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Quantitative susceptibility mapping (QSM) demonstrates elevated iron content in Parkinson’s disease (PD) patients within the basal ganglia, though it has infrequently been studied in relation to gait difficulties including freezing of gait (FOG). Our purpose was to relate QSM of basal ganglia and extra-basal ganglia structures with qualitative and quantitative gait measures in PD.
This case–control study included PD and cognitively unimpaired (CU) participants from the Comprehensive Assessment of Neurodegeneration and Dementia study. Whole brain QSM was acquired at 3T. Region of interests (ROIs) were drawn blinded manually in the caudate nucleus, putamen, globus pallidus, pulvinar nucleus of the thalamus, red nucleus, substantia nigra, and dentate nucleus. Susceptibilities of ROIs were compared between PD and CU. Items from the FOG questionnaire and quantitative gait measures from PD participants were compared to susceptibilities.
Twenty-nine participants with PD and 27 CU participants were included. There was no difference in susceptibility values in any ROI when comparing CU versus PD (p > 0.05 for all). PD participants with gait impairment (n = 23) had significantly higher susceptibility in the putamen (p = 0.008), red nucleus (p = 0.01), and caudate nucleus (p = 0.03) compared to those without gait impairment (n = 6). PD participants with FOG (n = 12) had significantly higher susceptibility in the globus pallidus (p = 0.03) compared to those without FOG (n = 17). Among quantitative gait measures, only stride time variability was significantly different between those with and without FOG (p = 0.04).
Susceptibilities in basal ganglia and extra-basal ganglia structures are related to qualitative measures of gait impairment and FOG in PD.
The motor thalamus is interconnected with the brainstem, cortex, and basal ganglia and plays major roles in planning, sequencing, and executing action. In this chapter, I highlight roles of input-defined thalamic circuits in motor sequence production and learning. Brainstem–motor thalamic pathways carry efference copy signals important for the production of both innate and learned motor sequences, for example, during saccades, grooming, and birdsong. Basal ganglia thalamocortical loops implement aspects of reinforcement learning, including the generation of motor exploration during vocal babbling. Classic "gating" models of basal ganglia–thalamic transmission fail to explain thalamic discharge during behavior, which instead appears strongly driven by cortical inputs. A challenge going forward is to determine if there are conserved principles of thalamic function across diverse motor thalamic subregions.
The higher-order thalamus (e.g., the pulvinar) is widely thought to play a critical role in its interactions with the neocortex, but identifying precisely what that role is has been somewhat challenging. Here, we describe how a computational approach to understanding the nature of learning and memory in the neocortex suggests three distinct, well-defined contributions of the thalamus: (1) attention, which is perhaps the most widely discussed function of the pulvinar, is supported by a pooled inhibition dynamic involving the thalamic reticular nucleus; (2) predictive learning, where the pulvinar serves as a kind of screen on which predictions are projected, and a temporal difference between predictions and subsequent outcomes can drive error-driven learning throughout the thalamocortical system; and (3) executive function in the circuits involving the frontal cortex, where the mediodorsal (MD) thalamus is largely similar anatomically to the pulvinar and could thus support similar attentional and predictive learning functions, whereas ventral thalamic nuclei receive inhibitory modulation from the basal ganglia, supporting a gating function to regulate action based on a strong competition of Go versus No Go informed by reinforcement learning. Taken together, these important modulatory and learning contributions of the thalamus suggest that a full computational understanding of the neocortex is significantly incomplete without an integration of the thalamic circuitry.
Anxiety can interfere with attention and working memory, which are components that affect learning. Statistical models have been designed to study learning, such as the Bayesian Learning Model, which takes into account prior possibilities and behaviors to determine how much of a new behavior is determined by learning instead of chance. However, the neurobiological basis underlying how anxiety interferes with learning is not yet known. Accordingly, we aimed to use neuroimaging techniques and apply a Bayesian Learning Model to study learning in individuals with generalized anxiety disorder (GAD).
Participants were 25 controls and 14 individuals with GAD and comorbid disorders. During fMRI, participants completed a shape-button association learning and reversal task. Using a flexible factorial analysis in SPM, activation in the dorsolateral prefrontal cortex, basal ganglia, and hippocampus were compared between groups during First Reversal. Beta values from the peak of these regions were extracted for all learning conditions and submitted to repeated measures analyses in SPSS.
