. This is because, on one side, these cells are in communication with two different microenvironments, tightly apposing blood vessels and in contact with the cerebrospinal fluid (CSF) through apical processes (Sawamoto et al. , 2006 Rolls et al. , 2007 Mirzadeh et al. , 2008 Tavazoie et al. , 2008). On the other side, the SVZ is very close to crucial areas of the midbrain (e.g. the basal ganglia and striatal structures) containing GABAergic neurons capable of efficiently regulating and modulating interconnections between several cortical and sub-cortical brain areas (Koos and Tepper, 1999).

As a matter of fact, SVZ NPCs protect striatal neurons from glutamatergic excitotoxicity, as seen in the early phase of ischaemic stroke and epilepsy, by releasing endogenous endocannabinoids, N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2AG) capable of binding to their specific receptors (CB1 and CB2) (Butti et al. , 2012). This NPC-mediated operational way of acting is tuned up during CNS-compartmentalized inflammatory insults. It is thus tempting to speculate that endogenous SVZ NPCs act as guardians of the brain, by sensing danger signals coming from the periphery and responding by down-modulating glutamatergic excitotoxic currents, whose deregulation might, in turn, be noxious for proper functioning of brain cells (see Figure 5.1). The above-mentioned strategic positioning of SVZ NPCs within the CNS supports this novel view while questioning the positioning as just representing a developmental relic. In addition, SVZ NPCs have been shown to be capable of exerting a physiological phagocytic activity that requires intracellular engulfment protein, ELMO1, to promote Rac activation downstream of phagocytic receptors (Lu et al. , 2011). Finally, SVZ NPCs may mediate suppression of high-grade astrocytomas (HGA) by releasing endovanilloids that activate the transient receptor potential vanilloid subfamily member-1 (TRPV1) on HGA cells, triggering their death and thus prolonging overall survival time (Stock et al. , 2012).


Figure 5.1 Structural and functional characteristics of NPCs in the SVZ. Schematic representation of the functional homeostatic role exerted by NPCs in the SVZ and striatum. SVZ NPCs may sense danger signals, coming from either the CSF or the blood, via Toll-like receptors (TLRs). TLR4 is triggered by several types of endogenous and exogenous danger signals, including those released from neural cells stressed by glutamate-induced excitoxicity (e.g. heat shock protein 70, saturated fatty acids, high-mobility group box 1 proteins (HMGB1) and β-defensins). As a consequence of such triggering, SVZ adult neural precursor cells increase the production of the endogenous cannabinoid AEA (blue dots) which, in turn, binds to pre- and post-synaptic CB1 receptors. CB1 receptor binding decreases Ca 2+ content within the presynaptic compartment, thus reducing glutamate release within the synaptic space. This regulatory mechanism reduces post-synaptic glutamatergic currents and glutamatergic-mediated excitotoxicity, thus representing an innate protective mechanism.

While possibly explaining the role of SVZ NPCs in non-human primates and humans, where the presence of a fully formed RMS is not yet substantiated (Sanai et al. , 2004, 2007), the homeostatic role of SVZ NPCs is also supported by recent evidence indicating a long-lasting neurogenic response reactive to injury. This has been observed in both patients (Marti-Fabregas et al. , 2010) and animal models (Bengzon et al. , 1997 Parent et al. , 1997 Jin et al. , 2001, 2010 Goings et al. , 2004) affected by neurological diseases, but it is not yet confirmed whether such approaches replace damaged and/or dead cells. In stroke, about 80–90% of newly formed SVZ-derived cells die within a few weeks without integrating into the spared neuronal circuitries (Arvidsson et al. , 2002), but they seem to protect against tissue injury through the secretion of neurotrophic factors in ischaemic CNS areas (Jin et al. , 2010). In the toxin-induced cuprizone model in which demyelination of the corpus callosum is induced, less than 4% of newly formed SVZ-derived cells differentiate into myelinating oligodendrocytes (Menn et al. , 2006). However, SVZ-derived newly formed NG2 + cells can still promote remyelination, by forming functional glutamatergic synapses with demyelinated axons (Etxeberria et al. , 2010). In experimental epilepsy, SVZ-derived cells migrating towards the hippocampus terminally differentiate into glial but not neuronal cells (Parent et al. , 2006). This is likely to exert a protective effect because in temporal lobe epilepsy newly born neurons aberrantly migrate and integrate in the dentate hilus, exacerbating the hippocampal epileptic activity (Hattiangady and Shetty, 2008).

Although the replacement of damaged cells seems not to be the prevailing and sole mechanism of reactive neurogenesis occurring in response to tissue damage (at least in the SVZ), it is very likely that the specific characteristics of the pathological environment influence the behaviour of SVZ-derived newly formed cells. As such, inflammation occurring as a consequence of autoimmunity and/or traumatic and ischaemic injuries has been variably shown to alter NPC proliferation and differentiation characteristics in a non-cell-autonomous fashion. On the other hand, when inflammation fades away and neurodegeneration prevails, endogenous NPCs tend to differentiate into multiple neuronal lineages, depending on the situation, that are partly capable of integrating into damaged neuronal circuits (Kokaia et al. , 2012). The increase in the numbers of microglia cells within the SVZ neurogenic area during inflammatory CNS conditions (Pluchino et al. , 2008) supports this working hypothesis, as does recent evidence emerging from NPC transplantation studies, which will be discussed in detail in this chapter. Briefly, while remaining undifferentiated, transplanted SVZ-derived NPCs might promote CNS tissue healing via the secretion of immunomodulatory and neuroprotective molecules capable of reducing detrimental tissue responses, the so-called bystander effect (Ourednik et al. , 2002 Pluchino et al. , 2003 Martino and Pluchino, 2006a Bacigaluppi et al. , 2009a,b).

