ArticleLiterature Review

Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Ann Rev Neurosci 9: 357-381

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Abstract

Information about the basal ganglia has accumulated at a prodigious pace over the past decade, necessitating major revisions in the authors' concepts of the structural and functional organization of these nuclei. Recent anatomical and physiological findings have further substantiated the concept of segregated basal ganglia-thalamocortical pathways, and reinforced the general principle that basal ganglia influences are transmitted only to restricted portions of the frontal lobe (even though the striatum receives projections from nearly the entire neocortex). Using the 'motor' circuit as a model, the authors have reexamined the available data on other portions of the basal ganglia-thalamocortical pathways and found that the evidence strongly suggests the existence of at least four additional circuits organized in parallel with the 'motor' circuit. In the discussion that follows, they review some of the anatomic and physiologic features of the 'motor circuit,' as well as the data that support the existence of the other proposed parallel circuits, which they have designated the 'oculomotor,' the 'dorsolateral prefrontal,' the 'lateral orbitofrontal,' and the 'anterior cingulate,' respectively. Each of these five basal ganglia-thalamocortical circuits appears to be centered upon a separate part of the frontal lobe. This list of basal ganglia-thalamocortical circuits is not intended to be exhaustive. In fact, if the conclusions suggested in this review are valid, future investigations might be expected to disclose not only further details (or the need for revisions) of these five circuits, but perhaps also the existence of additional parallel circuits whose identification is currently precluded by a paucity of data.

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... In DMTP and DNMTP the position of the correct choice is indicated by the randomly selected position of the preceding sample response (see Figure 1 for DNMTP example). The central thesis here is that rodent medial prefrontal cortex (mPFC) acts through afferent and efferent connections with multiple thalamic nuclei (Mair et al., 2021) and recurrent networks involving basal ganglia and thalamus (Alexander et al., 1986;Lee et al., 2020;Foster et al., 2021) to control actions motivated by and directed toward an intended outcome. The elaboration of these circuits during vertebrate evolution has been linked to the development of neural systems that underlie more abstract processes of human cognition Jablonka, 2010, 2021;Koechlin, 2014;Cisek, 2019). ...
... Large-scale mapping has revealed numerous functional domains in rodent striatum based on convergence and divergence of corticostriatal and thalamostriatal projections (Hintiryan et al., 2016;Hunnicutt et al., 2016). These are organized as subnetworks that are preserved through pallido/nigral and thalamic nodes and back as parallel closed loop circuits to the mPFC corticostriatal neurons from which they originate (Alexander et al., 1986;Lee et al., 2020;Foster et al., 2021). The evidence of multiple cortico-basal ganglia-thalamic subnetworks suggests that there is a high degree of functional heterogeneity within striatum. ...
... Both electrophysiological and behavioral findings (reviewed above) are consistent with the hypothesized distinction between ventral striatum processing reward signals and facilitating the motivational control of performance and dorsal striatum forming associations between sensory, motor, and limbic inputs to guide action selection and support the acquisition of goal-directed actions (Hart et al., 2014;Koechlin, 2014). Large-scale mapping studies, primarily in mice, have revealed parallel circuits that interconnect nodes in striatum, pallidum/substantia nigra, thalamus, and mPFC that appear organized to mediate distinct aspects of adaptive behavior (Alexander et al., 1986;Lee et al., 2020;Foster et al., 2021). Like central thalamus, lesions in discrete areas of striatum produce deficits comparable to the effects of lesions in anatomically related areas of mPFC (see above). ...
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Medial prefrontal cortex (mPFC) interacts with distributed networks that give rise to goal-directed behavior through afferent and efferent connections with multiple thalamic nuclei and recurrent basal ganglia-thalamocortical circuits. Recent studies have revealed individual roles for different thalamic nuclei: mediodorsal (MD) regulation of signaling properties in mPFC neurons, intralaminar control of cortico-basal ganglia networks, ventral medial facilitation of integrative motor function, and hippocampal functions supported by ventral midline and anterior nuclei. Large scale mapping studies have identified functionally distinct cortico-basal ganglia-thalamocortical subnetworks that provide a structural basis for understanding information processing and functional heterogeneity within the basal ganglia. Behavioral analyses comparing functional deficits produced by lesions or inactivation of specific thalamic nuclei or subregions of mPFC or the basal ganglia have elucidated the interdependent roles of these areas in adaptive goal-directed behavior. Electrophysiological recordings of mPFC neurons in rats performing delayed non-matching-to position (DNMTP) and other complex decision making tasks have revealed populations of neurons with activity related to actions and outcomes that underlie these behaviors. These include responses related to motor preparation, instrumental actions, movement, anticipation and delivery of action outcomes, memory delay, and spatial context. Comparison of results for mPFC, MD, and ventral pallidum (VP) suggest critical roles for mPFC in prospective processes that precede actions, MD for reinforcing task-relevant responses in mPFC, and VP for providing feedback about action outcomes. Synthesis of electrophysiological and behavioral results indicates that different networks connecting mPFC with thalamus and the basal ganglia are organized to support distinct functions that allow organisms to act efficiently to obtain intended outcomes.
... Current theories of OCD pathophysiology posit dysfunction in several distinct, yet overlapping brain circuits that involve connections from cortex to basal ganglia to thalamus and reciprocally back to cortex, known as cortico-striato-thalamocortical loops (CSTC) (2,3). A number of distinct networks within this pathway were described by Alexander et al. (4). based on anatomophysiological findings and have subsequently been validated based on functional connectivity maps (4)(5)(6). ...
... A number of distinct networks within this pathway were described by Alexander et al. (4). based on anatomophysiological findings and have subsequently been validated based on functional connectivity maps (4)(5)(6). However, the number of distinct networks has varied among descriptions, and the degree of topographical segregation between circuits remains an area of active research. ...
... One of the earliest circuits implicated in OCD is the lateral orbitofrontal-ventromedial caudate pathway. As described by Alexander et al. (4), neurons in the lateral orbitofrontal cortex (lOFC) project to the ventromedial caudate, dorsomedial globus pallidus internus (GPi), and ventral anterior thalamus before projecting back to the lOFC (4). The role of the lOFC in behavior adaption and reversal learning is well-established (7)(8)(9). ...
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Early research into neural correlates of obsessive compulsive disorder (OCD) has focused on individual components, several network-based models have emerged from more recent data on dysfunction within brain networks, including the the lateral orbitofrontal cortex (lOFC)-ventromedial caudate, limbic, salience, and default mode networks. Moreover, the interplay between multiple brain networks has been increasingly recognized. As the understanding of the neural circuitry underlying the pathophysiology of OCD continues to evolve, so will too our ability to specifically target these networks using invasive and noninvasive methods. This review discusses the rationale for and theory behind neuromodulation in the treatment of OCD.
... However, it is not necessarily the case that these individual connections link into a continuous polysynaptic circuit (DMS/ SNr/SNc/DLS). Indeed, anatomical and electrophysiological work in other basal ganglia circuits supports a largely parallel organization of DMS and DLS subcircuits (Alexander et al., 1986;Lee et al., 2020;Mandelbaum et al., 2019). The idea that an ascending spiral through the midbrain DA system could be a major route of crosstalk between otherwise parallel circuits has been appealing to behavioral neuroscientists, but evidence of a functional circuit at the synaptic level is lacking. ...
... By combining retrobead injections in striatum with our viral strategy in TH-2A-Flpo mice, we could investigate the structure and function of multiple striatonigrostriatal circuits. Because basal ganglia circuits are thought to operate primarily in parallel closed loops (Alexander et al., 1986;Haber et al., 2000;Lee et al., 2020;Mandelbaum et al., 2019;, we began by testing closed striatonigrostriatal loops through which the DLS and the DMS could regulate their own dopaminergic drive. ...
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The basal ganglia operate largely in closed parallel loops, including an associative circuit for goal-directed behavior originating from the dorsomedial striatum (DMS) and a somatosensory circuit important for habit formation originating from the dorsolateral striatum (DLS). An exception to this parallel circuit organization has been proposed to explain how information might be transferred between striatal subregions, for example, from the DMS to the DLS during habit formation. The “ascending spiral hypothesis” proposes that the DMS disinhibits dopamine signaling in the DLS through a tri-synaptic, open-loop striatonigrostriatal circuit. Here, we use transsynaptic and intersectional genetic tools to investigate both closed- and open-loop striatonigrostriatal circuits. We find strong evidence for closed loops, which would allow striatal subregions to regulate their own dopamine release. We also find evidence for functional synapses in open loops. However, these synapses are unable to modulate tonic dopamine neuron firing, questioning the prominence of their role in mediating crosstalk between striatal subregions.
... *Address correspondence to this author at the University Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000 Grenoble, France; Tel: +33 4 56 52 05 99; Fax: +33 4 56 52 05 98; E-mail: veronique.coizet@univ-grenoble-alpes.fr Sensori-motor, associative and limbic regions of the cortex form functional loops with the equivalent regions of the BG -the striatum, pallidum and substantia nigra pars reticulata (SNr) [16]. These distinct subdivisions also characterize the STN [17], an anatomical segregation consistent with the involvement of the STN in motor control, and also in cognitive and emotional tasks that have been extensively studied in humans and animals (for a review see [18]). ...
... An important component of the general architecture of the cortical-BG connectivity, which has been argued to reflect the function of the BG, is the parallel, mainly segregated, closed-loop projections that originate from, and return to, the same neocortical domains [16]. A few years ago, we extended this idea by suggesting that many sensori-motor subcortical structures from the brainstem with the capacity to guide movement also have connections with the BG that may represent a series of parallel, at least partially, closed loops [35]. ...
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The subthalamic nucleus (STN) is classically subdivided into sensori-motor, associative and limbic regions which is consistent with the involvement of this structure in motor control, but also in cognitive and emotional tasks. However, the function of the sensory inputs to the STN’s sensori-motor territory is comparatively less well explored, although sensory responses have been reported in this structure. There is still a paucity of information regarding the characteristics of that subdivision and its potential functional role in the basal ganglia processing and more widely in associated networks. In this Perspective paper, we summarize the type of sensory stimuli that have been reported to activate the STN, describe the complex sensory properties of the STN and its anatomical link to a sensory network involving the brainstem, characterized in our recent work. Analyzing the sensory input to the STN led us to suggest the existence of previously unreported three-lateral subcortical loops between the basal ganglia and the brainstem which do not involve the cortex. Anatomically, these loops closely link the STN, the substantia nigra pars reticulata and various structure from the brainstem such as the superior colliculus and the parabrachial nucleus. We also discuss the potential role of the STN in the control of sensory activity in the brainstem and its possible contribution to favoring sensory habituation or sensitization over brainstem structures to optimize the best selection of action at a given time.
... The CBGT circuit provides a neural substrate that can control or tune how information is processed when a choice is being made among a set of available actions [5,47]. After calibrating a computational model of the CBGT network to produce similar firing rates to those observed experimentally, we fit network decision-making behavior with a DDM model and performed CCA to reveal relationships among network synaptic weights and firing rates and the DDM parameters. ...
... The observation that specific control ensembles associate with specific factor configurations of the DDM provides a theoretical link between two disparate arms of the CBGT literature. On the one hand, there is the classical model of CBGT circuits as playing a critical role in action selection [47], through inhibition of competing action plans [5]. On the other hand, there is the emerging literature suggesting a critical role for CBGT systems in movement vigor [22,23]. ...
Article
In situations featuring uncertainty about action-reward contingencies, mammals can flexibly adopt strategies for decision-making that are tuned in response to environmental changes. Although the cortico-basal ganglia thalamic (CBGT) network has been identified as contributing to the decision-making process, it features a complex synaptic architecture, comprised of multiple feed-forward, reciprocal, and feedback pathways, that complicate efforts to elucidate the roles of specific CBGT populations in the process by which evidence is accumulated and influences behavior. In this paper we apply a strategic sampling approach, based on Latin hypercube sampling, to explore how variations in CBGT network properties, including subpopulation firing rates and synaptic weights, map to variability of parameters in a normative drift diffusion model (DDM), representing algorithmic aspects of information processing during decision-making. Through the application of canonical correlation analysis, we find that this relationship can be characterized in terms of three low-dimensional control ensembles within the CBGT network that impact specific qualities of the emergent decision policy: responsiveness (a measure of how quickly evidence evaluation gets underway, associated with overall activity in corticothalamic and direct pathways), pliancy (a measure of the standard of evidence needed to commit to a decision, associated largely with overall activity in components of the indirect pathway of the basal ganglia), and choice (a measure of commitment toward one available option, associated with differences in direct and indirect pathways across action channels). These analyses provide mechanistic predictions about the roles of specific CBGT network elements in tuning the way that information is accumulated and translated into decision-related behavior.
... The insula predictive coding mechanism elaborated above, although detailed, is not entirely new, as previous works have already proposed how active inference and predictive coding may be used for interoceptive inference [14,23,35] and how interoceptive information is processed in the posterior and anterior insula [14,20,21]. Anatomical studies demonstrating the existence of parallel networks linking the PFC and striatum [61,144,145] have paved the way to understand cognitive, emotional and motivational functions and dysfunctions of the basal ganglia, previously thought to be exclusively involved in motor control [64,103,129,[146][147][148][149][150][151][152][153][154][155]. Oriented by these network approaches and in contrast to the earlier insula models, the IMAC model, however, suggests that insula active interoceptive inference functions can be better understood in light of its parallel connections with PFC sub-regions, namely the dorsolateral PFC (DLPFC), the ventromedial PFC (VMPFC), the supplementary motor area (SMA), with the striatum and neuromodulatory input from the dopaminergic and acetylcholinergic systems (figure 2). ...
... The PFC and striatum sub-regions form anatomical parallel loops specialized for processes implicated in adaptive behaviour, such as decision making, learning, emotion, motivation and sequential behaviours [129,144,[146][147][148][149][156][157][158][159]. The VMPFC-vStriatum and DLPFC-mStriatum loops are recruited in early stages of learning, when behaviour is erratic, guided by external reward signals and require attention, but their activities diminish as learning progresses and behaviour becomes automatic, fast and less error-prone [129,148,149]. ...
