A Role for the Claustrum in Salience Processing?

The claustrum (CLA) is a subcortical structure, present only in mammals, whose function remains uncertain. Previously, using resting-state functional magnetic resonance imaging (rs-fMRI) in awake head-fixed rats, we found evidence that the CLA is part of the rodent homolog of the default mode network (DMN; Smith et al., 2017). This network emerged as strong functional connections between the medial prefrontal cortex (mPFC), mediodorsal (MD) thalamus, and CLA in the awake state, which was not present following administration of isoflurane anesthesia. In the present report, we review evidence indicating that the rodent CLA also has connections with structures identified in the rodent homolog of the salience network (SN), a circuit that directs attention towards the most relevant stimuli among a multitude of sensory inputs (Seeley et al., 2007; Menon and Uddin, 2010). In humans, this circuit consists of functional connections between the anterior cingulate cortex (ACC) and a region that encompasses both the CLA and insular cortex. We further go on to review the similarities and differences between the functional and anatomical connections of the CLA and insula in rodents using both rs-fMRI and neuroanatomical tracing, respectively. We analyze in detail the connectivity of the CLA with the cingulate cortex, which is a major node in the SN and has been shown to modulate attention. When considered with other recent behavior and physiology studies, the data reveal a role for the CLA in salience-guided orienting. More specifically, we hypothesize that limbic information from mPFC, MD thalamus, and the basolateral amygdala (BLA) are integrated by the CLA to guide modality-related regions of motor and sensory cortex in directing attention towards relevant (i.e., salient) sensory events.

Annotations

(06/10/2023, 09:28:54 )

CLA involvement in Salience Network (SN) as well as Default Mode Network (DMN) -> more than just senso-motoric structure

“Our results demonstrate a role for the CLA in both the DMN and the SN” (Smith et al., 2019, p. 11)

“these findings expand the view of the CLA from being only a sensorimotor structure (Smith and Alloway, 2014), and suggest it has a role in emotional and salience processes, owing to its anatomical and functional connectivity with limbic and affective brain regions” (Smith et al., 2019, p. 11)

Claustrum (CLA) is part of rodent Default Mode Network (DMN)

“Previously, using resting-state functional magnetic resonance imaging (rs-fMRI) in awake head-ﬁxed rats, we found evidence that the CLA is part of the rodent homolog of the default mode network (DMN; Smith et al., 2017)” (Smith et al., 2019, p. 1)

“we propose the Claustrum (CLA) serves as a limbic-sensorimotor interface, facilitating salience-guided orienting during sensory exploration”

(Smith et al., 2019, p. 11)

CLA connections: mPFC and Mediodorsal Thalamus (MD) during awake state but not during Anesthesia interpreted as “mPFC-CLA-MD thalamus circuit, the rodent homolog of the Default Mode Network (DMN)”

“strong functional connections between the medial prefrontal cortex (mPFC), mediodorsal (MD) thalamus, and CLA in the awake state” (Smith et al., 2019, p. 1)

“In the awake state, our study revealed strong functional connections of the CLA with the medial prefrontal cortex (mPFC) and mediodorsal (MD) thalamus (i.e., nodes of the DMN) that are significantly attenuated in response to anesthetic induced loss of consciousness.” (Smith et al., 2019, p. 2)

“Additionally, we observed strong functional mPFC connections with the CLA and MD thalamus. These connections were not present in the isoflurane-induced anesthetized state (Figure 2D), as indicated by significant reductions in the connectivity strength of the voxels in these regions” (Smith et al., 2019, p. 3)

“These results provide evidence of an mPFC-CLA-MD thalamus circuit, the rodent homolog of the DMN, which is disrupted by isoflurane anesthesia” (Smith et al., 2019, p. 4)

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CLA salience: “connections with structures identiﬁed in the rodent homolog of the Salience Network (SN)”, directing attention

“that the rodent CLA also has connections with structures identiﬁed in the rodent homolog of the salience network (SN), a circuit that directs attention towards the most relevant stimuli among a multitude of sensory inputs. In humans, this circuit consists of functional connections between the anterior cingulate cortex (ACC) and a region that encompasses both the CLA and insular cortex” (Smith et al., 2019, p. 1)