As already anticipated, CNS pathology results in loss of either neural or glial cells and disrupts the cyto-architecture of the tissue that is defined during development, when neurons and glia precociously acquire specific positional identities (Hochstim et al. , 2008 Sauka-Spengler and Bronner-Fraser, 2008) and their integrity is required for correct CNS functioning (Eroglu and Barres, 2010). Therefore, cell replacement strategies would represent an ideal therapeutic approach for CNS disorders, owing to the fact that it not only aims at substituting dead cells with newly differentiated ones but also promotes functional integration into neural circuits of newly formed cells (Ingber and Levin, 2007 Poss, 2010).

With this in mind, several cell replacement–based therapeutic strategies have been established. The results, obtained so far, reveal that this approach does represent a rational and realistic therapeutic strategy for only a restricted category of neurological disorders, and the success of this strategy is very much dependent on the cell type to be substituted and on the CNS region damaged. Cell replacement is efficacious in disorders in which degeneration is caused by either intrinsic cellular defects of, or extrinsic factors that are no longer active in, a specific cell population residing within a discrete CNS area, but where the general architecture of the tissue is maintained. In animal models of Parkinson’s disease (PD), dopaminergic neuronal precursors – derived from different animal species (Dunnett et al. , 1987 Wictorin et al. , 1992 Isacson and Deacon, 1996 Starr et al. , 1999) and cell sources (Dunnett et al. , 1987 Shim et al. , 2007 Wernig et al. , 2008) – can survive, re-innervate the striatum and ameliorate clinical outcome, when grafted either in the substantia nigra or in the striatum (Gaillard and Jaber, 2011). In animal models of genetically induced dysmyelination and/or hypomyelination (i.e. shiverer mouse) (Ben-Hur et al. , 2005 Duncan et al. , 2011) or chemically induced demyelination (Blakemore and Franklin, 2008), intraparenchymal transplantation of many different myelinating cell types extensively remyelinates denuded axons (Windrem et al. , 2004 Buchet et al. , 2011 Sim et al. , 2011).

In contrast, cell replacement has been only partially satisfactory in a persistently unfavourable environment, where different cell sub-populations in different CNS areas are affected and where the tissue architecture is altered, such as in stroke, spinal cord injury (SCI), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) (Chen and Palmer, 2008). In stroke and SCI animal models, NPCs from multiple sources have been demonstrated to functionally integrate into the host neural circuits and differentiate into neurons (Kelly et al. , 2004 Cummings et al. , 2005 Buhnemann et al. , 2006 Yan et al. , 2007 Daadi et al. , 2009 Braz et al. , 2012). Likewise, in animal models of MS and SCI, both NPC and glial-restricted progenitors can remyelinate injured axons (Archer et al. , 1997 Pluchino et al. , 2003 Keirstead et al. , 2005 Lee et al. , 2009 Sharp et al. , 2010 Yang et al. , 2010). However, it still remains to be demonstrated if this cell replacement mechanism is the sole mechanism functionally accountable for the clinical amelioration (Dubois-Dalcq et al. , 2005 Pluchino et al. , 2005 Bacigaluppi et al. , 2009b Sahni and Kessler, 2010). Other mechanisms that will be discussed in this chapter (e.g. the bystander effect) may also contribute to the therapeutic effect observed upon NPC transplantation.

Another issue is the degree of complexity of the tissue patterning that transplanted cells need to restore. PD and focal demyelination are diseases in which specific cell types are necessary to re-establish appropriate interactions at the cellular level in PD dopaminergic circuits should be restored within the striatal region, while in demyelinating disorders a properly functioning saltatory conduction should be achieved via efficient remyelination. However, very few studies have been able to demonstrate that cell transplantation might lead to the generation of long-distance connections in diseases in which degeneration impairs multiple widespread afferent–efferent connections, such as ALS and other motor neuron disorders (Verstraete et al. , 2011), Huntington’s disease (HD) (Wolf et al. , 2008) or spinocerebellar ataxias (Di Giorgio et al. , 2011 Yohn et al. , 2008 Solodkin et al. , 2011 Lepore et al. , 2011).

The last issue to be considered when designing therapies aimed at promoting cell replacement is the timing of cell transplantation. In primary neurodegeneration, transplantation should be performed at the beginning of the neurodegenerative process in order to limit the cascade of events leading to the degeneration of other cell populations. Data clearly show that transplanted NPCs acquire an appropriate terminally differentiated fate and integrate functionally in the host tissue (Goldman, 2005 Breysse et al. , 2007 Lindvall and Kokaia, 2010), an event particularly evident when there is a partial preservation of the neuronal circuits’ cyto-architecture (Shihabuddin et al. , 1996). On the other hand, while early transplantation is recommended in degenerative diseases, in primary inflammatory disorders (e.g. stroke, SCI and MS) transplantation aimed at cell replacement would be useful only during the post-acute phase of the disease (Karimi-Abdolrezaee et al. , 2006 Bacigaluppi et al. , 2009b) when the inflammatory phase is limited. It is now clear that the immune milieu can influence, either detrimentally or protectively, the fate of transplanted cells (Carpentier and Palmer, 2009 Deverman and Patterson, 2009 Ransohoff, 2009 Giannakopoulou et al. , 2011 Muja et al. , 2011 Kokaia et al. , 2012).