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In the brain, the insular cortex receives a vast amount of interoceptive information, ascending through deep brain structures, from multiple visceral organs. The unique hierarchical and modular architecture of the insula suggests specialization for processing interoceptive afferents. Yet, the biological significance of the insula's neuroanatomical architecture, in relation to deep brain structures, remains obscure. In this opinion piece, we propose the Insula Hierarchical Modular Adaptive Interoception Control (IMAC) model to suggest that insula modules (granular, dysgranular and agranular), forming parallel networks with the prefrontal cortex and striatum, are specialized to form higher order interoceptive representations. These interoceptive representations are recruited in a context-dependent manner to support habitual, model-based and exploratory control of visceral organs and physiological processes. We discuss how insula interoceptive representations may give rise to conscious feelings that best explain lower order deep brain interoceptive representations, and how the insula may serve to defend the body and mind against pathological depression.
... Its various cortical and subcortical interconnections make it an ideal target for non-invasive brain stimulation studies (Guse et al., 2010;Dedoncker et al., 2016). It is functionally interconnected with the orbitofrontal cortex, large parts of the neocortex, the parietal cortex, the cingulate cortex, and the subcortical basal ganglia, thalamus, and hippocampus (Alexander et al., 1986;Petrides and Pandya, 1999;Tekin and Cummings, 2002;Tik et al., 2017). Animal studies demonstrated that the frontal cortex controls the release of dopamine in the striatum (Murase et al., 1993;Karreman and Moghaddam, 1996;Keck et al., 2002;Kanno et al., 2004). ...
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Transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) have been shown to modulate functional connectivity. Their specific effects seem to be dependent on the pre-existing neuronal state. We aimed to precondition frontal networks using tDCS and subsequently stimulate the left dorsolateral prefrontal cortex (lDLPFC) using TMS. Thirty healthy participants underwent excitatory, inhibitory or sham tDCS for 10 min, as well as an excitatory intermittent theta-burst (iTBS) protocol (600 pulses, 190 s, 20 x 2-sec trains), applied over the lDLPFC at 90% of the individual resting motor threshold. Functional connectivity was measured in three task-free resting state fMRI sessions, immediately before and after tDCS, as well as after iTBS. Testing the whole design did not yield any significant results. Analysis of the connectivity between the stimulation site and all other brain voxels, contrasting only the interaction effect between the experimental groups (excitatory vs inhibitory) and the repeated measure (post-tDCS vs post-TMS), revealed significantly affected voxels bilaterally in the anterior cingulate and paracingulate gyri, the caudate nuclei, the insula and operculum cortices, as well as the Heschl's gyrus. Post-hoc ROI-to-ROI analyses between the significant clusters and the striatumshowed post-tDCS, temporo-parietal-to-striatal and temporo-parietal-to-fronto-cingulate differences between the anodal and cathodal tDCS group, as well as post-TMS, striatal-to-temporo-parietal differences between the anodal and cathodal groups and frontostriatal and interhemispheric temporo-parietal cathodal-sham group differences. Excitatory iTBS to a tDCS-inhibited lDLPFC thus yielded more robust functional connectivity to various areas as compared to excitatory iTBS to a tDCS-enhanced DLPFC. Even considering reduced statistical power due to low subject numbers, results demonstrate complex, whole-brain stimulation effects. They are possibly facilitated by cortical homeostatic control mechanisms and show feasibility of using tDCS to modulate subsequent TMS effects. This proof-of-principle study might stimulate further research into the principle of preconditioning that might be useful in the development of protocols using DLPFC as a stimulation site for the treatment of depression.
... This finding is consistent with the cerebellum's role in EF processing due to its extensive reciprocal connections with areas of the cerebrum, including the prefrontal and posterior parietal cortex and the basal ganglia (Stoodley and Schmahmann, 2010;Bostan et al., 2013). Contradictorily, no correlation was found with the prefrontal-striatal circuit, which is impaired in SCA3 and plays a crucial role in higherorder cognitive functions (Alexander et al., 1986;Yap et al., 2022b). Instead, strong correlations were found between general intelligence and precentral gyrus and superior occipital gyrus (De Rezende et al., 2015). ...
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Background Spinocerebellar ataxia type 3 (SCA3) is a complex cerebrocerebellar disease primarily characterized by ataxia symptoms alongside motor and cognitive impairments. The heterogeneous clinical presentation of SCA3 necessitates correlations between magnetic resonance imaging (MRI) and clinical findings in reflecting progressive disease changes. At present, an attempt to systematically examine the brain-behavior relationship in SCA3, specifically, the correlation between MRI and clinical findings, is lacking.Objective We investigated the association strength between MRI abnormality and each clinical symptom to understand the brain-behavior relationship in SCA3.Methods We conducted a systematic review on Medline and Scopus to review studies evaluating the brain MRI profile of SCA3 using structural MRI (volumetric, voxel-based morphometry, surface analysis), magnetic resonance spectroscopy, and diffusion tensor imaging, including their correlations with clinical outcomes.ResultsOf 1,767 articles identified, 29 articles met the eligibility criteria. According to the National Institutes of Health quality assessment tool for case-control studies, all articles were of excellent quality. This systematic review found that SCA3 neuropathology contributes to widespread brain degeneration, affecting the cerebellum and brainstem. The disease gradually impedes the cerebral cortex and basal ganglia in the late stages of SCA3. Most findings reported moderate correlations (r = 0.30–0.49) between MRI features in several regions and clinical findings. Regardless of the MRI techniques, most studies focused on the brainstem and cerebellum.Conclusions Clinical findings suggest that rather than individual brain regions, the connectivity between different brain regions in distributed networks (i.e., cerebellar-cerebral network) may be responsible for motor and neurocognitive function in SCA3. This review highlights the importance of evaluating the progressive changes of the cerebellar-cerebral networks in SCA3 patients, specifically the functional connectivity. Given the relative lack of knowledge about functional connectivity on SCA3, future studies should investigate possible functional connectivity abnormalities in SCA3 using fMRI.
... The results showed that the c-Fos level in M1, along with TH levels in SN and ST, is the most important index among the hub regions related to acupuncture effects, implying the role of M1 in the brain network of PD. There have been several reports showing the importance of M1 in PD (Alexander et al., 1986;Lang and Lozano, 1998;Murer et al., 2002;Dejean et al., 2012;Vitrac et al., 2014). M1, which controls skilled movement, receives inputs from the other cortex and thalamus, and the thalamus integrates data from the basal ganglia and cerebellum to generate output motor commands from layer 5 pyramidal tract neurons, sending convergent signals to connect directly to descending motor pathways (Aeed et al., 2021). ...
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Parkinson’s disease (PD) is a multilayered progressive brain disease characterized by motor dysfunction and a variety of other symptoms. Although acupuncture has been used to ameliorate various symptoms of neurodegenerative disorders, including PD, the underlying mechanisms are unclear. Here, we investigated the mechanism of acupuncture by revealing the effects of acupuncture treatment on brain neural responses and its functional connectivity in an animal model of PD. We observed that destruction of neuronal network between many brain regions in PD mice were reversed by acupuncture. Using machine learning analysis, we found that the key region associated with the improvement of abnormal behaviors might be related to the neural activity of M1, suggesting that the changes of c-Fos in M1 could predict the improvement of motor function induced by acupuncture treatment. In addition, acupuncture treatment was shown to significantly normalize the brain neural activity not only in M1 but also in other brain regions related to motor behavior (striatum, substantia nigra pars compacta, and globus pallidus) and non-motor symptoms (hippocampus, lateral hypothalamus, and solitary tract) of PD. Taken together, our results demonstrate that acupuncture treatment might improve the PD symptoms by normalizing the brain functional connectivity in PD mice model and provide new insights that enhance our current understanding of acupuncture mechanisms for non-motor symptoms.
... Our finding of reduced putamen connectivity within the SN in psychotic patients is in line with previous results (Karcher et al., 2019;Orliac et al., 2013;Tu et al., 2012). The putamen is a central part of the striatum, which is known for its role in motor function and cognitive tasks (Alexander et al., 1986;Simpson et al., 2010). In schizophrenia, structural and functional abnormality within the putamen is well documented (Brandt and Bonelli, 2008; 21 Menon et al., 2001), and there is vast evidence of reduced cortico-striatal connectivity often associated with symptom severity (Avram et al., 2018;Fornito et al., 2013;Koch et al., 2014). ...
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In schizophrenia and schizoaffective disorder cognitive deficits are a reliable characteristic predicting a poor functional outcome. It has been theorized that both the default mode network (DMN) and the salience network (SN) play a crucial role in cognitive processes and aberrant functional connectivity within these networks in psychotic patients has been reported. The goal of this study was to reveal potential links between aberrant functional connectivity within these networks and impaired cognitive performance in psychosis. We chose two approaches for cognitive assessment, first the MATRICS Consensus Cognitive Battery (MCCB) combined into a global score and second the disorganization factor derived from a five-factor model of the Positive and Negative Syndrome Scale (PANSS) known to be relevant for cognitive performance. DMN and SN were identified using independent component analysis on resting-state functional magnetic resonance imaging data. We found significantly decreased connectivity within the right supplementary motor area (SMA) and bilateral putamen in patients with psychosis (n=70; 27F/43M) compared to healthy controls (n=72; 28F/44M). Within patients, linear regression analysis revealed that aberrant SMA connectivity was associated with impaired global cognition, while dysfunctional bilateral putamen connectivity predicted disorganization. There were no significant changes in connectivity within the DMN. Results support the hypothesis that SN dysfunctional connectivity is important in the pathobiology of cognitive deficits in psychosis. For the first time we were able to show the involvement of dysfunctional SMA connectivity in this context. We interpret the decreased SN connectivity as evidence of reduced functionality in recruiting brain areas necessary for cognitive processing. 3
... Moreover, dysfunction in the projections of the basal ganglia and orbitofrontal cortex may lead to altered fronto-striatial connectivity patterns [145]. Cortico-basal ganglia circuits are involved in monitoring the motor and cognitive aspects of altered cortical processes [145][146][147] and thus influence sensorimotor, limbic and cognitive functions [121,148,149]. These circuits are known to play a key role in ALS pathology [150] and act as an underlying substrate in the control of motor and cognitive capabilities of the prefrontal cortex [149]. ...
Article
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Amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disorder characterized by progressive degeneration of upper motor neurons and lower motor neurons, and frontotemporal regions resulting in impaired bulbar, limb, and cognitive function. Magnetic resonance imaging studies have reported cortical and subcortical brain involvement in the pathophysiology of ALS. The present study investigates the functional integrity of resting-state networks (RSNs) and their importance in ALS. Intra- and inter-network resting-state functional connectivity (Rs-FC) was examined using an independent component analysis approach in a large multi-center cohort. A total of 235 subjects (120 ALS patients; 115 healthy controls (HC) were recruited across North America through the Canadian ALS Neuroimaging Consortium (CALSNIC). Intra-network and inter-network Rs-FC was evaluated by the FSL-MELODIC and FSLNets software packages. As compared to HC, ALS patients displayed higher intra-network Rs-FC in the sensorimotor, default mode, right and left fronto-parietal, and orbitofrontal RSNs, and in previously undescribed networks including auditory, dorsal attention, basal ganglia, medial temporal, ventral streams, and cerebellum which negatively correlated with disease severity. Furthermore, ALS patients displayed higher inter-network Rs-FC between the orbitofrontal and basal ganglia RSNs which negatively correlated with cognitive impairment. In summary, in ALS there is an increase in intra- and inter-network functional connectivity of RSNs underpinning both motor and cognitive impairment. Moreover, the large multi-center CALSNIC dataset permitted the exploration of RSNs in unprecedented detail, revealing previously undescribed network involvement in ALS.
... Our finding of reduced putamen connectivity within the SN in psychotic patients is in line with previous results (Karcher et al., 2019;Orliac et al., 2013;Tu et al., 2012). The putamen is a central part of the striatum, which is known for its role in motor function and cognitive tasks (Alexander et al., 1986;Simpson et al., 2010). In schizophrenia, structural and functional abnormality within the putamen is well documented (Brandt and Bonelli, 2008;Menon et al., 2001), and there is vast evidence of reduced cortico-striatal connectivity often associated with symptom severity (Avram et al., 2018;Fornito et al., 2013;Koch et al., 2014). ...
Article
In schizophrenia and schizoaffective disorder cognitive deficits are a reliable characteristic predicting a poor functional outcome. It has been theorized that both the default mode network (DMN) and the salience network (SN) play a crucial role in cognitive processes and aberrant functional connectivity within these networks in psychotic patients has been reported. The goal of this study was to reveal potential links between aberrant functional connectivity within these networks and impaired cognitive performance in psychosis. We chose two approaches for cognitive assessment, first the MATRICS Consensus Cognitive Battery (MCCB) combined into a global score and second the disorganization factor derived from a five-factor model of the Positive and Negative Syndrome Scale (PANSS) known to be relevant for cognitive performance. DMN and SN were identified using independent component analysis on resting-state functional magnetic resonance imaging data. We found significantly decreased connectivity within the right supplementary motor area (SMA) and bilateral putamen in patients with psychosis (n = 70; 27F/43M) compared to healthy controls (n = 72; 28F/44M). Within patients, linear regression analysis revealed that aberrant SMA connectivity was associated with impaired global cognition, while dysfunctional bilateral putamen connectivity predicted disorganization. There were no significant changes in connectivity within the DMN. Results support the hypothesis that SN dysfunctional connectivity is important in the pathobiology of cognitive deficits in psychosis. For the first time we were able to show the involvement of dysfunctional SMA connectivity in this context. We interpret the decreased SN connectivity as evidence of reduced functionality in recruiting brain areas necessary for cognitive processing.
... In recent years, researchers discovered that patients with depression exhibit a wide distribution of localized abnormal brain functional areas as compared with HCs, and these abnormal brain areas are located in the previously proposed neuropathological circuit of depression, namely, the CSPT neurotransmission pathway (40)(41)(42). The above mentioned circuit is composed of distributed neuroanatomical loops that connect the prefrontal cortex, basal ganglia, and thalamus in an integrated manner to support different emotional, cognitive, and motor processes (43,44). The results of this study suggest that most of these brain regions are involved in the CSPT circuit. ...