CLA connections: Salience Network (SN) consists of functional connections between Anterior Cingulate Cortex (ACC), Claustrum (CLA) and Insula

In humans, this circuit consists of functional connections between the anterior cingulate cortex (ACC) and a region that encompasses both the CLA and insular cortex” (Smith et al., 2019, p. 1)

CLA salience: “the data reveal a role for the CLA in salience-guided orienting”

(Smith et al., 2019, p. 1)

CLA function and FM3 Literature Claustrum

CLA attention: “directing attention (Mathur, 2014; Goll et al., 2015; Atlan et al., 2018; White et al., 2018),” (Smith et al., 2019, p. 2)
CLA salience: “salience detection (Smythies et al., 2012),” (Smith et al., 2019, p. 2)
CLA sensory integration: “multisensory integration (Edelstein and Denaro, 2004” (Smith et al., 2019, p. 2)
“cross-modal transfer (Hadjikhani and Roland, 1998)” (Smith et al., 2019, p. 2)
CLA Binding: “perceptual binding (Crick and Koch, 2005)” (Smith et al., 2019, p. 2)
“cognition (Jackson et al., 2018)” (Smith et al., 2019, p. 2)
CLA consciousness: “consciousness (Koubeissi et al., 2014; Stiefel et al., 2014; Kurada et al., 2019)” (Smith et al., 2019, p. 2)
Default Mode Network (DMN) and Salience Network (SN): “(Smith et al., 2017). This study revealed connections from the CLA to several nodes in the default mode network (DMN) and in the salience network (SN); both of which are thought to serve distinct cognitive functions (Menon, 2011; Smith et al., 2017)” (Smith et al., 2019, p. 2)

CLA salience, CLA attention: “recent studies indicate that the CLA plays a role in salience detection, attentional processing, and possibly cognition (Remedios et al., 2010, 2014; Goll et al., 2015; Atlan et al., 2018; Jackson et al., 2018), particularly via its connections with Cg cortex (Chia et al., 2017; White and Mathur, 2018; White et al., 2018)” (Smith et al., 2019, p. 6) (Gyrus Cinguli)

CLA connections: Strong inputs from limbic structures, especially Basolateral Amygdala (BLA), interpreted here as “salience signals”, which are directed to motor and Sensory Cortex

“anatomical studies have revealed strong inputs to the CLA from limbic structures, especially the basolateral amygdala (BLA; Atlan et al., 2018; Zingg et al., 2018). We hypothesize that these limbic inputs may provide ‘‘salience signals’’ to the CLA, which are then relayed to sensory and motor cortices to coordinate sensory exploration towards relevant stimuli” (Smith et al., 2019, p. 2)

Default Mode Network (DMN): BOLD signals in vmPFC, Posterior Cingulate Cortex (PCC) and Mediodorsal Thalamus (MD)

“The DMN consists of strongly correlated BOLD signals in the ventromedial prefrontal cortex (vmPFC), posterior cingulate cortex (PCC), and MD thalamus” (Smith et al., 2019, p. 2)

[[Salience Network (SN)]]

“The frontoinsular seed revealed strong functional connectivity to the dACC, as well as subcortical areas including MD thalamus, periaqueductal gray, extended amygdala, and others (Figure 1A). The known functions and modalities processed in these brain regions (including attention, sensory, visceral, affective, limbic, etc.) led the authors to conclude that this network, anchored by frontoinsular cortex and dACC, processes perceptual salience and thus termed it the ‘‘salience network.’’” (Smith et al., 2019, p. 2)

Salience Network (SN): high correlation with Visual Analog Scores (VAS) from Anxiety measures

“Specifically, the strength of functional connectivity within the SN was strongly correlated (r2 = 0.89) with visual analog scores (VAS) from a pre-scan anxiety assay (Figure 1C). This correlation suggests a tight link between the strength of the SN and states of vigilance” (Smith et al., 2019, p. 2)

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“as shown in Figure 1B, a strong correlation exists between a subject’s level of anxiety and the connectional strength of the SN” (Smith et al., 2019, p. 11)