Despite the initial perception that transplantation of NPCs could serve to replace only damaged cells, recent experimental studies have shown that NPCs could exert a plethora of different neuroprotective effects, spanning from neurotrophic support to immunomodulation, when transplanted in chronic inflammatory neurological disorders. (See Figure 5.2.)


Figure 5.2 Operational mechanism(s) of action of endogenous and transplanted NPCs. The extent of tissue regeneration driven by endogenous as well as transplanted multipotent NPCs is very much dependent on the different operational mechanism(s) of action that such cells adopt while interacting with CNS resident and blood-borne infiltrating mononuclear cells, homing within the microenvironment during both physiological and/or pathological circumstances. Both cell-autonomous and non-cell-autonomous mechanisms may affect the final fate and behaviour of endogenous and transplanted NPCs as well as their interactions with CNS resident and CNS-infiltrating cells. While cell-autonomous mechanisms driving terminal differentiation of exogenous versus transplanted NPCs tend to prevail in pathological conditions mainly characterized by neuronal degeneration and mild reactive inflammation (mainly driven by CNS resident microglia), non-cell-autonomous mechanisms mainly affect NPCs when acute or chronic non-resolving inflammation is ongoing. As a matter of fact, endogenous and transplanted NPCs sense the inflammatory environment and, within such an environment, might promote tissue homeostasis and repair by releasing at the site of tissue damage a milieu of constitutively expressed molecules (chemokines, cytokines, growth factors and stem cell regulators) capable of immunomodulation and trophic support, the so-called bystander effect. The bystander effect is made possible by the fact that inflammation inhibits NPC proliferation, thus maintaining NPCs in an undifferentiated state this is the best situation possible for NPCs to release constitutively a wide set of neuroprotective molecules. However, cell-autonomous mechanisms, driving terminal differentiation during lineage commitment, limit the amount of molecules constitutively released by NPCs due to epigenetic restriction of transcriptional circuits.

To what extent the interaction between the inflammatory microenvironment and transplanted NPCs results in protective versus detrimental effects is still far from being fully elucidated. Some of these ideas are discussed below.


Materials and methods

The behavioral methods employed in this study and the behavioral results are the same as those we reported in a recent study, in which we compared activity in TPJ during orienting and reorienting of endogenous and exogenous attention 41 . To maximize the effects of these two types of attention, i.e. the benefits at the attended location and concurrent costs at the unattended location, we used optimal spatial and temporal parameters (for reviews see 1,2 ). To enable direct comparison between endogenous and exogenous attention, the same participants performed the same orientation discrimination task under both types of attention. The fMRI methods employed in this study are the same as those used in that study 41 , but here, instead of analyzing TPJ activity, we analyzed activity in occipital areas.

Participants

Five participants (two male and three female, 24–30 years-old) participated in the study. They all had normal or corrected-to-normal vision. The University Committee on Activities Involving Human Subjects at New York University approved the experimental protocol (IRB # 10-7094), and participants provided written informed consent. All methods were performed in accordance with US regulations and the Declaration of Helsinki. Our study used single-participant ROI-based analysis, and thus had a small sample size. The same sample size that has been used in many fMRI studies in our labs (e.g. 25,27,41,76,121,122,123,124,125 ), as well as in other labs (e.g. 126,127,128,129,130 ). Each participant performed nine scanning sessions: one session to obtain a set of three high-resolution anatomical volumes, two sessions for retinotopic mapping, three sessions for the exogenous attention condition and three sessions for the endogenous attention condition (with the order counterbalanced among participants). Participants performed several practice sessions outside the scanner prior to the first scanning session of each attention condition.

Stimuli

Stimuli were generated on a Macintosh computer using the MGL toolbox 131 in MATLAB (MathWorks). Stimuli were presented on a flat-panel display (NEC, LC-XG250 MultiSync LCD 2110 refresh rate: 60 Hz resolution: 1024 × 768 pixels) positioned at the rear of the scanner bore and housed in a Faraday box with an electrically conductive glass front. The display, calibrated and gamma corrected using a linearized lookup table, was at a viewing distance of 172 cm from the participant, and visible through an angled mirror attached to the head coil. A central, white fixation cross (0.3°) was presented throughout the experiment. The two stimuli were two 4-cpd gratings windowed by raised cosines (3° of diameter 7% contrast), one in each bottom quadrant (5° horizontal eccentricity − 2.65° altitude 5.66° of eccentricity from the central fixation to the stimulus center). Both endogenous cues and exogenous cues were white rectangles (0.7°). The endogenous cues appeared adjacent to the fixation cross indicating one of the two lower quadrants (0.35° horizontal eccentricity from the edge of the fixation cross, and 0.35° altitude). The exogenous cues appeared adjacent to an upcoming grating stimulus, vertically aligned with the stimulus and above the horizontal meridian (1° away from the edge of the grating stimulus and the edge of the cue 4.44° horizontal eccentricity from the edge of the fixation cross).

Behavioral procedure

An exogenous attention condition trial lasted 1700 ms, whereas an endogenous attention condition trial lasted 1900 ms, the only difference being the stimulus-onset asynchronies (SOA) between the cue and the display the timing of all the visual stimuli was the same in both attention conditions (Fig. 1 the display is not at scale for illustration purposes). In the pre-cue condition (40% of the trials), a cue preceded the two gratings. In 40% the post-cue condition, the cue followed the presentation of the gratings. In 'cue-only' trials (10% of the trials), the gratings were not presented. In 'blank' trials (10% of the trials), neither a cue nor the gratings were presented. These trials were then included in the GLM analysis to model the contribution of the visual signal produced by the cue (see MRI procedure). For both pre-cue and post-cue trials, participants were asked to press one of two keys to report the orientation of a target grating, i.e. clockwise or counter-clockwise compared to vertical. Participants pressed a third key in the case of cue-only and blank trials.

