Human centromedian-parafascicular complex signals sensory cues for goal-oriented behavior selection

Experimental research has shown that the centromedian-parafascicular complex (CM-Pf) of the intralaminar thalamus is activated in attentional orienting and processing of behaviorally relevant stimuli. These observations resulted in the hypothesis that the CM-Pf plays a pivotal role in goal-oriented behavior selection. We here set out to test this hypothesis with electrophysiological recordings from patients with electrodes implanted in CM-Pf for deep brain stimulation (DBS) treatment of chronic neuropathic pain. Six patients participated in (1) an auditory three-class oddball experiment, which required a button press to target tones, but not to standard and deviant tones and in (2) a multi-speaker experiment with a target word that required attention selection and a target image that required response selection. Subjects showed transient neural responses (8-15 Hz) to the target tone and the target word. Two subjects additionally showed transient neural responses (15-25 Hz) to the target image. All sensory target stimuli were related to an internal goal and required a behavior selection (attention selection, response selection). In group analyses, neural responses were greater to target tones than deviant and standard tones and to target words than other task-relevant words that did not require attention selection. The transient neural responses occurred after the target stimuli but prior to the overt behavioral response. Our results demonstrate that in human subjects the CM-Pf is involved in signaling sensory inputs related to goal-oriented selection of behavior

The Cognitive Thalamus as a gateway to mental representations

Historically, the thalamus has been viewed as little more than a relay, simply transferring information to key players of the cast, the cortex and hippocampus, without providing any unique functional contribution. In recent years, evidence from multiple laboratories researching different thalamic nuclei has contradicted this idea of the thalamus as a passive structure. Dated models of thalamic functions are being pushed aside, revealing a greater and far more complex contribution of the thalamus for cognition. In this Viewpoint, we show how recent data support novel views of thalamic functions that emphasize integrative roles in cognition, ranging from learning and memory to flexible adaption. We propose that these apparently separate cognitive functions may, in fact, be supported by a more general role in shaping mental representations. Several features of thalamocortical circuits are consistent with this suggested role and we highlight how divergent and convergent thalamocortical and corticothalamic pathways may complement each other to support these functions. Furthermore, the role of the thalamus for subcortical integration is highlighted as a key mechanism for maintaining and updating representations. Finally, we discuss future areas of research and stress the importance of incorporating new experimental findings into existing knowledge to continue developing thalamic models. The presence of thalamic pathology in a number of neurological conditions reinforces the need to better understand the role of this region in cognition

Cortical and subcortical contributions to human cognitive flexibility

Cognitive flexibility enables individuals to respond adaptively to an ever-changing world. Neurally, flexibility is underpinned by involvement from across the cerebrum, and there is evidence from animal and human neuroscience suggesting that integration of cortical and thalamic signals in the striatum is necessary for appropriate behavioural control. A commonly used assay of flexibility is reversal learning, an associative learning task with high inter-species translatability. Evidence from animal literature has clearly defined the importance of the striatal cholinergic system in regulating striatal activity and output from the basal ganglia, and there is nascent evidence suggesting this system operates in a similar way in humans. However, there is a need to further disentangle the role of cortical, striatal, and thalamic regions during reversal learning in humans to better understand how the system works, and whether it has heterogeneous functionality in different contexts. Furthermore, as studying these processes is not trivial, further methodological work is required to enable us to understand the system. In chapter two we systematically assess an automated parcellation technique for identifying specific thalamic nuclei. Despite generally being treated as a homologous structure in neuroimaging work, nuclei within the thalamus have dissociable roles, and have diverse contributions to cognitive functioning, including reversal learning. We found mixed efficacy for segmentations across the thalamus, with some regions being more accurately defined relative to a “gold standard” atlas than others. Crucially, we find that the centromedian and parafascicular nuclei, which have an important role in reversal learning, are clearly defined and have little overlap with contiguous regions. These results show we can use this automated parcellation technique to identify specific thalamic nuclei that are relevant for cognitive flexibility and use these parcellations to study functionally relevant processes. Recent work has demonstrated that the functional relevance of the striatal cholinergic system can be studied in vivo using magnetic resonance spectroscopy by separating the peaks of different metabolites. But this non-conventional approach has not yet been widely adopted, and work is needed to determine its reliability. Chapter three presents test-retest reliability data on the use of magnetic resonance spectroscopy to study cholinergic activity in the striatum and cortex. We find measures of choline containing compounds are highly correlated when peaks are separated and when they are not. Across time we find that choline concentrations are relatively inconsistent, and that this was due to changes in the functionally relevant metabolite choline. Conversely, metabolites that we think are not functionally relevant were stable over time. We believe these differences may underly differences in acetylcholine function over time and may explain some intra-individual behavioural variability. In chapter four we use functional magnetic resonance imaging and psychophysiological interaction analysis to study corticostriatal and thalamostriatal connectivity during serial reversal learning. Functional connectivity between the centromedian-parafascicular nuclei of the thalamus and the associative dorsal striatum, and between the lateral-orbitofrontal cortex and the associative dorsal striatum was related to processing feedback during reversal learning. Specifically, thalamostriatal connectivity was found across the task, and may reflect a general error signal used to identify potential changes in context. Conversely, corticostriatal connectivity was found to be specific to when behaviour changed and suggests this may be a mechanism for the implementing adaptive change. We also show findings from exploratory work that may explain further how the cortex supports flexibility during reversal learning. Lastly, we used magnetic resonance spectroscopy to investigate whether the state of the cholinergic system at rest is related to reversal learning performance and latent measures of behaviour using computational modelling. Choline concentrations at rest showed significant functional relevance to our measures of reversal learning. More specifically, we found that errors during reversal learning, and learning rates for positive and negative prediction errors, explained significant variance in choline. However, the relationship between choline levels and task performance presented here differ from previous work which instead used a multi-alternative reversal learning task, and suggests that the striatal cholinergic system may have dissociable roles in different contexts. Overall, we show that the striatum, its cholinergic interneuron system, and its afferent projections from the cortex and thalamus, are associated with performance during serial reversal learning. Moreover, these findings suggest that the system may operate in separable ways in different contexts which may be dependent on internal representations of task structure