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Background Previous studies found that transcutaneous auricular vagus nerve stimulation (taVNS) was clinically effective in treating a case of treatment-resistant depression (TRD). However, the brain neural mechanisms underlying the immediate effects of taVNS treatment for TRD have not been elucidated.Materials and Methods Differences in the amplitude of low-frequency fluctuations (ALFF) between TRD and healthy control (HC) groups were observed. The TRD group was treated with taVNS for 30 min, and changes in ALFF in the TRD group before and after immediate treatment were observed. The ALFF brain regions altered by taVNS induction were used as regions of interest to analyze whole-brain functional connectivity (FC) changes in the TRD group.ResultsA total of 44 TRD patients and 44 HCs completed the study and were included in the data analysis. Compared with the HC group, the TRD group had increased ALFF in the left orbital area of the middle frontal gyrus. After taVNS treatment, ALFF in the left orbital area of the middle frontal gyrus and right middle frontal gyrus decreased in the TRD group, while ALFF in the right orbital area of the superior frontal gyrus increased. The FC in the left orbital area of the middle frontal gyrus with left middle frontal gyrus and the right inferior occipital gyrus was significantly increased.Conclusion Transcutaneous auricular vagus nerve stimulation demonstrates immediate modulation of functional activity in the emotional network, cognitive control network, and visual processing cortex, and may be a potential brain imaging biomarker for the treatment of TRD.
... the basal ganglia, the cerebellum, and the cortex, the thalamus participates in feedback and feed-forward mechanisms and plays a modulatory role in the integration of information across the parallel motor, cognitive and limbic circuits (Alexander et al., 1986;Haber and McFarland, 2001;Borra et al., 2015;Quartarone et al., 2020). Our results further highlight the importance of the thalamus in MSA patients with FOG symptoms. ...
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Freezing of gait (FOG) in multiple system atrophy (MSA) is characterized by a higher risk of falls and a reduced quality of life; however, the mechanisms underlying these effects have yet to be identified by neuroimaging. The aim of this study was to investigate the differences in functional network when compared between MSA patients with and without freezing. Degree centrality (DC) based on the resting-state functional magnetic resonance imaging was computed in 65 patients with MSA and 36 healthy controls. Brain regions with statistically different DC values between groups were selected as seed points for a second seed-based functional connectivity (FC) analysis. The relationships between brain activity (DC and FC alterations) and the severity of freezing symptoms were then investigated in the two groups of patients with MSA. Compared to MSA patients without FOG symptoms (MSA-nFOG), patients with MSA-FOG showed an increased DC in the left middle temporal gyrus but a reduced DC in the right superior pole temporal gyrus, left anterior cingulum cortex, left thalamus, and right middle frontal gyrus. Furthermore, in patients with MSA-FOG, the DC in the left thalamus was negatively correlated with FOG scores. Using the left thalamus as a seed, secondary seed-based functional connectivity analysis revealed that patients with MSA-FOG commonly showed the left thalamus-based FC abnormalities in regions related to cognition and emotion. In contrast to the patients with MSA-nFOG, patients with MSA-FOG showed an increased FC between the left thalamus and the left middle temporal gyrus (MTG), right inferior parietal lobule (IPL), bilateral cerebellum_8, and left precuneus. Freezing of gait is associated with centrality of the impaired thalamus network. Abnormal FC between the thalamus and left MTG, right IPL, bilateral cerebellum_8, and left precuneus was involved in FOG. These results provide new insight into the pathophysiological mechanism of FOG in MSA.
... 62,63 Specific dlPFC circuits have been shown to support selfregulation and habit learning, 62 which are associated with goal-oriented planning. 64,65 Additionally, dlPFC circuits play an important role in social motivation and their disruption has been postulated to represent the neural basis for social-interaction and communicative deficits in ASD. 66 Some previous studies 53,67,68 have found that increased GM volumes and numbers of neurons indicate structural abnormalities in dlPFC circuits in children with ASD. ...
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Purpose: This study used the graph-theory approach, degree centrality (DC) to analyze whole-brain functional networks at the voxel level in children with ASD, and investigated whether DC changes were correlated with any clinical variables in ASD children. Methods: The current study included 86 children with ASD and 54 matched healthy subjects Aged 2-5.5 years. Next, chloral hydrate induced sleeping-state functional magnetic resonance imaging (ss-fMRI) datasets were acquired from these ASD and healthy subjects. For a given voxel, the DC was calculated by calculating the number of functional connections with significantly positive correlations at the individual level. Group differences were tested using two-sample t-tests (p < 0.01, AlphaSim corrected). Finally, relationships between abnormal DCs and clinical variables were investigated via Pearson's correlation analysis. Results: Children with ASD exhibited low DC values in the right middle frontal gyrus (MFG) (p < 0.01, AlphaSim corrected). Furthermore, significantly negative correlations were established between the decreased average DC values within the right MFG in ASD children and the total ABC scores, as well as with two ABC subscales measuring highly relevant impairments in ASD (ie, stereotypes and object-use behaviors and difficulties in language). Conclusion: Taken together, the results of our ss-fMRI study suggest that abnormal DC may represent an important contribution to elucidation of the neuropathophysiological mechanisms of preschoolers with ASD.
... Pathology of these brain regions in patients with Parkinson's disease has likewise been linked to overestimation and underproduction of suprasecond time intervals (Pastor et al., 1992). However, other brain regions are involved as well, for instance, dorsolateral pre-frontal cortex (Lewis and Miall, 2003) to which the basal ganglia have extended connections (Alexander et al., 1986). Further brain imaging and stimulation studies are needed before we can pin down the brain regions associated with vestibular timing tasks. ...
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As the cerebellum is involved in vestibular and time-keeping processes, we asked if the latter are related. We conducted three experiments to investigate the effects of vestibular stimulation on temporal processing of supra-second durations. In Experiment 1, subjects had to perform temporal productions of 10- and 15-s intervals either standing on both feet or while being engaged in the difficult balancing task of standing on one foot with their eyes closed (or open for control purposes). In Experiment 2, participants were required to produce intervals of 5, 10, 15, and 20 s while standing on both feet with their eyes open or closed, which constituted an easier balancing task. In Experiment 3, we removed the active balancing; temporal productions of the same four durations had to be performed with the eyes open or closed during the passive vestibular stimulation induced by the oscillatory movements of a swing. Participants produced longer intervals when their eyes were closed, but active balancing was not the culprit. On the contrary, temporal over-production was particularly pronounced during the passive vestibular stimulation brought about by the swing movements. Taken together, the experiments demonstrate that the contraction of the subjective time during balancing tasks with closed eyes is most likely of vestibular origin.
... he basal ganglia are a group of subcortical nuclei in the brain that are important for integrating information and processing cortical input for motor and cognitive functions [1]. The basal ganglia play an important role in controlling voluntary movements [2,3]. The striatum and Subthalamic Nucleus (STN) are the entry points of the basal ganglia and the inner part of the Globus Pallidus (Gpi) and the Cubstantia Nigra (SNr) are the exit stations of the basal ganglia. ...
Article
Background and Aim: Deep Brain Stimulation (DBS) surgery is increasingly performed to treat movement disorders. In these patients, a rechargeable or non-rechargeable battery is placed under their subcutaneous chest after implantation of an electrode in the basal ganglia of the brain, which has different battery life. Methods and Materials/Patients: In this study, three databases, including PubMed, ScienceDirect, Scopus without time limit, and Google Scholar search engine were examined by two independent researchers. Results: In the initial search, a total of 338 data were found. Then, by reviewing the title and summary of articles, 17 articles were included in the study and then 13 articles were reviewed in full text. The results of the articles were divided into two subgroups of battery life related to the types or subtypes of movement disorders indicated by DBS and battery life related to the types of IPG models. Conclusion: Battery life in Parkinson’s movement disorder and tremor is longer than in dystonia. Also, the battery life of Soletra model is longer than Kinetra and Kinetra model is longer than Activa, and any battery replacement surgery reduces battery life.
... 12 13 Research has traditionally suggested the functional loops with in the basal ganglia are segregated circuits. 13 However, there is increasing evidence that these circuits are not segregated and play an important role in modulating motor control based on mood, memory and cognition. 12 Indeed, research has shown that a unidirectional influence of the limbic loop over the motor loop in animal models. ...
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Background Previous reports suggest that group therapeutic singing (GTS) may have a positive effect on motor symptoms in persons with Parkinson’s disease (PD). Objective To determine the effect of a single session of GTS on clinical motor symptoms. Methods Clinical motor symptom assessment was completed immediately before and after 1 hour of GTS in 18 participants. Results A significant decrease in average scores for gait and posture and tremor, but not speech and facial expression or bradykinesia was revealed. Conclusion These results support the notion that GTS is a beneficial adjuvant therapy for persons with PD that warrants further research.
... Similarly, a high percentage of patients with TBI also show significant alterations upon neuropsychological examination, similar to those presented by patients with psychotic symptoms, particularly in executive functions and memory (Berrios, 2013). These alterations have been associated with post-traumatic structural lesions located in different brain regions, such as the frontal cortex (dorsolateral and orbitofrontal), and, in those structures that form the so-called fronto-subcortical circuits (Alexander et al., 1986;Pettersson-Yeo et al., 2011). ...
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Background Positive symptoms of schizophrenia are associated with significant difficulties in daily functioning, and these difficulties have been associated with impaired executive functions (EEFF). However, specific cognitive and socio-emotional executive deficits have not been fully established. Objective The present study has several objectives. First, we aimed to examine the specific deficits in cognitive and socio-emotional EEFF in a group of patients with schizophrenia with a predominance of positive symptoms, as well as to determine if these patients present clinically significant scores in any of the three fronto-subcortical behavioral syndromes: Dorsolateral, Orbitofrontal, or Anterior Cingulate. Method The sample consisted of 54 patients, 27 with a predominance of positive symptoms, and 27 healthy controls matched for gender, age, and education. The two groups completed four cognitive and three socio-emotional EEFF tasks. In the group of patients, positive symptoms were evaluated using the scale for the Evaluation of Positive Symptoms (SANS), while the behavioral alterations associated with the three fronto-subcortical syndromes were evaluated using the Frontal System Behavior Scale (FrSBe). Results The patients, in comparison with a control group, presented specific deficits in cognitive and socio-emotional EEFF. In addition, a high percentage of patients presented clinically significant scores on the three fronto-subcortical syndromes. Conclusion The affectation that these patients present, in terms of both cognitive and emotional components, highlights the importance of developing a neuropsychological EEFF intervention that promotes the recovery of the affected cognitive capacities and improves the social and emotional functioning of the affected patients.
... Two oscillatory regimes at 0.1 Hz and between 0.4 and 0.5 Hz were observed in single-unit spike trains (Totah et al., 2018). (E) Cortical-basal ganglia-thalamocortical loop with excitatory (red) and inhibitory (blue) pathways (Alexander et al., 1990) and the thalamic sensory input. ...
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Spontaneous Infra-Slow Fluctuations (ISFs) of the human EEG (EEG-ISFs) were discovered 60 years ago when appropriate amplifiers for their recordings were designed. To avoid skin-related artifacts the recording of EEG-ISFs required puncturing the skin under the electrode. In the beginning of the 21st century the interest in EEG-ISFs was renewed with the appearance of commercially available DC-coupled amplified and by observation of ISFs of the blood oxygen level–dependent (BOLD) functional magnetic resonance imaging signal at a similar frequency. The independent components of irregular EEG-ISFs were shown to correlate with BOLD signals which in turn were driven by changes in arousal level measured by galvanic skin response (GSR), pupil size and HRV. There is no consensus regarding the temporal organization of EEG-ISFs: some studies emphasize the absence of peaks on EEG-ISFs spectra, some studies report prominent oscillations with frequency around 0.1 or 0.02 Hz, while some emphasize multiple discrete infraslow oscillations. No studies used parameters of EEG-ISFs as neuromarkers to discriminate psychiatric patients from healthy controls. Finally, a set of working hypotheses is suggested that must be tested in future research to solve the enigma of EEG-ISFs.
... Originally proposed by Alexander et al. [8][9][10], the frontal-striatal circuits include five parallel segregated circuits connecting selected cortical areas to the basal ganglia and thalamus. Of particular relevance to substance use disorders is the frontal-striatal circuit linking the prefrontal cortex (PFC), nucleus accumbens (NAc), and ventral tegmental area (VTA). ...
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Independently, chronic cocaine use and HIV-1 viral protein exposure induce neuroadaptations in the frontal-striatal circuit as evidenced by both clinical and preclinical studies; how the frontal-striatal circuit responds to HIV-1 infection following chronic drug use, however, has remained elusive. After establishing experience with both sucrose and cocaine self-administration, a pretest-posttest experimental design was utilized to evaluate preference judgment, a simple form of decision-making dependent upon the integrity of frontal-striatal circuit function. During the pretest assessment, male rats exhibited a clear preference for cocaine, whereas female animals preferred sucrose. Two posttest evaluations (3 days and 6 weeks post inoculation) revealed that, independent of biological sex, inoculation with chimeric HIV (EcoHIV), but not saline, disrupted decision-making. Prominent structural alterations in the frontal-striatal circuit were evidenced by synaptodendritic alterations in pyramidal neurons in the medial prefrontal cortex. Thus, the EcoHIV rat affords a valid animal model to critically investigate how the frontal-striatal circuit responds to HIV-1 infection following chronic drug use.
Chapter
Parkinson disease (PD) is a heterogeneous and progressive neurodegenerative disorder. PD was traditionally defined as a movement disorder resulting from loss of dopamine in the basal ganglia, but its pathology is now known to be more widespread, involving both the central and peripheral nervous system, and leading to various motor and nonmotor signs and symptoms. Recent discoveries have led to major insights into the neurobiology of PD, in particular the pathophysiology and the central role of cellular α-synuclein aggregation in the pathogenesis of genetic and sporadic forms of PD. While insights into the pathophysiology have resulted in novel pharmacological and surgical therapies addressing the parkinsonian motor signs, efforts to halt the progression of the disease have so far failed. Exploration of novel molecular and interventional targets in genetic cellular and animal models and the introduction of biomarkers to stratify patients for clinical trials offer hope for the development of more effective symptomatic and neuroprotective therapies.