In both exogenous and endogenous condition, cues were presented for 67 ms, indicating either the bottom left or right quadrant of the screen. The inter-stimulus interval (ISI) between the cue and the grating stimuli was 50 ms for exogenous and 250 ms for endogenous conditions, resulting in SOA of 117 ms and 317 ms. We used the same timings for pre- and post-cue conditions (e.g. 9,25,65,76 ). These delays are optimal to manipulate exogenous and endogenous attention, while keeping the trial duration as similar as possible, and have been shown to maximize the behavioral consequences of each attention condition 46,132,133,134 .

The behavioral effects of endogenous attention are sustained (e.g. 105 ) and thus, as shown in ERP studies (e.g. 135 ), are still present in later brain activity. Additionally, during 300 ms following cue onset, the brain responses elicited by exogenous and endogenous cues differ (for review see 1 ). The two grating stimuli were then displayed for 50 ms. For the postcue trials we kept the timings of cue and stimuli constant but inverted the order of their presentation (e.g. 9,25,65,76 ). A response cue, presented for 800 ms at the end of the trial after both the cue and the stimuli had disappeared, indicated which one of the two gratings was the target (50% of the trials on the right and the remaining 50% and on the left). The maximum delay between the offset of the grating stimuli and the onset of the response cue was shorter (

400 ms max in the endogenous condition) than typically associated with a demand for working memory (> 600 ms 136 ). Immediately following each trial, a change of color of the fixation cross provided visual feedback to the participants, i.e. green for correct or red for incorrect responses. The fixation cross did not change color if participants had missed the response window, i.e. if they had not pressed any key after 530 ms.

In the exogenous attention condition, a peripheral cue was presented, which was not informative regarding the target location or orientation. When the cue location matched the target location, it was considered a valid trial (50% of the trials), otherwise it was considered an invalid trial (the remaining 50% of the trials). In the endogenous attention condition, a central cue pointed to either the left or right quadrant. The cue was informative of the target location but not its orientation (75% valid trials and 25% invalid trials). Participants were informed of this validity. It is important to note that: (1) cue validity does not affect cueing effectiveness for exogenous attention, although it does so for endogenous attention (e.g. 3,137,138 ) (2) the short timing and non-informative cue in the exogenous condition ensured that no voluntary component could be involved in the exogenous attentional effect.

Endogenous and exogenous attention conditions were performed in separate sessions to ensure optimal manipulation of each attention system. Participants performed two practice sessions outside the scanner before the first session of each attentional scanning condition. To equate task difficulty for both attention conditions, using a staircase procedure, the tilt of the target grating was adjusted for each participant to achieve

80% correct performance in the valid trials in each attention condition. In each of the six experimental scanning sessions (three sessions of exogenous attention and three of endogenous), participants performed 14 runs of 40 trials each, as well as a run of stimulus localizer (see MRI procedure). The tilt was then adjusted between runs to maintain overall performance at

Eye position was monitored during all scanning sessions using an infrared video camera system (Eyelink 1K, SR Research, Ottawa, Ontario, http://www.sr-research.com/EL_1000.html). Trials in which the participants blinked or broke fixation (1.5° radius from central fixation) at any point from fixation onset to response cue offset were identified and regressed separately in the MRI analysis, and removed from the behavioral analysis (13% ± 4% of the trials on average across all participants).

MRI Procedure

Scanning

Imaging was conducted on a 3T Siemens Allegra head-only scanner (Erlangen, Germany), using a Siemens NM-011 head coil (to transmit and receive) to acquire anatomical images, a receive-only 8-channel surface coil array (Nova Medical, Wilmington, MA) to acquire functional images. To minimize participants' head movements, padding was used.

For each participant, three high-resolution anatomic images were acquired in one scanning session, using a T1-weighted magnetization-prepared rapid gradient echo (MPRAGE) sequence (FOV = 256 × 256 mm 176 sagittal slices 1 × 1 × 1 mm voxels), and were co-registered and averaged. Using FreeSurfer (public domain software http://surfer.nmr.mgh.harvard.edu), the gray matter was segmented from these averaged anatomical volumes. All subsequent analyses were constrained only to voxels that intersected gray matter.

T2*-weighted echo-planar imaging sequence (i.e. functional images TR = 1750 ms TE = 30 ms flip angle = 90°) measured blood oxygen level-dependent (BOLD) changes in image intensity 139 . In each volume, 28 slices covered the occipital and posterior parietal lobes and were oriented 45° to the calcarine sulcus (FOV = 192 × 192 mm resolution = 2 × 2 × 2.5 mm no gap). To align functional images from different sessions to the same high-resolution anatomical volume for each participant, we acquired an additional T1-weighted anatomical images in the same slices as the functional images (spin echo TR = 600 ms TE = 9.1 ms flip angle = 90° resolution = 1.5 × 1.5 × 3 mm) during each scanning session, and used them in a robust image registration algorithm.

MRI data pre-processing

Imaging data were analyzed in MATLAB, using mrTools 140 and custom software. To allow longitudinal magnetization to reach steady state, the first eight volumes of each run were discarded. Spatial distortion was corrected using the B0 static magnetic field measurements performed in each session. The functional data were then motion corrected, the linear trend was removed, and a temporal high-pass filter was applied (cutoff: 0.01 Hz) to remove slow drifts and low-frequency noise in the fMRI signal.