Deep brain stimulation for disorders of consciousness and diminished motivation:A search for awakenings

This thesis deals with patients who are amongst the most severely affected after severe brain injury: those with permanent disorders of consciousness or diminished motivation. The research in this thesis is an attempt to improve consciousness and the general behavioral performance of these patients with the use of experimental interventions, including medication (such as zolpidem), and more invasive procedures, such as deep brain stimulation (DBS). The thesis contains extensive descriptions of the role of the intralaminar thalamus in the arousal regulation system, the importance of recognizing and treating secondary complications after brain injury, such as hydrocephalus, as well as a pathophysiological elaboration on akinetic mutism: a severe disorder of diminished motivation. Moreover, it describes the neurophysiological changes that accompany the paradoxical effects of zolpidem, a sleeping pill that temporarily induces ‘awakenings’ in some patients with severe brain injury. Further, it describes the first clinical and neurophysiological results of an N=6 trial of DBS in patients with a minimally conscious state and shows the importance of recognizing pathological changes from the brain’s ‘physiological baseline’ that seem to disturb normal brain functions. The thesis concludes with a description of the use of moral case deliberation in dealing with research dilemmas in patients with loss of autonomy after severe brain injury

Identifying characteristics of thalamo-cortical changes and their relationship with symptoms in schizophrenia [Utvrđivanje obilježja talamo-kortikalnih promjena i njihovog odnosa sa simptomima u shizofreniji]

Hypothesis of the doctoral thesis was that, using resting-state functional magnetic resonance imaging (fMRI), patients diagnosed with schizophrenia would exhibit stable and specific patterns of thalamic connectivity changes that will show different relationship with specific symptoms of psychotic disorders. The aims of the study were to characterize in a more detailed way changes in thalamo-cortical connectivity (over- and under-connectivity) in a clinical sample compared to healthy controls, by using state-of-the-art resting-state functional resonance and Human Connectome Project protocols, as well as to more specifically determine within-thalamus differences and their relative contribution to described connectivity changes. Finally, the aim was to determine relationship between identified connectivity changes and specific symptoms of the disorder. Subjects for the study were pooled from multiple centers, as part of an existing initiative, Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium, created with a goal of investigating intermediate phenotypes across psychotic disorders. Study procedures and data analyses were done under the approved Yale University project Characterizing Clinical and Pharmacological Neuroimaging Biomarkers. Following identification of subjects that passed stringent quality controls for fMRI data, and matching with the clinical and healthy control populations, study included 436 psychosis probands (167 schizophrenia patients, 119 schizoaffective disorder patients, and 150 patients diagnosed with bipolar disorder with history of psychosis) and 219 matched healthy controls. Whole-thalamus seed-based analyses were used to determine thalamic connectivity changes, followed by parcellation of thalamus using a priori defined functional subnuclei, and data-driven clustering, to define details of the thalamo-cortical dysconnectivity in schizophrenia and psychotic disorders. Both in schizophrenia, and in the wider psychosis spectrum, there was a robust pattern of thalamic over-connectivity with sensory and motor regions, as well as with associative areas tasked with integration of lower-level inputs, and under-connectivity with cerebellar regions. Interestingly, previously reported under-connectivity with prefrontal regions was evident only in dorsal attention functional thalamic subnucleus connectivity map. Nine functional thalamic subnuclei showed relatively different thalamic connectivity changes, ranging from altogether missing effects to wide-spread over- /under-connectivity, but overall followed same general dysconnectivity pattern described for the whole thalamus. Clustering analyses revealed that the data-driven clustering, released from constraints of a priori defined thalamic subnuclei, resulted in solutions that significantly differed from existing functional subnuclei or anatomical divisions, with areas centered on mediodorsal nucleus and ventral lateral areas driving the dysconnectivity effect. In schizophrenia, thalamo-cortical connectivity changes showed relationship with negative symptoms, as well as with excitation and disorganization subscale scores, suggesting that a more pronounced over- or under-connectivity effect predicted more pronounced specific symptoms. Under-connectivity effect of the dorsal attention functional subnucleus (including reduced connectivity with prefrontal cortical regions) also correlated with disorientation. In conclusion, thalamo-cortical dysconnectivity patterns of seemingly correlated over- and under-connectivity effects seems to be robustly present in schizophrenia, but also across the psychosis spectrum. Although the same general pattern exists across different thalamic regions, its extent differs among different thalamic functional subnuclei suggesting that the effect is driven by specific associative functional subnuclei. Finally, although thalamo-cortical connectivity changes might be linked to a more non-specific disease severity or trait indicators, negative symptoms, disorganization, and excitation seem to be connected more directly to those changes than positive symptoms or emotional dysregulation