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Semantic cognition is a complex multifaceted brain function involving multiple processes including sensory, semantic, and domain-general cognitive systems. However, it remains unclear how these systems cooperate with each other to achieve effective semantic cognition. Here, we used independent component analysis (ICA) to investigate the functional brain networks that support semantic cognition. We used a semantic judgment task and a pattern-matching control task, each with 2 levels of difficulty, to disentangle task-specific networks from domain-general networks. ICA revealed 2 task-specific networks (the left-lateralized semantic network [SN] and a bilateral, extended semantic network [ESN]) and domain-general networks including the frontoparietal network (FPN) and default mode network (DMN). SN was coupled with the ESN and FPN but decoupled from the DMN, whereas the ESN was synchronized with the FPN alone and did not show a decoupling with the DMN. The degree of decoupling between the SN and DMN was associated with semantic task performance, with the strongest decoupling for the poorest performing participants. Our findings suggest that human higher cognition is achieved by the multiple brain networks, serving distinct and shared cognitive functions depending on task demands, and that the neural dynamics between these networks may be crucial for efficient semantic cognition.
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The striatum and its cortical circuits play central roles in the pathophysiology of obsessive-compulsive disorder (OCD). The striatum is subdivided by cortical connections and functions; however, the anatomical aberrations in different cortico-striatal connections and coexisting microstructural anomalies in striatal subregions of OCD patients are poorly understood. Thus, we aimed to elucidate the aberrations in cortico-striatal white matter (WM) connectivity and the associated subregional microstructure of the striatum in patients with OCD. From diffusion tensor/kurtosis imaging of 107 unmedicated OCD patients and 110 matched healthy controls (HCs), we calculated the cortico-striatal WM connectivity and segmented the striatum using probabilistic tractography. For the segmented striatal subregions, we measured average diffusion kurtosis values, which represent microstructural complexity. Connectivity and mean kurtosis values in each cortical target and associated striatal subregions were compared between groups. We identified significantly reduced orbitofrontal WM connectivity with its associated striatal subregion in patients with OCD compared to that in HCs. However, OCD patients exhibited significantly increased caudal-motor and parietal connectivity with the associated striatal subregions. The mean kurtosis values of the striatal subregions connected to the caudal-motor and parietal cortex were significantly decreased in OCD patients. Our results highlighted contrasting patterns of striatal WM connections with the orbitofrontal and caudal-motor/parietal cortices, thus supporting the cortico-striatal circuitry imbalance model of OCD. We suggest that aberrations in WM connections and the microstructure of their downstream regions in the caudal-motor-/parietal-striatal circuits may underlie OCD pathophysiology and further provide potential neuromodulation targets for the treatment of OCD.
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Introduction: The basal ganglia and related dopaminergic cortical areas are important neural systems underlying motor learning and are also implicated in impulse control disorders (ICDs). Motor learning impairments and ICDs are frequently observed in Parkinson's disease (PD). Nevertheless, the relationship between motor learning ability and ICDs has not been elucidated. Methods: We examined the relationship between motor learning ability and gambling propensity, a possible symptom for prodromal ICDs, in PD patients. Fifty-nine PD patients without clinical ICDs and 43 normal controls (NC) were administered a visuomotor rotation perturbation task and the Iowa Gambling Task (IGT) to evaluate motor learning ability and gambling propensity, respectively. Participants also performed additional cognitive assessments and underwent brain perfusion SPECT imaging. Results: Better motor learning ability was significantly correlated with lower IGT scores, i.e., higher gambling propensity, in PD patients but not in NC. The higher scores on assessments reflecting prefrontal lobe function and well-preserved blood perfusion in prefrontal areas were correlated with lower IGT scores along with better motor learning ability. Conclusions: Our findings suggest that better motor learning ability and higher gambling propensity are based on better prefrontal functions, which are in accordance with the theory that the prefrontal cortex is one of the common essential regions for both motor learning and ICDs.
Article
Dopamine is known to play a role in the pathogenesis of psychotic symptoms, but the mechanisms driving dopaminergic dysfunction in psychosis remain unclear. Considerable attention has focused on the role of corticostriatothalamic (CST) circuits, given that they regulate, and are modulated by, the activity of dopaminergic cells in the midbrain. Preclinical studies have proposed multiple models of CST dysfunction in psychosis, each prioritizing different brain regions and pathophysiological mechanisms. A particular challenge is that CST circuits have undergone considerable evolutionary modification from the rodent to primate and human brains, complicating comparisons across species. Here, we consider preclinical models of CST dysfunction in psychosis and evaluate the degree to which they are supported by evidence from human resting-state fMRI studies conducted across the psychosis continuum, ranging from subclinical schizotypy to established schizophrenia. In partial support of some preclinical models, human studies indicate that dorsal CST and hippocampal-striatal functional dysconnectivity are apparent across the psychosis spectrum and may represent a vulnerability marker for psychosis. In contrast, midbrain dysfunction may emerge when symptoms warrant clinical assistance and may thus be a trigger for illness onset. The major difference between clinical and preclinical findings is the strong involvement of the dorsal CST in the former, consistent with an increasing prominence of this circuitry in the primate brain. We close by underscoring the need for high-resolution characterization of phenotypic heterogeneity in psychosis to develop a refined understanding of how dysfunction of specific circuit elements gives rise to distinct symptom profiles.
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Functional imaging studies of neurotypical adults report activation in the left putamen during speech production. The current study asked how stroke survivors with left putamen damage are able to produce correct spoken responses during a range of speech production tasks. Using functional magnetic resonance imaging, activation during correct speech production responses was assessed in 5 stroke patients with circumscribed left dorsal striatal lesions, 66 stroke patient controls who did not have focal left dorsal striatal lesions, and 54 neurotypical adults. As a group, patients with left dorsal striatal damage (our patients of interest) showed higher activation than neurotypical controls in the left superior parietal cortex during successful speech production. This effect was not specific to patients with left dorsal striatal lesions as we observed enhanced activation in the same region in some patient controls and also in more error-prone neurotypical participants. Our results strongly suggest that enhanced left superior parietal activation supports speech production in diverse challenging circumstances, including those caused by stroke damage. They add to a growing body of literature indicating how upregulation within undamaged parts of the neural systems already recruited by neurotypical adults contributes to recovery after stroke.
Article
The precise cortical and subcortical mechanisms of Tourette syndrome (TS) are still not fully understood. In the present retrospective analysis, adolescent and adult medication-naïve patients showed increased DA transporter (DAT) binding in nucleus caudate (CAUD), putamen (PUT) and/or whole neostriatum (NSTR). D2 receptor (R) binding and DA release were not different from controls throughout the nigrostriatal and mesolimbocortical system. When patients were medication-free (either medication-naïve or under withdrawal), DAT was still increased in PUT, but not different from controls in CAUD, NSTR and ventral striatum (VSTR). SERT was unaltered in midbrain/pons (MP), but decreased in PUT, thalamus (THAL) and hypothalamus. D2R was unaltered throughout the nigrostriatal and mesolimbocortical system, while DA release was not different from controls in PUT, CAUD and NSTR, but elevated in VSTR. 5-HT2AR binding was unaltered in neocortex and cingulate. In acutely medicated adults, DAT was unaltered in PUT, but still increased in CAUD, whereas DA release remained unaltered throughout the nigrostriatal and mesolimbocortical system. When part of the patients was acutely medicated, vesicular monoamine transporter (VMAT2), DAT, SERT and DA synthesis were not different from controls in striatal regions, whereas D2R was decreased in NSTR, THAL, frontal cortex and limbic regions. Conversely, 5-HT2AR binding was unaltered in striatal regions and THAL, but increased in neocortical and limbic areas. It may be hypothesized that both the DA surplus and the 5-HT shortage in key regions of the nigrostriatal and mesolimbic system are relevant for the bouts of motor activity and the deficiencies in inpulse control.
Article
Introduction Motor reserve refers to the individual capacity to cope with nigrostriatal dopamine depletion in Parkinson's disease (PD). This study aimed to explore the white matter structural network associated with motor reserve in patients with newly diagnosed PD. Methods A total of 238 patients with early-stage drug-naïve PD who underwent ¹⁸F-FP-CIT PET and brain MRI scans at initial assessment were enrolled. We estimated individual motor reserve based on the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) scores and dopamine transporter availability in the posterior putamen using a residual model. Then, we performed threshold-free network-based statistics (TFNBS) analysis to identify the structural brain network associated with the estimated motor reserve. We also assessed the effect of the network connectivity strength on the longitudinal increase in levodopa-equivalent dose (LED). Results The mean age at PD symptom onset was 69.10 ± 9.03 years and the mean UPDRS-III score at the time of PD diagnosis was 22.44 ± 9.72. TFNBS analysis identified a motor reserve-associated structural network whose nodes were mainly in the frontal region and cerebellum. Higher network strength (i.e., greater motor reserve) was associated with a slower longitudinal increase in LED during a 3-year follow-up period. Conclusion The structural brain network is associated with motor reserve in patients with PD. Connectivity strength within the identified network indicates the individual's capacity to tolerate PD-related pathologies, which is maintained with disease progression and affects the long-term motor prognosis of PD.
Article
Tractography combined with regions of interest (ROIs) has been used to non-invasively study the structural connectivity of the cortex as well as to assess the reliability of these connections. However, the subcortical connectome (subcortex to subcortex) has not been comprehensively examined, in part due to the difficulty of performing tractography in this complex and compact region. In this study, we performed an in vivo investigation using tractography to assess the feasibility and reliability of mapping known connections between structures of the subcortex using the test-retest dataset from the Human Connectome Project (HCP). We further validated our observations using a separate unrelated subjects dataset from the HCP. Quantitative assessment was performed by computing tract densities and spatial overlap of identified connections between subcortical ROIs. Further, known connections between structures of the basal ganglia and thalamus were identified and visually inspected, comparing tractography reconstructed trajectories with descriptions from tract-tracing studies. Our observations demonstrate both the feasibility and reliability of using a data-driven tractography-based approach to map the subcortical connectome in vivo.
Article
Patients with obsessive compulsive disorder (OCD) exhibit tremendous heterogeneity in structural and functional neuroimaging aberrance. However, most previous studies just focus on group-level aberrance of a single modality ignoring heterogeneity and multimodal features. On that account, we aimed to uncover OCD subtypes integrating structural and functional neuroimaging features with the help of a multiview learning method and examined multimodal aberrance for each subtype. Ninety-nine first-episode untreated patients with OCD and 104 matched healthy controls (HCs) undergoing structural and functional MRI were included in this study. Voxel-based morphometric and amplitude of low-frequency fluctuation (ALFF) were adopted to assess gray matter volumes (GMVs) and the spontaneous neuronal fluctuations respectively. Structural/functional distance network was obtained by calculating Euclidean distance between pairs of regional GMVs/ALFF values across patients. Similarity network fusion, one of multiview learning methods capturing shared and complementary information from multimodal data sources, was used to fuse multimodal distance networks into one fused network. Then spectral clustering was adopted to categorize patients into subtypes. As a result, two robust subtypes were identified. These two subtypes presented opposite GMV aberrance and distinct ALFF aberrance compared with HCs while shared indistinguishable clinical and demographic features. In addition, these two subtypes exhibited opposite structure-function difference correlation reflecting distinct adaptive modifications between multimodal aberrance. Altogether, these results uncover two objective subtypes with distinct multimodal aberrance and provide a new insight into taxonomy of OCD.
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Groove—defined as the pleasurable urge to move to a rhythm—depends on a fine-tuned interplay between predictability arising from repetitive rhythmic patterns, and surprise arising from rhythmic deviations, for example in the form of syncopation. The perfect balance between predictability and surprise is commonly found in rhythmic patterns with a moderate level of rhythmic complexity and represents the sweet spot of the groove experience. In contrast, rhythms with low or high complexity are usually associated with a weaker experience of groove because they are too boring to be engaging or too complex to be interpreted, respectively. Consequently, the relationship between rhythmic complexity and groove experience can be described by an inverted U-shaped function. We interpret this inverted U shape in light of the theory of predictive processing and provide perspectives on how rhythmic complexity and groove can help us to understand the underlying neural mechanisms linking temporal predictions, movement, and reward. A better understanding of these mechanisms can guide future approaches to improve treatments for patients with motor impairments, such as Parkinson’s disease, and to investigate prosocial aspects of interpersonal interactions that feature music, such as dancing. Finally, we present some open questions and ideas for future research.
Article
Objectives: Chronic occupational manganese (Mn) exposure is characterized by motor and cognitive dysfunction. This study aimed to investigate structural abnormalities in Mn-exposed welders compared to healthy controls (HCs). Methods: Thirty-five HCs and forty Mn-exposed welders underwent magnetic resonance imaging (MRI) scans in this study. Based on T1-weighted MRI, the voxel-based morphometry (VBM), structural covariance, and receiver operating characteristic (ROC) curve were applied to examine whole-brain structural changes in Mn-exposed welders. Results: Compared to HCs, Mn-exposed welders had altered gray matter volume (GMV) mainly in the medial prefrontal cortex, lentiform nucleus, hippocampus, and parahippocampus. ROC analysis indicated the potential highest classification power of the hippocampus/parahippocampus. Moreover, distinct structural covariance patterns in the two groups were associated with regions, mainly including the thalamus, insula, amygdala, sensorimotor area, and middle temporal gyrus. No significant relationships were found between the findings and clinical characteristics. Conclusions: Our findings showed Mn-exposed welders had changed GMV and structural covariance patterns in some regions, which implicated in motivative response, cognitive control, and emotional regulation. These results might provide preliminary evidence for understanding the pathophysiology of Mn overexposure. Key points: • Chronic Mn exposure might be related to abnormal brain structural neural mechanisms. • Mn-exposed welders had morphological changes in brain regions implicated in emotional modulation, cognitive control, and motor-related response. • Altered gray matter volume in the hippocampus/parahippocampus and putamen might serve as potential biomarkers for Mn overexposure.