Retinotopic mapping

We followed well-established conventional traveling-wave, phase-encoded methods. Using clockwise and counter-clockwise rotating checkerboard wedges, we measured phase maps of polar angle. Using contracting and expending checkerboard rings, we measured eccentricity maps 94,95,96,97 . Figure 2 (left panel) shows the visual areas of interest that were drawn by hand on flattened surface of the brain, following published conventions 96,97,122,141 .

Stimulus localizer

In each scanning session of the main experiment, participants completed one stimulus localizer run (6 runs overall, 4 min each). A run consisted of 16 cycles (17.5 s) of a block alternation protocol between stimulus on (8.75 s) and stimulus off (8.75 s). Participants only had to fixate the central cross throughout each run. The stimuli were at the same location, and of the same size and spatial frequency as those in the main experiment, except at full contrast and their phase and orientation changed randomly every 200 ms to avoid adaptation. To define the cortical representation of the gratings, we then averaged the data across the 6 runs and followed the same methods as for the retinotopic mapping. Voxels that responded positively during the blocks when the grating stimuli were presented were used to restrict each retinotopic ROI. The fMRI time series from each voxel were fit to a sinusoid. To be conservative, only voxels whose best-fit sinusoid had a phase value between 0 and pi, and a coherence between the best-fit sinusoid and the time series greater than 0.2 were included in the ROI (Fig. 2, right panel). Analysis performed without restricting the ROI to this coherence level yielded similar results.

Event-related analysis

fMRI time series were averaged across voxels in each ROI (separately for each hemisphere) and then concatenated across runs. The data were denoised using GLMDenoise 142 , and fMRI response amplitudes were computed using linear regression, with twelve regressors: 8 combinations of right and left valid and invalid pre- and post-cue, right and left cue-only, blank (no cue nor stimulus) and eye-movements (blink or broken fixation). For each ROI in each hemisphere, the resulting fMRI response amplitudes (for correct trials only) were then averaged across participants.


Behavioral neuroscience as a scientific discipline emerged from a variety of scientific and philosophical traditions in the 18th and 19th centuries. In philosophy, people like René Descartes proposed physical models to explain animal as well as human behavior. Descartes suggested that the pineal gland, a midline unpaired structure in the brain of many organisms, was the point of contact between mind and body. Descartes also elaborated on a theory in which the pneumatics of bodily fluids could explain reflexes and other motor behavior. This theory was inspired by moving statues in a garden in Paris. [4] Electrical stimulation and lesions can also show the affect of motor behavior of humans. They can record the electrical activity of actions, hormones, chemicals and effects drugs have in the body system all which affect ones daily behavior.

Other philosophers also helped give birth to psychology. One of the earliest textbooks in the new field, The Principles of Psychology by William James, argues that the scientific study of psychology should be grounded in an understanding of biology.

The emergence of psychology and behavioral neuroscience as legitimate sciences can be traced from the emergence of physiology from anatomy, particularly neuroanatomy. Physiologists conducted experiments on living organisms, a practice that was distrusted by the dominant anatomists of the 18th and 19th centuries. [5] The influential work of Claude Bernard, Charles Bell, and William Harvey helped to convince the scientific community that reliable data could be obtained from living subjects.

Even before the 18th and 19th century, behavioral neuroscience was beginning to take form as far back as 1700 B.C. [6] The question that seems to continually arise is: what is the connection between the mind and body? The debate is formally referred to as the mind-body problem. There are two major schools of thought that attempt to resolve the mind–body problem monism and dualism. [4] Plato and Aristotle are two of several philosophers who participated in this debate. Plato believed that the brain was where all mental thought and processes happened. [6] In contrast, Aristotle believed the brain served the purpose of cooling down the emotions derived from the heart. [4] The mind-body problem was a stepping stone toward attempting to understand the connection between the mind and body.

Another debate arose about localization of function or functional specialization versus equipotentiality which played a significant role in the development in behavioral neuroscience. As a result of localization of function research, many famous people found within psychology have come to various different conclusions. Wilder Penfield was able to develop a map of the cerebral cortex through studying epileptic patients along with Rassmussen. [4] Research on localization of function has led behavioral neuroscientists to a better understanding of which parts of the brain control behavior. This is best exemplified through the case study of Phineas Gage.

The term "psychobiology" has been used in a variety of contexts, emphasizing the importance of biology, which is the discipline that studies organic, neural and cellular modifications in behavior, plasticity in neuroscience, and biological diseases in all aspects, in addition, biology focuses and analyzes behavior and all the subjects it is concerned about, from a scientific point of view. In this context, psychology helps as a complementary, but important discipline in the neurobiological sciences. The role of psychology in this questions is that of a social tool that backs up the main or strongest biological science. The term "psychobiology" was first used in its modern sense by Knight Dunlap in his book An Outline of Psychobiology (1914). [7] Dunlap also was the founder and editor-in-chief of the journal Psychobiology. In the announcement of that journal, Dunlap writes that the journal will publish research ". bearing on the interconnection of mental and physiological functions", which describes the field of behavioral neuroscience even in its modern sense. [7]

In many cases, humans may serve as experimental subjects in behavioral neuroscience experiments however, a great deal of the experimental literature in behavioral neuroscience comes from the study of non-human species, most frequently rats, mice, and monkeys. As a result, a critical assumption in behavioral neuroscience is that organisms share biological and behavioral similarities, enough to permit extrapolations across species. This allies behavioral neuroscience closely with comparative psychology, evolutionary psychology, evolutionary biology, and neurobiology. Behavioral neuroscience also has paradigmatic and methodological similarities to neuropsychology, which relies heavily on the study of the behavior of humans with nervous system dysfunction (i.e., a non-experimentally based biological manipulation).