Claustrum (CLA) DTI studies

“recent studies have examined the anatomical connectivity of the human CLA using diffusion tensor imaging (Milardi et al., 2013; Torgerson and Van Horn, 2014; Torgerson et al., 2015)” (Smith et al., 2019, p. 3)

Caution: close proximity of CLA and Insula

“Because of the close proximity between the CLA and the surrounding insula, results produced by attempts at dissociating the functional connectivity between these two structures, even with higher magnet strengths in rodent studies (4.7–7T), must be interpreted cautiously” (Smith et al., 2019, p. 5)

CLA salience: detection of novel/salient stimuli, however no certainty what brain regions could be involved

“Most notably, electrophysiology recordings in the CLA of non-human primates lead the investigators to propose that ‘‘the claustrum detects the occurrence of novel or salient sensory events’’ (Remedios et al., 2014). However, it is unknown what brain regions could imbue the CLA with information about the novelty, importance, or relative value of competing stimuli” (Smith et al., 2019, p. 6)

CLA salience: Amygdala could decide stimulus salience

“Some authors suggest that the relative salience of stimuli could be determined by the amygdala, and particularly its inputs to the CLA (Gattass et al., 2014).” (Smith et al., 2019, p. 6)

CLA connections: proposed network

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CLA salience: Visual saliency circuit; CLA connections to Frontal Eye Field (FEF) and Visual Cortex

“the rodent visual system serves a strong role in rodent predation behavior (Hoy et al., 2016), as well as threat detection, particularly regarding over-head, looming stimuli (Wallace et al., 2013; De Franceschi et al., 2016)” (Smith et al., 2019, p. 9)

“overhead visual stimuli likely represent predatory birds, activating a bottom-up visual response from superior colliculus, known to be involved in visual salience (Comoli et al., 2003)” (Smith et al., 2019, p. 9)

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“In Figure 9B, we propose a ‘‘visual salience circuit’’ (VSC) consisting of both a bottom-up visual processing pathway and a top-down cortical visuomotor control pathway. We propose that the VSC is a combination of limbic structures (including BLA and MD thalamus) that convey information about stimulus value (valence) to the CLA, which in turn coordinates the frontal eye fields and visual cortices to direct attention via cortical visuomotor output; ultimately shifting the eyes toward novel, salient stimuli such as unexpected predators (Figure 9A)” (Smith et al., 2019, p. 10)

CLA connections: projections from Frontal Eye Field (FEF) to CLA and Mediodorsal Thalamus (MD) might be involved in shifting attention

“we hypothesize that the strong bilateral projections from the frontal eye fields to the CLA and MD thalamus support the direct cortico-cortical connections to seamlessly shift attention between both threats” (Smith et al., 2019, p. 10)

CLA connections to Gyrus Cinguli is relevant for CLA salience processing & Top-down expectation signals

“The connectivity between the CLA and Cg cortex is of particular interest with regards to salience processing. The human SN is defined as coupling between the dACC and a region that appears to encompass the CLA” (Smith et al., 2019, p. 11)

“A recent study corroborates the importance of the CLA-Cg connection in salience processing by demonstrating that Cg cortex imbues the CLA with ‘‘top-down’’ expectation signals related to task-relevant sensory information that likely underlies attentional mechanisms (White et al., 2018)” (Smith et al., 2019, p. 11)

CLA attention: “Another recent study also found behavioral evidence that the CLA provides resilience to distraction

(Atlan et al., 2018)” (Smith et al., 2019, p. 11)

Parkinson’s disease: decreased CLA connections, especially visuo-motor & CLA attention

“A recent fMRI study of Parkinson’s disease patients has found significant decreases in the functional connectivity of the CLA compared to age-matched control patients, especially ‘‘with areas mainly involved in visuomotor and attentional systems’’ (Arrigo et al., 2018)” (Smith et al., 2019, p. 11)

[[CLA future research]]

“Future neuroimaging and optogenetic behavioral studies are necessary to demonstrate what role, if any, the CLA plays in emotional processing, particularly with regard to anxiety” (Smith et al., 2019, p. 11)

CLA emotion “Future research on the CLA will no doubt lead to fundamental breakthroughs in our understanding of emotional processing in health and disease”