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Introduction In the early 20th century a link between infection and speech disfluency was discussed. Recent reports indicate that PANS (Pediatric Acute-onset Neuropsychiatric Syndrome), and PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections) may be associated with a high incidence of speech disfluency. The present study specifically investigates disfluency and other speech symptoms following onset of PANS and PANDAS. Prevalence of previously reported speech related symptoms vocal tics, selective mutism and “baby talk” is included. The present study also aims to explore possible changes in articulation and intelligibility, distress due to speech impairment, and effect of PANS or PANDAS medication on speech symptoms. Methods A questionnaire was distributed to caregivers of children with diagnosed or suspected PANS or PANDAS. In total 55 individuals in Sweden were included. Results Onset of speech disfluency in association with PANS or PANDAS was reported by 54.5% of the caregivers. Most frequent disfluency symptoms were higher speech rate, superfluous verbal behavior, verbal blocks and associated motor symptoms. Previous findings of vocal tics, baby talk and mutistic behavior are supported. The present study also exposed previously unreported symptoms such as impaired articulation, reduced intelligibility, reduced speech production and language impairment. Eleven caregivers reported that medical treatment had a positive effect on speech fluency. Conclusions A connection between PANS and PANDAS and speech disfluency is supported, and a possible link between infection and disfluency is reactualized. Reported disfluency shares several characteristics with stuttering and cluttering, but the caregivers did not consistently associate it with stuttering. The present study also sheds new light on how symptoms of “baby talk”, selective mutism and vocal tics might be viewed in this population. In all, the results indicate a substantial impact on speech fluency, speech and language in affected children, reducing quality of life.
Article
Background: Neuroimaging studies have shown that the functional connectivity (FC) of corticostriatal circuits in nonmanifesting leucine-rich repeat kinase 2 (LRRK2) G2019S mutation carriers mirrors neural changes in idiopathic Parkinson's disease (PD). In contrast, neural network changes in LRRK2 G2385R and R1628P mutations are unclear. We aimed to investigate the FC of corticostriatal circuits in nonmanifesting LRRK2 G2385R and R1628P mutation carriers (NMCs). Methods: Twenty-three NMCs, 28 PD patients, and 29 nonmanifesting noncarriers (NMNCs) were recruited. LRRK2 mutation analysis was performed on all participants. Clinical evaluation included MDS-UPDRS. Results: When compared to NMNCs, NMCs showed significantly reduced FC between the caudate nucleus and superior frontal gyrus and cerebellum, and between the nucleus accumbens and parahippocampal gyrus, amygdala, and insula. We also found increased striatum-cortical FC in NMCs. Conclusions: Although the corticostriatal circuits have characteristic changes similar to PD, the relatively intact function of the sensorimotor striatum-cortical loop may result in less possibility of developing parkinsonian motor symptoms for the NMCs. This study helps explain why LRRK2 G2385R and R1628P mutations are risk factors rather than pathogenic mutations for PD and suggests that various LRRK2 mutations have distinct effects on neural networks.
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Background: Serendipity and observations have a noble tradition in medicine, including neurology, and are responsible for many medical treatments (carbamazepine for tic douloureux, amantadine for Parkinson's disease, gabapentin for restless legs…). We aimed at examining the contribution of serendipity and observations to functional neurosurgery. Scholarly publications relevant to the history of functional neurosurgery for movement and psychiatric disorders were reviewed, starting from the pre-stereotactic era. The documents were scrutinized with respect to indications for surgery, surgical methods, and brain targets, in view of determining whether serendipitous discoveries and other observations contributed to various functional neurosurgical procedures. Summary: James Parkinson's observation that tremors disappeared in the arm of a person with shaking palsy after a hemiparetic stroke encouraged neurosurgeons in the first half of the 20th century to perform ablative procedures on central motor pathways. Following a lobotomy performed by Browder that extended too far medially in a psychiatric patient with coexisting Parkinson's disease (PD), it was noted that the Parkinsonian signs improved. This encouraged Russel Meyers to carry out open surgery on the caudate nucleus and basal ganglia in PD. Cooper introduced ligation of the anterior choroidal artery as a treatment for PD following a surgical accident during a pedunculotomy. Cooper later started to perform stereotactic surgery on the ventrolateral thalamus following the pathological finding that an intended pallidal lesion had in fact targeted the thalamus. Leksell discovered the ideal location of a pallidal lesion being in the posteroventral area empirically, long before the advent of the basal ganglia model of PD. Modern Deep Brain Stimulation (DBS) that started in the thalamus for tremor was the result of an observation by Benabid that intraoperative high-frequency stimulation during a thalamotomy reduced tremor. Both the discoveries of the anterior limbic subthalamic nucleus as a DBS target for OCD and the medial forebrain bundle as a DBS target for depression occurred by chance. Hamani and Lozano observed memory flashbacks in a patient who was undergoing DBS for obesity, which led to the discovery of the fornix as a potential DBS target for Alzheimer's disease. Key messages: In the history of functional neurosurgery, serendipity and observations have resulted in discoveries of several procedures, brain targets for lesioning or DBS as well as new clinical surgical indications. In this era of neuromodulation, this technology should be exquisite in allowing potential serendipitous discoveries, provided that clinicians remain both observant and prepared.
Chapter
The amygdala is central for social and emotional processing and has been implicated in various disorders including autism spectrum disorder (ASD) and Alzheimer's disease (AD). Animal research and some limited research with humans has indicated that widespread alterations in neuronal development or neuronal loss in the basolateral and other amygdala subnuclei may be a contributing factor to variations in social behaviours. Yet, the basolateral amygdala is comprised of three subnuclei, each with a specialized role related to the coordination of emotional regulation. Due to their small size, the nuclei which comprise the basolateral amygdala remain understudied in humans in vivo. In this work, we describe methodology to examine the basolateral amygdala and other subnuclei in human ex vivo medial temporal lobe prosections using ultrahigh-field magnetic resonance imaging (MRI) at 9.4 T. Manual segmentations of the amygdala subnuclei on MR images, verified with immunohistochemical data, provide a robust three-dimensional atlas of the human amygdala. The goal is to apply the atlas to in vivo MRI scans to examine basolateral amygdala macrostructural development attributed to social cognitive dysfunction in ASD and other neurodevelopmental disorders. Furthermore, the atlas can be used to examine MRI-based correlates of neuronal loss commonly seen in neurodegenerative disorders.
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Obesity is related to overconsumption of high-calorie (HiCal) food, which is modulated by brain reward and inhibitory control circuitries. The basal ganglia (BG) are a key set of nuclei within the reward circuitry, but obesity-associated functional and structural abnormalities of BG have not been well studied. Resting-state functional MRI with independent component analysis (ICA) and probabilistic tractography were employed to investigate differences in BG-related functional-(FC) and structural connectivity (SC) between 32 patients with obesity (OB) and 35 normal-weight (NW) participants. Compared to NW, OB showed significantly lower FC strength in the caudate nucleus within the BG network, and seed-based FC analysis showed lower FC between caudate and dorsolateral prefrontal cortex (DLPFC), which was negatively correlated with craving for HiCal food cues. Further SC analysis revealed that OB showed lower SC than NW between left caudate and left DLPFC as measured with fractional anisotropy (FA). Alterations in FC and SC between caudate and DLPFC in obese patients, which highlights the role of BG network in modulating the balance between reward and inhibitory-control.
Article
Introduction Perinatal stroke affects millions of children and results in lifelong disability. Two forms prevail: arterial ischemic stroke (AIS), and periventricular venous infarction (PVI). With such focal damage early in life, neural structures may reorganize during development to determine clinical function, particularly in the contralesional hemisphere. Such processes are increasingly understood in the motor system, however, the role of the basal ganglia, a group of subcortical nuclei that are critical to movement, behaviour, and learning, remain relatively unexplored. Perinatal strokes that directly damage the basal ganglia have been associated with worse motor outcomes, but how developmental plasticity affects bilateral basal ganglia structure is unknown. We hypothesized that children with perinatal stroke have alterations in bilateral basal ganglia volumes, the degree of which correlates with clinical motor function. Methods Children with AIS or PVI, and controls, aged 6-19 years, were recruited from a population-based cohort. MRIs were acquired on a 3T GE MR750w scanner. High-resolution T1-weighted images (166 slices, 1mm isotropic voxels) underwent manual segmentations of bilateral caudate and putamen. Extracted volumes were corrected for total intracranial volume. A structure volume ratio quantified hemispheric asymmetry of caudate and putamen (non-dominant/dominant hemisphere structure volume) with ratios closer to 1 reflecting a greater degree of symmetry between structures. Participants were additionally dichotomized by volume ratios into two groups, those with values above the group mean (0.8) and those below. Motor function was assessed using the Assisting Hand Assessment (AHA) and the Box and Blocks test in affected (BBTA) and unaffected (BBTU) hands. Group differences in volumes were explored using Kruskal-Wallis tests, and interhemispheric differences using Wilcoxon. Partial Spearman correlations explored associations between volumes and motor function (factoring out age, and whole-brain white matter volume, a proxy for lesion extent). Results In the dominant (non-lesioned) hemisphere, volumes were larger in AIS compared to PVI for both the caudate (p<0.05) and putamen (p<0.01) but comparable between stroke groups and controls. Non-dominant (lesioned) hemisphere volumes were larger for controls than AIS for the putamen (p<0.05), and for the caudate in PVI (p=0.001). Interhemispheric differences showed greater dominant hemisphere volumes for the putamen in controls (p<0.01), for both the caudate (p<0.01) and putamen (p<0.001) in AIS, and for the caudate (p=0.01) in PVI. Motor scores did not differ between AIS and PVI thus groups were combined to increase statistical power. Better motor scores were associated with larger non-dominant putamen volumes (BBTA: r=0.40, p=0.011), and larger putamen volume ratios (BBTA: r=0.52, p<0.001, AHA: r=0.43, p<0.01). For those with relatively symmetrical putamen volume ratios (ratio > group mean of 0.8), age was positively correlated with BBTA (r=0.54, p<0.01) and BBTU (r=0.69, p<0.001). For those with more asymmetrical putamen volume ratios, associations with motor function and age were not seen (BBTA: r=0.21, p=0.40, BBTU: r=0.37, p=0.13). Conclusion Specific perinatal stroke lesions affect different elements of basal ganglia development. PVI primarily affected the caudate, while AIS primarily affected the putamen. Putamen volumes in the lesioned hemisphere are associated with clinical motor function. The basal ganglia should be included in evolving models of developmental plasticity after perinatal stroke.
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The direct and indirect pathways of the basal ganglia are classically thought to promote and suppress action, respectively¹. However, the observed co-activation of striatal direct and indirect medium spiny neurons² (dMSNs and iMSNs, respectively) has challenged this view. Here we study these circuits in mice performing an interval categorization task that requires a series of self-initiated and cued actions and, critically, a sustained period of dynamic action suppression. Although movement produced the co-activation of iMSNs and dMSNs in the sensorimotor, dorsolateral striatum (DLS), fibre photometry and photo-identified electrophysiological recordings revealed signatures of functional opponency between the two pathways during action suppression. Notably, optogenetic inhibition showed that DLS circuits were largely engaged to suppress—and not promote—action. Specifically, iMSNs on a given hemisphere were dynamically engaged to suppress tempting contralateral action. To understand how such regionally specific circuit function arose, we constructed a computational reinforcement learning model that reproduced key features of behaviour, neural activity and optogenetic inhibition. The model predicted that parallel striatal circuits outside the DLS learned the action-promoting functions, generating the temptation to act. Consistent with this, optogenetic inhibition experiments revealed that dMSNs in the associative, dorsomedial striatum, in contrast to those in the DLS, promote contralateral actions. These data highlight how opponent interactions between multiple circuit- and region-specific basal ganglia processes can lead to behavioural control, and establish a critical role for the sensorimotor indirect pathway in the proactive suppression of tempting actions.
Article
Unilateral dopamine (DA) depletion produces ipsiversive turning behavior, and the injection of DA receptor agonists can produce contraversive turning, but the underlying mechanisms remain unclear. We conducted in vivo recording and pharmacological and optogenetic manipulations to study the role of DA and striatal output in turning behavior. We used a video‐based tracking program while recording single unit activity in both putative medium spiny projection neurons (MSNs) and fast‐spiking interneurons (FSIs) in the dorsal striatum bilaterally. Our results suggest that unilateral DA depletion reduced striatal output from the depleted side, resulting in asymmetric striatal output. Depletion systematically altered activity in both MSNs and FSIs, especially in neurons that increased firing during turning movements. Like D1 agonist SKF 38393, optogenetic stimulation in the depleted striatum increased striatal output and reversed biased turning. These results suggest that relative striatal outputs from the two cerebral hemispheres determine the direction of turning: mice turn away from the side of higher striatal output and towards the side of the lower striatal output.
Chapter
The use of neurophysiological monitoring during surgical procedures has developed extensively in the past decade to become an important adjunctive technique to assist surgical teams and add more safety to surgical treatment approaches. In stereotactic and functional neurosurgery, the outcome results are intimately related to the target definition and adverse effect avoidance. In stereotactic-guided procedures, as in movement disorder surgery, the targets are deep seated in the brain. Therefore, the neurophysiological monitoring aims to avoid damage to the nervous tissue and participates in the decision-making of target localization, improving outcome. Stereotactic localization relies on perioperative imaging, frame-based patient’s head registration, and individual anatomical landmarks. Stereotactic-mounted probes are used for neuronal activity recording (microelectrode recording and local field potential), impedance monitoring, or controlled electrical stimulation to complement final target definition and correct positioning of the deep brain stimulation electrodes. This chapter covers the use of neurophysiological techniques used for movement disorder surgery.