Synonyms for behavioral neuroscience include biopsychology, biological psychology, and psychobiology. [8] Physiological psychology is a subfield of behavioral neuroscience, with an appropriately narrower definition.

The distinguishing characteristic of a behavioral neuroscience experiment is that either the independent variable of the experiment is biological, or some dependent variable is biological. In other words, the nervous system of the organism under study is permanently or temporarily altered, or some aspect of the nervous system is measured (usually to be related to a behavioral variable).

Disabling or decreasing neural function Edit

    – A classic method in which a brain-region of interest is naturally or intentionally destroyed to observe any resulting changes such as degraded or enhanced performance on some behavioral measure. Lesions can be placed with relatively high accuracy "Thanks to a variety of brain 'atlases' which provide a map of brain regions in 3-dimensional "stereotactic coordinates.
  • Surgical lesions – Neural tissue is destroyed by removing it surgically.
  • Electrolytic lesions – Neural tissue is destroyed through the application of electrical shock trauma.
  • Chemical lesions – Neural tissue is destroyed by the infusion of a neurotoxin.
  • Temporary lesions – Neural tissue is temporarily disabled by cooling or by the use of anesthetics such as tetrodotoxin.

Enhancing neural function Edit

  • Electrical stimulation – A classic method in which neural activity is enhanced by application of a small electric current (too small to cause significant cell death).
  • Psychopharmacological manipulations – A chemical receptor agonist facilitates neural activity by enhancing or replacing endogenous neurotransmitters. Agonists can be delivered systemically (such as by intravenous injection) or locally (intracerebrally) during a surgical procedure.
  • Synthetic Ligand Injection – Likewise, Gq-DREADDs can be used to modulate cellular function by innervation of brain regions such as Hippocampus. This innervation results in the amplification of γ-rhythms, which increases motor activity. [15] – In some cases (for example, studies of motor cortex), this technique can be analyzed as having a stimulatory effect (rather than as a functional lesion). excitation – A light activated excitatory protein is expressed in select cells. Channelrhodopsin-2 (ChR2), a light activated cation channel, was the first bacterial opsin shown to excite neurons in response to light, [16] though a number of new excitatory optogenetic tools have now been generated by improving and imparting novel properties to ChR2 [17]

Measuring neural activity Edit

    Optical techniques – Optical methods for recording neuronal activity rely on methods that modify the optical properties of neurons in response to the cellular events associated with action potentials or neurotransmitter release.
      (VSDs) were among the earliest method for optically detecting neuronal activity. VSDs commonly changed their fluorescent properties in response to a voltage change across the neuron's membrane, rendering membrane sub-threshold and supra-threshold (action potentials) electrical activity detectable. [18] Genetically encoded voltage sensitive fluorescent proteins have also been developed. [19] relies on dyes [20] or genetically encoded proteins [21] that fluoresce upon binding to the calcium that is transiently present during an action potential. is a technique that relies on a fusion protein that combines a synaptic vesicle membrane protein and a pH sensitive fluorescent protein. Upon synaptic vesicle release, the chimeric protein is exposed to the higher pH of the synaptic cleft, causing a measurable change in fluorescence. [22]

    Genetic techniques Edit

      – The influence of a gene in some behavior can be statistically inferred by studying inbred strains of some species, most commonly mice. The recent sequencing of the genome of many species, most notably mice, has facilitated this technique. – Organisms, often mice, may be bred selectively among inbred strains to create a recombinant congenic strain. This might be done to isolate an experimentally interesting stretch of DNA derived from one strain on the background genome of another strain to allow stronger inferences about the role of that stretch of DNA. – The genome may also be experimentally-manipulated for example, knockout mice can be engineered to lack a particular gene, or a gene may be expressed in a strain which does not normally do so (the 'transgenic'). Advanced techniques may also permit the expression or suppression of a gene to occur by injection of some regulating chemical.

    Computational models - Using a computer to formulate real-world problems to develop solutions. [26] Although this method is often focused in computer science, it has begun to move towards other areas of study. For example, psychology is one of these areas. Computational models allow researchers in psychology to enhance their understanding of the functions and developments in nervous systems. Examples of methods include the modelling of neurons, networks and brain systems and theoretical analysis. [27] Computational methods have a wide variety of roles including clarifying experiments, hypothesis testing and generating new insights. These techniques play an increasing role in the advancement of biological psychology. [28]

    Limitations and advantages Edit

    Different manipulations have advantages and limitations. Neural tissue destroyed as a primary consequence of a surgery, electric shock or neurotoxin can confound the results so that the physical trauma masks changes in the fundamental neurophysiological processes of interest. For example, when using an electrolytic probe to create a purposeful lesion in a distinct region of the rat brain, surrounding tissue can be affected: so, a change in behavior exhibited by the experimental group post-surgery is to some degree a result of damage to surrounding neural tissue, rather than by a lesion of a distinct brain region. [29] [30] Most genetic manipulation techniques are also considered permanent. [30] Temporary lesions can be achieved with advanced in genetic manipulations, for example, certain genes can now be switched on and off with diet. [30] Pharmacological manipulations also allow blocking of certain neurotransmitters temporarily as the function returns to its previous state after the drug has been metabolized. [30]

    In general, behavioral neuroscientists study similar themes and issues as academic psychologists, though limited by the need to use nonhuman animals. As a result, the bulk of literature in behavioral neuroscience deals with mental processes and behaviors that are shared across different animal models such as:

    • Sensation and perception
    • Motivated behavior (hunger, thirst, sex)
    • Control of movement
    • Learning and memory
    • Sleep and biological rhythms
    • Emotion

    However, with increasing technical sophistication and with the development of more precise noninvasive methods that can be applied to human subjects, behavioral neuroscientists are beginning to contribute to other classical topic areas of psychology, philosophy, and linguistics, such as:

    Behavioral neuroscience has also had a strong history of contributing to the understanding of medical disorders, including those that fall under the purview of clinical psychology and biological psychopathology (also known as abnormal psychology). Although animal models do not exist for all mental illnesses, the field has contributed important therapeutic data on a variety of conditions, including:


    Discussion

    Altered endogenous opioid activity may be a mechanism for impaired emotion regulation during social rejection and acceptance in MDD. Despite strong, sustained negative affect during rejection in both groups, MOR activation in multiple brain regions was found only in HCs, whereas MDD patients showed MOR deactivation in the amygdala and slower emotional recovery from rejection. During acceptance, both groups reported increased positive affect, with MDD patients showing greater increases from baseline compared with HCs. However, this increase returned rapidly toward baseline after acceptance trials had ended. In MDD patients, MOR deactivation during acceptance was found in the NAcc, a reward structure. MOR activation in the NAcc in HCs but not in MDD patients was positively correlated with increases in the desire for social interaction, suggesting opioid involvement in the motivation to seek out positive social interaction during acceptance in HCs, but not in MDD patients.

    During social rejection, MDD patients did not show significant activation in volumes of interest, whereas in HCs, MOR activation was found in the right NAcc, left and right amygdala, midline thalamus and periaqueductal gray (Figures 2a and b, Table 1), as previously described. 29 These structures are high in MOR concentrations and part of a pathway by which stressors can influence mood and motivation 42 thus, MOR activation in these structures may reduce the negative impact of stressors. In contrast, MDD patients showed MOR deactivation in the amygdala (Figure 2c), which may contribute to blood-oxygen-level-dependent hyperactivity in the amygdala in MDD patients in response to negative social cues such as peer rejection. 43 The present study also found a strong negative correlation between MOR activation in the pgACC, an area involved in emotion regulation, 44 and increased ratings of negative affect during rejection in HCs but not in MDD patients (Figure 3e). Similarly, previous studies found a strong negative correlation between MOR activation in the pgACC and increased ratings of negative affect during self-induced sadness in HCs 40 but not in MDD patients. 45 Thus, in MDD an absence of MOR activation plus greater MOR deactivation in the amygdala, and the lack of relationship between MOR activation in the pgACC and negative affect may contribute to sustained negative affect after rejection.

    Ego Resiliency is a trait conceptualized by Block 36 as the ability to psychologically adapt across situations, and has been shown to correlate with faster emotional and physiological recovery from threat. 37 Consistent with this concept, levels of Ego Resiliency were positively correlated with MOR activation in the amygdala, periaqueductal gray and sgACC in HCs during rejection, as previously described. 29 This relationship was not found in any volumes of interest in MDD patients (Figures 3a, b, and c), possibly due to significantly lower Ego Resiliency ratings in MDD patients. The positive relationship between Ego Resiliency and MOR activation in HCs suggests that MOR activation during rejection is protective or adaptive. This hypothesis is consistent with the finding that Ego Resiliency was positively correlated with changes in self-esteem in HCs but not in MDD patients during rejection (Figure 3d). Path analyses in a larger sample size may test the hypothesis that MOR activation mediates the relationship between Ego Resiliency and changes in self-esteem during rejection.

    As with social rejection, there were marked differences between groups during social acceptance, including MOR activation/deactivation, changes in affect and relationships between those measures. HCs showed activation in the left anterior insula and right amygdala, and deactivation in the midline thalamus and sgACC, whereas MDD patients showed activation in the midline thalamus and deactivation in the left NAcc (Figures 2e, f, g, and h). In HCs, this pattern of MOR activation is consistent with increased MOR activation in the anterior insula following amphetamine administration 46 and in the amygdala during an amusing video clip, 47 suggesting that MOR activation in these areas is related to positive affect. Also in HCs, MOR deactivation during acceptance in the midline thalamus and sgACC, both of which project heavily to the NAcc, 42, 48 is a possible mechanism for facilitating positive affect. In rats, a MOR agonist injected into the medial thalamus raised the threshold for both pain and reward. 49 Similarly, MOR deactivation in the sgACC may facilitate increased NAcc activity when one is liked. 50 In contrast, MDD patients showed MOR activation in the midline thalamus, which may impede sustained positive affect. MDD patients also did not show MOR deactivation in the sgACC, a region shown to be functionally associated with anhedonia. 51, 52 Unexpectedly, MDD patients reported a greater increase in positive affect relative to baseline during acceptance compared with HCs, however this increase was short-lived (Figure 1f), consistent with a recent study showing that MDD patients can indeed experience positive affect, but with a shorter duration compared with HCs. 53 Moreover, only HCs showed significant increases in self-esteem and the desire for social interaction after acceptance (Supplementary Table 2). Thus, in response to social acceptance, MDD patients showed short-lived increases in positive affect that did not significantly increase self-esteem or social motivation.