Article
Self‐control is important for long‐term success and could be a protective factor against maladaptive behaviours such as excessive gaming activity or Internet gaming disorder (IGD). However, the neurobiological basis of self‐control and its relationship to IGD remain elusive. Using resting‐state fMRI data from 89 participants aged from 18 to 26, we found that self‐control and the number of IGD symptoms (IGD‐S) were positively and negatively correlated with functional connectivity between right ventral striatum (rVS) and dorsal anterior cingulate cortex (dACC), respectively. A mediation analysis indicated that self‐control influenced IGD‐S partially through the rVS‐dACC connectivity. In addition, step‐wise regression analyses revealed that the rVS connectivity in a reward‐anticipation limbic pathway contributed to IGD‐S but not self‐control, independent of the dACC pathway. These results suggest that the cingulate–ventral striatal functional connectivity may serve as an important neurobiological underpinning of self‐control to regulate maladaptive behaviours such as these manifesting IGD through striatal circuitry balance. The ventral striatum (VS) connectivity to dorsal anterior cingulate cortex (dACC) correlates with both self‐control and IGD. The VS connectivity to the amygdala‐parahippocampus region makes an additional contribution to IGD.
Article
Mapping structural spatial change (i.e., gradients) in the striatum is essential for understanding the function of the basal ganglia in both health and disease. We developed a method to identify and quantify gradients of microstructure in the single human brain in vivo. We found spatial gradients in the putamen and caudate nucleus of the striatum that were robust across individuals, clinical conditions, and datasets. By exploiting multiparametric quantitative MRI, we found distinct, spatially dependent, aging-related alterations in water content and iron concentration. Furthermore, we found cortico-striatal microstructural covariation, showing relations between striatal structural gradients and cortical hierarchy. In Parkinson’s disease (PD) patients, we found abnormal gradients in the putamen, revealing changes in the posterior putamen that explain patients’ dopaminergic loss and motor dysfunction. Our work provides a noninvasive approach for studying the spatially varying, structure-function relationship in the striatum in vivo, in normal aging and PD.
Chapter
This chapter discusses common movement disorders and subtle neurological findings in developmental and psychiatric disorders in childhood, focusing on the three most common conditions likely to be seen in a pediatric movement disorder clinic: attention deficit hyperactivity disorder, obsessive compulsive disorder, and autism spectrum disorder. Understanding the interrelationship between these disorders and movement disorders is important for medical decision making, particular with regard to assessing disease-related impairment and prioritizing therapeutic interventions. Phenomenological overlap with drug-induced movement disorders (Chapter 22) and symptom rating scales area also discussed.
Chapter
The basal ganglia are large subcortical structures comprising several interconnected nuclei in the forebrain, diencephalon, and midbrain. Historically, the basal ganglia have been viewed as a component of the motor system. However, there is now substantial evidence that the basal ganglia interact with all of frontal cortex and with the limbic system. Thus, the basal ganglia likely have a role in cognitive and emotional function in addition to their role in motor control. Indeed, most diseases of the basal ganglia cause a combination of movement, affective, and cognitive disorders with the movement disorder being predominant. The motor circuits of the basal ganglia are better understood than the other circuits, but because of similar organization of the circuitry, conceptual understanding of basal ganglia motor function can provide a useful framework for understanding cognitive and affective function, too.
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The recent paper “Reward is Enough” by Silver, Singh, Precup and Sutton posits that the concept of reward maximisation is sufficient to underpin all intelligence, both natural and artificial, and provides a suitable basis for the creation of artificial general intelligence. We contest the underlying assumption of Silver et al. that such reward can be scalar-valued. In this paper we explain why scalar rewards are insufficient to account for some aspects of both biological and computational intelligence, and argue in favour of explicitly multi-objective models of reward maximisation. Furthermore, we contend that even if scalar reward functions can trigger intelligent behaviour in specific cases, this type of reward is insufficient for the development of human-aligned artificial general intelligence due to unacceptable risks of unsafe or unethical behaviour.
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Brain-computer interfaces provide an artificial link by which the brain can directly interact with the environment. To achieve fine brain-computer interface control, participants must modulate the patterns of the cortical oscillations generated from the motor and somatosensory cortices. However, it remains unclear how humans regulate cortical oscillations, the controllability of which substantially varies across individuals. Here, we performed simultaneous electroencephalography (to assess brain-computer interface control) and functional magnetic resonance imaging (to measure brain activity) in healthy participants. Self-regulation of cortical oscillations induced activity in the basal ganglia-cortical network and the neurofeedback control network. Successful self-regulation correlated with striatal activity in the basal ganglia-cortical network, through which patterns of cortical oscillations were likely modulated. Moreover, basal ganglia-cortical network and neurofeedback control network connectivity correlated with strong and weak self-regulation, respectively. The findings indicate that the basal ganglia-cortical network is important for self-regulation, the understanding of which should help advance brain-computer interface technology. Simultaneous fMRI-EEG in 26 healthy participants indicate that the basal ganglia cortical network and the neurofeedback control network play different roles in self-regulation, providing further insight into the neural correlates for brain-machine interface control and feedback.
Article
Goal-directed locomotion requires control signals that propagate from higher order areas to regulate spinal mechanisms. The corticosubthalamic hyperdirect pathway offers a short route for cortical information to reach locomotor centers in the brainstem. We developed a task in which head-fixed mice run to a visual landmark and then stop and wait to collect the reward and examined the role of secondary motor cortex (M2) projections to the subthalamic nucleus (STN) in controlling locomotion. Our behavioral modeling, calcium imaging, and optogenetics manipulation results suggest that the M2-STN pathway can be recruited during visually guided locomotion to rapidly and precisely control the pedunculopontine nucleus (PPN) of the mesencephalic locomotor region through the basal ganglia. By capturing the physiological dynamics through a feedback control model and analyzing neuronal signals in M2, PPN, and STN, we find that the corticosubthalamic projections potentially control PPN activity by differentiating an M2 error signal to ensure fast input-output dynamics.
Article
Alterations in the structural maturation of the amygdala subnuclei volumes are associated with anxiety behaviors in adults and children with neurodevelopmental and associated disorders. This study investigated the relationship between amygdala subnuclei volumes and anxiety in 233 children and adolescents (mean age = 11.02 years; standard deviation = 3.17) with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and children with obsessive compulsive disorder (OCD), as well as typically developing (TD) children. Parents completed the Child Behavior Checklist (CBCL), and the children underwent structural MRI at 3 T. FreeSurfer software was used to automatically segment the amygdala subnuclei. A general linear model revealed that children and adolescents with ASD, ADHD, and OCD had higher anxiety scores compared to TD children (p < .001). A subsequent interaction analysis revealed that children with ASD (B = 0.09, p < .0001) and children with OCD (B = 0.1, p < .0001) who had high anxiety had larger right central nuclei volumes compared with TD children. Similar results were obtained for the right anterior amygdaloid area. Amygdala subnuclei volumes may be key to identifying children with neurodevelopmental disorders or those with OCD who are at high risk for anxiety. Findings may inform the development of targeted behavioral interventions to address anxiety behaviors and to assess the downstream effects of such interventions.
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The organization of cortical projections to the caudate nucleus was investigated in the rhesus monkey, using the autoradiographic tracing method. Following injections of tritiated leucine and proline into selected pre- and post-Rolandic association areas in the frontal, parietal, occipital and temporal lobes, widespread projections were observed to one, or more typically, more than one of the major subdivisions of the caudate nucleus. When cortical areas having strong reciprocal cortico-cortical connections were compared, a considerable communality of their cortico-caudate projections was noted; depending on the location of the cortical areas, the region of common distribution lay within the head, the body, or the tail of the caudate nucleus. This correlation between cortico-cortical and cortico-striate projections characterized all pairs of cases studied. It suggests a previously undescribed principle of organization within the telencephalon, namely, that areas of cerebral cortex having reciprocal cortico-cortical connections, while having unique overall patterns of projection to the caudate nucleus, project, in part, to one and the same region of the nucleus. This might imply that a given region of the caudate nucleus receives input not only from a particular area of cortex, but also from all other cortical areas reciprocally interconnected with that area.
Article
Monkeys were trained to perform a delayed response (DR) task. A visual cue—placement of food under one of two test objects—was succeded by a delay of 18 sec, during which the test objects were concealed and out of reach. At the end of the delay, the objects were made accessible for choice and, if the choice was correct, for reward.Single unit activity was recorded from thalamic nuclei during DR performance. The parvo- and magnocelularis portions of the nucleus medialis dorsalis (MD) were principally explored. Units spontaneously exhibiting rhytmic firing were commonly observed, particularly in MD pars magnocellularis. According to temporal patterns of firing frequency changes during DR trials, 6 different types of units were distinguished. Approximately one-half of all the units sampled in MD, pars parvocellularis, showed sustained elevations of discharge during the delay. These findings are comparable to those made in a separate study of the prefrontal cortical area to which MD, pars parvocellularis, is connected.The firing changes correlated with the behavioral task are interpreted as manifestations of a functional involvement of MD, together with the prefrontal cortex, in DR performance. The possible nature of this involvement is discussed in relation to the available evidence from anatomical, electrophysiological and behavioral research.
Article
Single or multiple electrolytic lesions were placed in various parts of the head of the caudate nucleus and in the putamen. The degenerated fibers were impregnated with the Nauta technique and followed to their destination. It was found that the lateral areas of the caudate nucleus project to the external segment of the globus pallidus and in lesser degree to the internal segment. Fibers from the middle part of the caudate nucleus end in both segments equally. The most medial caudate regions are connected mainly to the internal segment. The caudatonigral fibers end in the rostral substantia nigra, pars reticulata, and have a similar distribution pattern mediolaterally. This topical organization seems to exist also in the anteroposterior direction. The putamen projects to both segments of the globus pallidus and to the substantia nigra, pars reticulata, posterior to a frontal level through the oculomotor roots. There is a topical arrangement also in the putaminonigral connections anteroposteriorly. The double striatal influence from the caudate nucleus and putamen exerted upon the pallidum and substantia nigra does not overlap since the caudate fibers are distributed in the mediodorsal pallidum, while its ventrolateral remaining part receives connections from the putamen. In the substantia nigra the caudate fibers end in parts rostral to the oculomotor roots and the putaminonigral fibers terminate in areas posterior to this level.
Article
The efferent connections from area 6 and adjacent regions of area 9 were investigated in 9 adult monkeys (Macaca fascicularis) using the autoradiographic technique. Injection fields throughout these regions projected ipsilaterally to area 7 in the parietal lobe, n. caudatus, claustrum, n. ventralis anterior, n. parafascicularis, n. medialis dorsalis, n. reticularis thalami, colliculus superior, griseum centralis, griseum pontis and n. reticularis tegmenti pontis. The dorsolateral and medial aspects of areas 6 and 9 projected to the caudal cingulate gyrus, n. ventralis lateralis pars caudalis and n. interstitialis of Cajal. Axons originating in the ventrolateral cortex of areas 6 and 9 terminated in the orbital cortex. Projections arising from area 6 were traced to area 4, into the ventral bank of the rostral cingulate sulcus, to putamen, n. centralis superior lateralis, area X and its caudal continuation within n. ventralis posterior lateralis pars oralis, to n. ruber pars parvocellularis as well as the bulbar reticular formation. Adjacent prefrontal areas projected to the medial aspect of area 24, to areas 19, 20, 21 and 49/27 and to parts of the lateral thalamic nuclear group. This prefrontal projection pattern was in many respects also seen in cases injected into the dorsolateral portion of area 6, while its medial and ventrolateral subdivisions showed additional projections to n. ventralis medialis, the medial parts of centrum medianum as well as spinal and prorhinal projections, respectively.Furthermore, extensive bilateral connections were found within the frontal lobe, to basal ganglia, n. parafascicularis, n. centralis thalami, n. ruber, griseum pontis, n. reticularis tegmenti pontis, bulbar reticular formation and, more selectively, to colliculus superior and n. medialis dorsalis. Evidence was also presented for direct prefrontal connections to amygdala and corticonigral projections arising from areas 6 and 9. The results are discussed with respect to the intermediate position of area 6 between primary motor and prefrontal cortex as well as to differences of projection patterns within area 6 itself and, in particular, the supplementary motor area.Copyright © 1978 S. Karger AG, Basel
Article
The efferent projections of the subthalamic nucleus were studied with the autoradiographic tracing technique in Rhesus monkey and cat. From the data it appears that the major efferent projections of the nucleus are to the pallidal complex and the substantia nigra. In both monkey and cat, the projection to the pallidal complex is truly massive and is directed at both pallidal segments. The projection field includes an infracommissural part of the pallidal complex bordering on the substantia innominata. In the monkey the termination in the pallidal complex is organized in several characteristic bands oriented parallel to the medullary laminae. The subthalamo-pallidal projection in monkey further appears to be topographically organized. The projections to the substantia nigra is prominent in both cat and monkey though not as massive as that to the pallidal complex. The distribution of termination in the substantia nigra favors the more ventral strata near the cerebral peduncle. In the monkey the terminal distribution appears to avoid regions of the substantia nigra containing pigmented neurons and it is suggested that the subthalamonigral pathway may prefer non-dopaminergic neurons. In addition to the above major projections, sparse projections were noted to the thalamic nuclei ventralis lateralis and ventralis anterior, to the putamen, and to the mesencephalic nucleus tegmenti pedunculopontinus, pars compacta. The findings are discussed.
Article
An atlas of transverse sections of the globus pallidus and striatum was established in macaque with reference to ventricular coordinates. The three-dimensional geometry of the striato-pallidal complex was investigated by means of sagittal and horizontal reconstructions. Both a personal case studied with autoradiography and data from literature were used to analyze the distribution of cortical axons into the striatum. One may distinguish two striatal territories: one, somatotopically arranged, sensorimotor territory extending over the major part of the putamen; and the other, an associative territory, comprising the caudate nucleus and antero-medial and postero-inferior parts of the putamen. The striato-pallido-nigral bundle was studied using Golgi, Perls, and Fink-Heimer techniques. The bundle is described in four parts: prepallidal (subdivided into caudato-pallidal and putamino-pallidal subparts), transpallidal, pallido-nigral, and nigral. The tracing of the limit between the caudate (associative) and putaminal (essentially sensorimotor) territories shows that the two components are of roughly the same size in the pallidum. The data were compared with geometry and orientation of the dendritic arborizatons of large pallidal neurons analyzed in Yelnik et al. (1984). Each pallidal dendritic disc is able to receive axons from a wide region of the striatum. This leads to a convergence on pallidal neurons of striatal axons from different striatal somatotopic strips and from the sensorimotor and associative territories. This is an indication that the globus pallidus may have an integrative role.
Article
The prefrontal corticotectal projection was studied in macaque and cebus monkeys using the horseradish peroxidase technique. Following stereotaxic horseradish peroxidase injections into the superior colliculus, large numbers of retrogradely-labelled corticotectal neurons were observed in the prearcuate frontal eye field cortex, dorsal and ventral convexity and sulcus principalis cortex, as well as on the medial aspect of the prefrontal cortex. These experiments, taken together with anterograde data derived from other cases in which horseradish peroxidase gel implants were made in various subregions of the granular prefrontal cortex, suggested a topographic organization of prefrontal projections to the tectum. Area 8 (frontal eye field) primarily projected to the stratum intermedium. The dorsal sulcus principalis cortex projected most heavily to the deeper stratum intermedium, stratum profundum and central gray matter, and gave rise to a characteristic line of puffs in the dorsal stratum intermedium. The rostral dorsal convexity and medial prefrontal cortex projected primarily to the stratum profundum and central gray matter. The orbitofrontal cortex lacked projections to the superior colliculus and only contained retrogradely-labelled neurons when the injection spread into the central gray matter. It was also observed that prefrontal corticotectal fibers followed 2 divergent routes to the superior colliculus: the classically-described ‘pedunculo-tegmental’ route, and a ‘transthalamic’ pathway.This more detailed description of a major cortical input to the tectum not only contributes to our understanding of the functional organization of both the granular frontal cortex and the colliculus, but suggests anatomical connectivity which may underlie their roles in oculomotor mechanisms.
Article
Although the functional significance of the midprincipalis region is well known, the afferent and efferent connections of this zone, in comparison to the anterior and posterior portions of the cortex lining the principal sulcus, are poorly understood. In 3 animals the retrograde tracer HRP and the anterograde tracers, tritiated proline, lysine and leucine, were injected into the sulcal cortex lining the principal sulcus. The cortex forming the banks of the principal sulcus was divided into anterior, middle and posterior sectors with one animal used for each zone.As expected from previous studies, the heaviest afferents to the cortex forming the principal sulcus were from the parvocellular portions of the medial dorsal nucleus. The medial pulvinar nucleus and the nucleus limitans projected to only the anterior and posterior portions of the cortex lining the principal sulcus. Projections were seen to all 3 sectors from the anterior, midline, intralaminar and lateral thalamic nuclei.Although cells were seen in the hypothalamus following injections in all 3 sectors of the cortex lining the principal sulcus, the heaviest hypothalamic projections were noted after injections into the mid-sector of the cortex. These HRP-positive cells were in the dorsal and lateral hypothalamic area, dorsal medial nucleus and in the lateral mammillary nucleus. These findings link the midprincipalis region with the prefrontolimbic circuit, and suggest that the midprincipalis region, n. medialis dorsalis, the mammillary bodies and perhaps the cingulate gyrus constitute part of an anatomical circuit concerned with memory processes.
Article
The term ‘association cortex’ refers to cerebral cortical regions other than primary motor and sensory areas. Association cortexes differ from the primary cortexes in terms of their laminar organization and their afferent and efferent connections. Because the association areas of the cerebral cortex are relatively remote from peripheral sensory input and direct motor output, they are presumed to subserve complex, integrative functions. Indeed, both clinical and experimental evidence implicate them in many different forms of complex behavior. Furthermore, their maximal development in humans provides additional proof of their relevance to higher functions.
Article
A reordering of priorities applied to the criteria for grouping neuronal populations suggests a simpler conceptual organization of the basal ganglia and telencephalon than that currently in general use. The proposed scheme reduces the emphasis of the obvious geographical divisions imposed by the major white matter bundles and the cerebral ventricle, and emphasizes instead such criteria as a common internal histology, similar input-output patterns and characteristic neurotransmitters.By these reordered criteria, almost the entire telencephalon can be subdivided into three concentric tiers. The outermost tier (tier I) encompasses the structures derived embryologically from the pallium, the neocortex and the allocortex. The second tier (tier II) includes the caudate nucleus, the putamen, the nucleus accumbens septi and parts of the olfactory tubercle. The third tier (tier III) is composed of the external pallidal segment, the internal paltidal segment, the nondopaminergic part of the substantia nigra, and perhaps also parts of the substantial innominata.It is suggested that while many characteristics of the telencephalon and basal ganglia lend themselves to subdivision into ‘sensory’, ‘motor’, ‘associational’ and ‘limbic’ sectors, at least some features of organization appear to transgress such distinctions. The proposed reorganization does not deny the existence of such classical functional and anatomical subdivisions but focuses attention instead on two distinct telencephalic outflow systems each of which appears to serve overlapping and widespread parts of the telecephalon. One outflow system leaves the structures in tier I to influence monosynaptically the diencephalon, mesencephalon, pons, medulla or even the spinal cord, while the other outflow system follows a polysynaptic route with at least two intermediate synapses, the first between the tier I and tier II neurons and a second between the tier II and tier III neurons.Some implications of this perspective perhaps useful to the physiologist, pathologist and clinician are discussed.
Article
By tracing radioactively labeled proteins transported by axonal flow, projections from area 4 to the ipsi- and contralateral neostriatum and claustrum were demonstrated in 7 monkeys. A reversed topographic organization was found on both sides for the corticoneostriatal and corticoclaustral projections. The most extensive terminal field could be observed in the putamen. In contrast, very few area 4 efferents seemed to terminate in the caudate nucleus. This suggests differential functions for the two striatal components in sensorimotor mechanisms. These unexpected results give further evidence for the superior sensitivity of the autoradiographic technique, although the limitations of the new method in delineating the injection field were noted.
Article
In spite of repeated demonstrations by degeneration technics, nigrothalamic fibers have been regarded with some skepticism. Attempts were made to trace- nigral efferent projections in the monkey by autoradiographic technics. Tritiated amino acids (L-leucine, L-lysine and L-proline), injected into portions of the substantia nigra (SN), labeled cells in four regions, designated as, (1) rostrolateral, (2) caudolateral, (3) rostromedial and (4) central. Rostrolateral nigral neurons transported radioactive label preferentially and abundantly to thalamic nuclei; localized isotope was found in parts of three thalamic nuclei, the medial part of the ventral lateral nucleus (VLm), the magnocellular part of the ventral anterior nucleus (VAmc), and the paralaminar part of the dorsomedial nucleus (DMpl). Lateral neurons in the caudal half of the SN transmitted radioactive label to the same thalamic nuclei as rostrolateral nigral neurons. Isotope transported to portions of the striatum was modest and localized. Radioactive label taken up by large cells in the caudal third of the SN was transported to portions of the striatum, but not to thalamic nuclei. Labeled nigral neurons in the medial two-thirds of the rostral half of the SN, and in the middle third of the central part of the SN, transported the label mainly to parts of the caudate nucleus and putamen. In these animals modest radioactive label was seen in VLm and VAmc, but not in other thalamic nucleus. There was no evidence that nigral neurons project to the subthalamic nucleus. No radioactive transport from nigral neurons was detected in the superior colliculus, the midbrain tegmentum, or the red nucleus, and none was transported to more caudal brain stem nuclei. Nigrothalamic fibers arise particularly from cells in rostral and lateral parts of the substantia nigra. While some cells in other parts of the nigra project to thalamic nuclei, these appear scattered and less numerous. Large cells in caudal parts of the SN do not project to thalamic nuclei. These observations confirm nigrothalamic projections to VLm and VAmc, and identify a new nigral projection to part of the dorsomedial nucleus of the thalamus (DMp1). No nigral efferent fibers project to any of the intralaminar thalamic nuclei.
Of the movement-related units in the globus pallidus and entopeduncular nucleus 30--40% show early (more than 500 msec) onsets of their movement-related activity preceding self-initiated 'elbow'-flexing movements in cats. The medial pericruciate motor cortex and the VL-VA thalamic nuclei display similar distributions of onset times, in contrast to the lateral cruciate cortex where 97% of neurons change their activity much later. The possible significance of the early activity is discussed in relation to the notion of 'response set'. It is suggested that these data support the concept that the basal ganglia participate in the enabling and sequencing of movements rather than in directly causing them to occur.
Article
We here report observations on the distribution of acetylcholinesterase (acetylcholine hydrolase, EC 3.1.1.7) in the striatum of the adult human, the rhesus monkey, and the cat. By the histochemical staining methods of Geneser-Jensen and Blackstad and of Karnovsky and Roots, compartments of low cholinesterase activity were identified in parts of the striatum in all three species. In frontal sections, these enzyme-poor zones appeared as a variable number of weakly stained approximately 0.5-mm-wide zones embedded in a darkly stained background. The zones varied in cross-sectional shape from round to elongated and were sometimes branched. They were most prominent in the head of the caudate nucleus. Three-dimensional reconstructions of serial sections through the caudate nucleus in the human and cat suggest that over distances of at least several millimeters, the zones of low enzyme activity form nearly continuous labyrinths.
Article
The anterior cingulate cortex receives thalamic afferents mainly from the midline and intralaminar nuclei rather than the anterior thalamic nuclei. In contrast, the posterior cingulate cortex receives afferents primarily from the anterior thalamic nuclei and from extensive cortical areas in the frontal, parietal, and temporal lobes. These contrasting afferents may provide a structural basis for pain-related functions of the anterior cingulate cortex.
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Monkeys were trained to perform two different motor acts, one involving muscle activity in distal forelimb muscles and the other in proximal forelimb and shoulder girdle muscles. After confirming spatial and temporal dissociation of muscle activity in the two motor acts, single unit activity in the supplementary motor area (SMA) was recorded. SMA neurons related with the distal and proximal forelimb movements were found to be arranged rostrocaudally with a considerable overlap. In the overlapping region, neurons related with the distal movement were located more deeply.
Article
The distribution of prefronto-caudate fibers in the caudate nucleus was studied autoradiographically in monkeys of various ages in which tritiated amino acids had been injected into the middle one-third of the length of the dorsal bank of the principal sulcus. The results indicate that, contrary to previous reports which had suggested a projection to only the head of the caudate nucleus, area 9 of Brodmann projects to the entire length of the nucleus. In the head of the caudate nucleus the cortico-caudate fibers are distributed in a pattern which is remarkable in two respects. First, the grains are not uniformly distributed but rather are segregated into clusters separated from one another by territories in which grain density does not exceed background. Second, individual clusters of grains, circular or elliptical in shape, surround grain free cores. These patterns of fiber distribution within the head of the nucleus are more sharply defined in newborn than in older monkeys. Our findings suggest that the caudate nucleus is organized more as an anatomic and functional mosaic than as the homogeneously organized structure that it is commonly considered to be.
Article
The cells of origin of the corticostriatal projection have been identified in squirrel monkeys by the use of the retrograde horseradish peroxidase method. In the subfields of the somatic sensory, motor, parietal and frontal areas of the cortex, cells projecting to the ipsilateral striatum are relatively sparsely distributed and form a group of small- to medium-sized pyramidal cells with an average somal diameter from area to area of 14-16 μm. Such cells are found only in layer V of the cortex (mainly in the more superficial parts of the layer). Since they are consistently smaller than the pyramidal cells of layer V that project to the brainstem and spinal cord and since they lie outside layer VI which gives rise to corticothalamic axons, the corticostriatal axons are unlikely to be collaterals of axons projecting to other sites. The cells of origin of the'crossed corticostriatal projection are also found in layer V and are pyramidal cells with somal diameters in the same range as above. They are found only in areas 4, 8 and 6. Studies with the anterograde, autoradiographic method in rhesus, cynomologous and squirrel monkeys, indicate that the somatic sensory areas project to most of the antero-posterior extent of the ipsilateral putamen. Subareas 3a, 3b, 1 and 2 of the somatic sensory cortex project to the same region and the projection overlaps similarly extensive projections from the motor and certain other areas of the cortex. However, in each case the pattern of terminal labeling is in the form of interrupted clusters, strips and bands. A single small injection of the cortex is associated with only one or two such clusters of terminal labeling. This seems to imply that individual corticostriatal fibers end in a very restricted manner and that the terminal ramifications of fibers from one cortical area may alternate in the putamen with those arising in other areas.
Article
The efferent projections from the cortical area 8 (frontal eye field) have been re-examined in four adult monkeys (Macaca fascicularis) by injecting small amounts of H3-proline into the rostral bank of sulcus arcuatus and using the autoradiographic tracing technique. Ipsilateral cortical projections could be traced into specific areas of the depths of sulcus principalis, sulcus temporalis superior and sulcus intraparietalis. Label was found contralaterally in area 8. Subcortical connections were observed ipsilaterally to n. caudatus, putamen, claustrum, n. ventralis anterior pars magnocellularis, n. medialis dorsalis pars multiformis and pars densocellularis, n. centralis lateralis and paracentralis, n. parafascicularis, n. pulvinar oralis, zone incerta, n. subthalamicus, pretectal area, colliculus superior and griseum pontis as well as the ipsi- and contralateral n. reticularis tegmenti pontis. Negative results were obtained with respect to the oculomotor nuclei, n. interstitials and Darkschewitsch as well as to the paramedian pontine reticular formation.
Article
Separate groups of monkeys were trained on delayed object alternation, delayed object matching, and delayed color matching, after which half the animals in each group received lesions of the cortex in the principal sulcus, and the other half, lesions of the inferior frontal convexity. The inferior convexity lesions produced severe and lasting impairments on all three tasks, perhaps as a result of the perseverative disorder that has been associated with damage to this region. By contrast, the principal sulcus lesions, which yield such severe deficits on spatial memory tasks, led to only small, transient disruptions on each of the three non-spatial tasks. According to these results, the non-spatial memory deficits that have been found after unrestricted lateral prefrontal lesions are due mainly to damage below the principal sulcus in the inferior prefrontal cortex. The function of the tissue in the principal sulcus itself, on the other hand, appears so far to be limited largely to the spatial modality.