    As previously reported in HCs, increased MOR activation in the NAcc was positively correlated with an increased desire for social interaction, 29 a finding consistent with a report in rats showing that MORs in the NAcc mediate social play behavior. 28 The present study showed that after acceptance, HCs but not MDD patients reported a greater desire for social interaction, and that MOR activation in the left NAcc was positively correlated with increased desire for social interaction (Figure 3f). In contrast, MDD patients showed MOR deactivation in the left NAcc, which may contribute to abnormal NAcc activity related to anhedonia in MDD patients. 54 Thus, in addition to having short-lived positive affect, MDD patients did not show increased social motivation, which in HCs was related to MOR activation in the NAcc.

    There were no significant differences in plasma cortisol levels between rejection or acceptance relative to baseline within groups, and no differences were found between groups. In HCs, a significant negative correlation was found between MOR activation in the amygdala and NAcc and changes in cortisol levels during rejection, suggesting top–down MOR regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Previous studies suggest that the MOR system has a role in dampening stress-induced HPA axis activity by inhibiting corticotropin-releasing hormone in the hypothalamus. 55, 56 Consistent with the hypothesis, MOR activation in the right amygdala was negatively correlated with cortisol levels during rejection (Figure 4a). Thus, MOR regulation of amygdala activity during rejection may dampen HPA axis activity, most likely through projections to the bed nucleus of the stria terminalis, which in turn projects to the hypothalamus. 57 MOR activation in the NAcc was also negatively correlated with cortisol (Figures 4b and c), although the pathway from the NAcc to the paraventricular nucleus of the hypothalamus is less clear and likely involves multisynaptic pathways. The inhibitory influence of MOR activation on cortisol levels has also been reported in HCs during placebo administration for pain. 58 Thus, MOR activation may dampen HPA activity during rejection, a mechanism impaired in MDD by the lack of MOR activation and/or the uncoupling of the MOR system and HPA axis.

    In HCs, the pattern of MOR activation during rejection was similar to that found during physical pain, 30, 59 supporting the theory that the regulation of social rejection and physical pain share overlapping neural pathways. 29, 31, 32, 38, 39, 60, 61, 62 In contrast to the present findings, previous studies found opposite patterns of MOR activity in HCs and MDD patients during recall of a sad autobiographical event (death of a friend or family member, romantic break-ups or divorce). These studies found MOR deactivation in HCs (pgACC, ventral pallidum, amygdala and inferior temporal cortex) 40 and MOR activation in MDD patients (anterior insula, thalamus, ventral basal ganglia and periamygdalar cortex). 45 It is likely that different patterns of MOR activation are involved in responding to exteroceptive cues (for example, pain, rejection) vs permissive, interoceptive cues (for example, self-induced sadness). For example, in functional magnetic resonance imaging studies where subjects viewed a photo of a romantic ex-partner (exteroceptive cue), increased blood-oxygen-level-dependent signal was found in the ventral striatum, thalamus, anterior insula and ACC. 38, 63 In contrast, recalling sad thoughts about a recent romantic break-up (interoceptive cue) resulted in deactivation in similar areas. 64

    The present study supports previous work in animal models and has the potential to translate into clinical applications. Interestingly, one of the earliest studies to show evidence for endogenous opioid release during social interactions was found in rats using subtractive autoradiography, 65 a method with conceptual similarities to the neuroimaging method used in the present study. This and other animal studies 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 along with the present study in humans suggest that the endogenous opioids serve similar roles in social behavior across several species, supporting future translational work. For example, animal studies may provide more detailed analysis of the genetic substrates causing altered MOR function in the social environment. Indeed, a functional variation of the MOR gene has been shown in humans to be associated with the dispositional and neural sensitivity to social rejection, 31 and may be useful in the early detection of vulnerability to MDD in the social environment. In summary, the present study supports further investigation of the interaction between the endogenous opioid system, social environment, and pathophysiology and maintenance of MDD.


    Differential impact of endogenous and exogenous attention on activity in human visual cortex

    How do endogenous (voluntary) and exogenous (involuntary) attention modulate activity in visual cortex? Using ROI-based fMRI analysis, we measured fMRI activity for valid and invalid trials (target at cued/un-cued location, respectively), for pre- or post-cueing in endogenous and exogenous conditions, while observers performed the same task. We found stronger modulation in contralateral than ipsilateral visual regions to the attended hemifield, and higher activity in the valid- than invalid-trials. For endogenous, modulation of stimulus-evoked activity due to a pre-cue increased along the visual hierarchy, but was constant due to a post-cue. In contrast, for exogenous, modulation of stimulus-evoked activity due to a pre-cue was constant along the visual hierarchy, but not modulated due to a post-cue. These findings reveal that endogenous and exogenous attention distinctly modulate activity in visual areas during orienting and reorienting of attention endogenous facilitates both the encoding and the readout of visual information whereas exogenous only facilitates the encoding of information.


    Watch the video: ΓΗΡΑΝΣΗ, ΝΕΥΡΙΚΟ ΣΥΣΤΗΜΑ, ΝΕΥΡΟΕΚΦΥΛΙΣΜΟΣ. Ageing, Nervous System, Neurodegeneration (June 2022).


Comments:

  1. Dennie

    I apologise, but this variant does not approach me. Who else, what can prompt?

  2. Amaru

    you said that correctly :)

  3. Jenci

    Hello, I went to your project from Yandex and Kaspersky began to swear at viruses = (

  4. Yas

    I congratulate, a remarkable idea

  5. Aviva

    In my opinion you are wrong. Enter we'll discuss it.

  6. Mular

    Totally agree with her. In this nothing in there and I think this is a very good idea.

  7. Libby

    I absolutely agree with you. There is something in this and the idea is excellent, I support it.



Write a message