Article
Cortical neurons projecting to cervical and lumbar segments of the spinal cord in five young and one adult monkeys were identified using the retrograde transport method following multiple unilateral injections of horseradish peroxidase (HRP) into the anterior horn at cervical and lumbar levels of the spinal cord. Somatotopically organized labeled neurons were found in the precentral and postcentral gyri, the rostral half of both the medial and dorsal aspects of area 5, the cingulate sulcus within the medial aspect of area 6, and the second somatosensory area within the lateral sulcus. All HRP-positive neurons were confined to cortical layer V or to a depth corresponding to the fifth layer in regions where delineation of cortical layers was obscured due to freezing or sectioning artifacts. Although cross-sectional areas of labeled neurons varied widely within each field, more large labeled neurons were present in the leg than in the arm subdivision of the precentral gyrus. HRP-positive neurons in the first and second somatosensory areas as well as those in the medial aspect of area 5 were of medium size, and those in the primary and supplementary motor areas as well as those within the dorsal aspect of area 5 were of medium or larger size.
Article
Three patients with well-mapped, circumscribed ablations of the medial part of the frontal lobe are reported. A specific clinical evolution in 3 stages was observed: (1) post-operatively there was global akinesia, more prominent contralaterally, with an arrest of speech; (2) recovery occurred suddenly but even then there was severe reduction of spontaneous motor activity contralaterally, an emotional type facial palsy and a reduction of spontaneous speech; (3) long after the operation the only sequela was disturbance of the alternating movements of the hands. The anatomical basis of these disorders appears to be a lesion of the supplementary motor area (SMA). Three main points have been discussed, namely: (1) the nature of the motor disorder which may be a disturbance of the function of the SMA in initiating and sustaining spontaneous and automatic motor activity; (2) the nature of the arrest of speech which appears not to be aphasic; the studies reported in the present paper do not support a left cerebral dominance for the SMA as suggested by previous studies; (3) the method of clinical examination appears to be important in distinguishing between spontaneous and voluntary motor and speech performance. Differences in method may account for differences between our findings and those reported in previous studies.
Article
Three simple demonstrations of prediction in tracking suggest that, when tracking a moving target, normal subjects do not simply follow it from moment to moment, but usually try to predict its future course. Their actions are thus directed, at least partly, towards its expected future movement. These three tests were given to 10 subjects suffering from Parkinson's disease. The results suggest that prediction is not as important a factor in their performance as it is in normals. Eight patients with intention or cerebellar tremor showed a greater degree of prediction in their tracking behaviour, although this was not always as accurate as that of the controls.
Article
The results of this study by the methods of autoradiographic fiber-tracing and retrograde cell-labeling confirm earlier reports of accumbens projections to the globus pallidus and to dorsal strata of the medial half of the substantia nigra. Also in accord with previous autoradiographic evidence, sparser projections could be traced to a variety of subcortical structures implicated in the circuitry of the limbic system: bed nucleus of the stria terminalis, septum, preoptic region, hypothalamus, ventral tegmental area, nuclei paratenialis and mediodorsalis thalami, and lateral habenular nucleus. Contrary to earlier reports, striatopallidal fibers from the accumbens were found to be distributed largely to the subcommissural part of the external pallidal segment (ventral pallidum of Heimer & Wilson, 1975) and to avoid almost entirely the internal pallidal segment (entopeduncular nucleus). Mesencephalic projections from the accumbens largely coincide with those from the preoptic region and hypothalamus; like the latter they prominently involve the region of the out-lying nigral cell groups A10 and A8 and extend caudally beyond the nigral complex to the cuneiform and parabrachial regions of the tegmentum as well as to caudoventral parts of the central grey substance.
Article
Reports from previous works has given different classifications for the nucleus accumbens. There also appears to be a general lack of information regarding the fiber connections of the nucleus. The present investigation was undertaken to clarify the connections of this structure. Silver impregnation methods were used to discern some of the afferent fibers of the nucleus, and autoradiographic techniques were used to locate target areas of efferent projections. Afferents were found to be predominately from the septum. Other sources of possible afferents were the mid cingulate gyrus and the ventral nucleus of the diagonal band. No argyrophilia was observed in the nucleus accumbens following transection of the fornix body, lesions of the anterior orbital frontal cortex or anterior cingulate gyrus. On the basis of grain counts made from autoradiographic studies, the nucleus accumbens projects predominately to the lateral hypothalamus. Counts above background were found in the cingulate gyrus, septum, ventral nucleus of the diagonal band, midline thalamic nuclei, habenula, caudate and substantia nigra. Thus, efferent projections appear to distribute to both limbic and extrapyramidal structures. Considering these connections and the functions reported by various workers the nucleus accumbens may serve as bridge between limbic and extrapyramidal motor systems effecting limbic influence in some movements.
Article
Radioactive amino acids were injected into area 4 in 7 monkeys (Macaca fascicularis). Ipsilateral corticothalamic projections were traced to Olszewski's nucleus ventralis lateralis pars oralis and pars medialis, the nucleus ventralis posterior lateralis pars oralis, the nucleus ventralis posterior medialis and inferior and to the nucleus reticularis. Some fibers appeared to terminate in the ipsilateral nucleus ventralis lateralis pars caudalis, the nucleus lateralis posterior and the nucleus subthalamicus.
Article
Because the globus pallidus gives rise to the principal efferent system of the corpus striatum and is traversed by several fibers systems, attempts were made to study the projections of its cells by autoradiographic technics. Tritiated amino acids (L-leucine, L-proline and L-lysine) were injected into: (1) the medial pallidal segment (MPS), (2) the MPS and the substantia innominata (SI), (3) portions of the MPS and the lateral pallidal segment (LPS) and (4) parts of the putamen. Cells labeled by injections of the MPS transported isotope to thalamic nuclei (ventral anterior, VApc, ventral lateral, VLo and VLm, and the centromedian, CM), the pedunculopontine nucleus (PPN), and the lateral habenular nucleus (Hbl). Labeled cells of the MPS and SI transported isotope to: (1) thalamic nuclei (VLo, VLm and CM), (2) PPN, (3) Hbl, (4) lateral and posterior regions of the hypothalamus, and (5) extensive dorsal regions of the substantia nigra (SN). Comparisons of label transported from uptake of isotope by cells of the MPS, and cells of both pallidal segments, suggest that the LPS projects fibers only to the subthalamic nucleus (STN). Not all regions of the STN appear to receive fibers from the LPS. Selectively labeled neurons of the putamen transport isotope to broad regions of both pallidal segments and to the pars reticulata of the SN. This study suggests that cells of the MPS project profusely and topographically to: (1) the rostral ventral tier thalamic nuclei (VApc, VLo and VLm), (2) lateral portions of CM, and (3) the PPN. Fibers of the lenticular fasciculus appear to terminate preferentially in VLo. Cells in sublenticular portions of SI, and those extending into the medullary laminae of the pallidum, appear to project to: (1) HBl via the stria medullaris, (2) the pars compacta of SN, (3) lateral and posterior regions of the hypothalamus, and (4) the so-called nucleus of the ansa lenticularis. Some fibers from cells of SI appear to join the dorsal stria terminalis, but none enter the inferior thalamic peduncle and none project to any part of the dorsomedial nucleus of the thalamus.
Article
Thalamic afferents to Macaque prefrontal cortex from the mediodorsal nucleus were examined by techniques specific for anterograde degeneration and axoplasmic transport. The sampling procedure employed permits establishing the extent of topographic projections to cortex from subcortical foci for the same brain which was surveyed subsequently in tracing specific neuronal connections by electron microscopy. Topographic and general laminar distribution of thalamic terminals are presented in terms of 3 subareas of prefrontal cortex. The dorsolateral and ventral (orbital) surfaces of prefrontal cortex receive respectively projections from the lateral and medial subdivision of the mediodorsal nucleus. In addition, the medial wall of the frontal lobe, including the dorsomedial part of the lateral convexity, heretofore regarded as athalamic, receives input from the caudal-dorsomedial aspect of the mediodorsal nucleus. Preliminary evidence suggests that axons from the mediodorsal nucleus terminate in the head of caudate nucleus, as Sachs-81 described 65 years ago in the first orthograde study of thalamo-prefrontal cortex connections.
Article
Amygdalostriatal projections have been studied in the monkey with the autoradiographic method for demonstrating axonal transport of tritiated amino acids. Amygdaloid fibers were found to project in a roughly topographical manner to widespread areas of the striatum and ventral striatum, including the nucleus accumbens, the striatal-like portions of the olfactory tubercle, ventral portions of the putamen and ventral and caudal parts of the caudate nucleus. The parvicellular part of the basal nucleus and the amygdalohippocampal area appear to be the major sources of fibers to the nucleus accumbens, whereas projections to the tail of the caudate nucleus seem to arise mainly from the magnocellular part of the basal nucleus. In many of these areas, the amygdalostriatal fibers are concentrated in patches.
Article
The nigrothalamocortical connections and their topography were analyzed by autoradiography and double or triple retrograde labeling with the fluorescent dyes Fast Blue, Diamidino Yellow, and Propidium Iodide. Injections of tritiated leucine into different parts of the substantia nigra (SN) revealed that the medial SN projects to the medial magnocellular subdivisions of the ventral anterior (VAmc) and mediodorsal (MDmc) nuclei of the thalamus while the lateral SN projects to the more lateral and more posterior part of the VAmc, and the paralaminar, parvicellular, and densocellular subdivisions of the mediodorsal nucleus (MDmf, MDpc, and MDdc). With the exception of the MDmf, terminal areas observed in the mediodorsal nucleus were in the form of scattered clusters of grains. Analysis of the thalamus in cases with fluorescent dye injections into the lateral orbital gyrus (Walker's area 11), principal sulcus (area 46), anterior bank of the arcuate gyrus (areas 8 and 45), supplementary motor area (area 6), and motor cortex (area 4) revealed topographic organization of the nigrothalamocortical projection system. The parts of the VAmc and MDmc which receive afferents from the medial part of the SN in turn project to the most anterior regions of the frontal lobe including principal sulcus and orbital cortex. The lateral posterior VAmc, MDmf, MDpc, and MDdc, all of which receive afferents from the lateral part of the SN; project to more posterior regions of the frontal lobe including, in addition to the principal sulcus, the frontal eye field and also areas of the premotor cortex. These findings indicate that the SN has preferential targets in the thalamus and cerebral cortex which are segregated from those of the globus pallidus and cerebellum. Whereas the motor cortex is the primary target of cerebellar output (Asanuma et al., '83b), and the premotor cortex is the target of pallidal output (Schell and Strick, '84), the SN output appears to be directed more anteriorally--to the prefrontal cortex.
Article
Attempts were made to: (1) define the regions of origin of the ansa lenticularis (AL) and the lenticular fasciculus (LF), and (2) determine if particular regions of the medial pallidal segment (MPS) project in an organized fashion to thalamic nuclei. The MPS was divided into rostral and caudal (by a plane through the LF), dorsal and ventral (by an appropriate plane), and medial and lateral (by the accessory medullary lamina) parts. Attempts were made to categorize various lesions of the MPS and degeneration was studied in transverse, sagittal and horizontal sections stained by the Nauta and Wiitanen technics. Corresponding Nissl-stained sections were used to delineate thalamic nuclei. Localized lesions in portions of the MPS (11 rostral and 10 caudal) were worthy of anatomical analysis in 21 monkeys. Data support the thesis that fibers of the AL arise predominantly from the outer part of the MPS and pass ventrally and medially through portions of the inner part of the MPS to their site of emergence. Fibers of the LF appear to arise from the inner part of the MPS and project dorsomedially through the internal capsule. Pallidothalamic projections to the rostral ventral tier thalamic nuclei [the ventral anterior (VApc) and the ventral lateral (VLo)] appear topographically organized in three cardinal dimensions. Rostral parts of the MPS project pre-dominantly to parts of VApc, while caudal parts of the MPS project primarily to parts of VLo. There also is a dorsoventral and mediolateral correspondence in the pallidal projection to VApc and VLo which exhibits overlap. Pallidothalamic projections to the contromedian nucleus (CM) terminate preponderantly in rostral and medial regions of the nucleus, and there appears to be a definite correspondence between parts of the MPS and parts of CM, only in the dorsoventral dimension.
Article
Recent findings on the afferent and efferent connexions of the striatum (the caudate nucleus and putamen) and globus pallidus have been summarized in an orderly sequence. The striatum receives afferent fibres from three main sources, the cerebral cortex, the intralaminar nuclei of the thalamus and the midbrain; the major features of each of these pathways are outlined. The striatum sends efferent fibres to the globus pallidus and the substantia nigra, and the two segments of the globus pallidus in turn project upon the subthalamic nucleus and upon the thalamus and midbrain tegmentum. Through the thalamus the major influence of the striopallidum is upon the motor area of the cerebral cortex, and it is suggested that through the midbrain tegmentum there may also be a descending influence upon the spinal cord. These findings from light microscopical investigations are synthesized with observations made in electron microscopic studies of the striatum and globus pallidus. On the basis of present knowledge of their structure and connexions attention is drawn to several marked similarities between these parts of the basal ganglia and the cerebellum.
Article
Lesions in caudal parts of the substantia nigra (SN) produced in 11 monkeys were localized to lateral, medial and central regions. Resulting degeneration was studied by the Wiitanen technic in transverse and sagittal sections. Ascending nigral efferents project into Forel's field H where they divide into medial and lateral bundles. Fibers of the medial bundle terminate in portions of the ventral lateral (VLm) and ventral anterior (VAmc) thalamic nuclei. Quantitatively larger numbers of fibers project laterally dorsal to, and within, the subthalamic nucleus. These nigral efferents traverse the internal capsule and globus pallidus to enter the putamen (P) and parts of the caudate nucleus (CN). Nigral efferent fibers in the globus pallidus appeared entirely en passage. The location of degeneration in the putamen appeared related to the part of the SN destroyed. An apparent correspondence exists between: (1) lateral parts of SN and dorsal regions of P, and (2) medial parts of SN and ventral regions of P. The pars reticularis of SN gives rise to nigrothalamic fibers while nigrostriatal fibers arise from the pars compacta. Data suggest that reciprocal topographic relationships may exist between nigrostriatal and strionigral projections and that these fibers appear to form a closed feedback loop concerned with dopamine transport. Lesions in SN concomitantly interrupt large numbers of corticotegmental and corticothalamic fibers.