Individuals with GAD showed less activation in the basal ganglia and the hippocampus only in the First Reversal compared with controls. This difference was not present in the Initial Learning and Second Reversal.
Given that the basal ganglia is associated with initial learning, and the hippocampus with transfer of knowledge from short to long term memory, our results suggest that GAD may engage these regions to a lesser extent during early accommodation or consolidation of learning, but have no longer term effects in brain activation patterns during subsequent learning.
Iron plays a key role in a broad set of metabolic processes. Iron deficiency is the most common nutritional deficiency in the world, but its neuropsychiatric implications in adolescents have not been examined.
Twelve- to 17-year-old unmedicated females with major depressive or anxiety disorders or with no psychopathology underwent a comprehensive psychiatric assessment for this pilot study. A T1-weighted magnetic resonance imaging scan was obtained, segmented using Freesurfer. Serum ferritin concentration (sF) was measured. Correlational analyses examined the association between body iron stores, psychiatric symptom severity, and basal ganglia volumes, accounting for confounding variables.
Forty females were enrolled, 73% having a major depressive and/or anxiety disorder, 35% with sF < 15 ng/mL, and 50% with sF < 20 ng/mL. Serum ferritin was inversely correlated with both anxiety and depressive symptom severity (r = −0.34, p < 0.04 and r = −0.30, p < 0.06, respectively). Participants with sF < 15 ng/mL exhibited more severe depressive and anxiety symptoms as did those with sF < 20 ng/mL. Moreover, after adjusting for age and total intracranial volume, sF was inversely associated with left caudate (Spearman's r = −0.46, p < 0.04), left putamen (r = −0.58, p < 0.005), and right putamen (r = −0.53, p < 0.01) volume.
Brain iron may become depleted at a sF concentration higher than the established threshold to diagnose iron deficiency (i.e. 15 ng/mL), potentially disrupting brain maturation and contributing to the emergence of internalizing disorders in adolescents.
Progressive brain structural MRI changes are described in schizophrenia and have been ascribed to both illness progression and antipsychotic treatment. We investigated treatment effects, in terms of total cumulative antipsychotic dose, efficacy and tolerability, on brain structural changes over the first 24 months of treatment in schizophrenia.
A prospective, 24-month, single-site cohort study in 99 minimally treated patients with first-episode schizophrenia, schizophreniform and schizoaffective disorder, and 98 matched healthy controls. We treated the patients according to a fixed protocol with flupenthixol decanoate, a long-acting injectable antipsychotic. We assessed psychopathology, cognition, extrapyramidal symptoms and BMI, and acquired MRI scans at months 0, 12 and 24. We selected global cortical thickness, white matter volume and basal ganglia volume as the regions of interest.
The only significant group × time interaction was for basal ganglia volumes. However, patients, but not controls, displayed cortical thickness reductions and increases in white matter and basal ganglia volumes. Cortical thickness reductions were unrelated to treatment. White matter volume increases were associated with lower cumulative antipsychotic dose, greater improvements in psychopathology and cognition, and more extrapyramidal symptoms. Basal ganglia volume increases were associated with greater improvements in psychopathology, greater increases in BMI and more extrapyramidal symptoms.
We provide evidence for plasticity in white matter and basal ganglia associated with antipsychotic treatment in schizophrenia, most likely linked to the dopamine blocking actions of these agents. Cortical changes may be more closely related to the neurodevelopmental, non-dopaminergic aspects of the illness.
Neurodegeneration with brain iron accumulation (NBIA) is a term used for a group of hereditary neurological disorders with abnormal accumulation of iron in basal ganglia. It is clinically and genetically heterogeneous with symptoms such as dystonia, dysarthria, Parkinsonism, intellectual disability, and spasticity. The age at onset and rate of progression are variable among individuals. Current therapies are exclusively symptomatic and unable to hinder the disease progression. Approximately 16 genes have been identified and affiliated to such condition with different functions such as iron metabolism (only two genes: Ferritin Light Chain (FTL) Ceruloplasmin (CP)), lipid metabolism, lysosomal functions, and autophagy process, but some functions have remained unknown so far. Subgroups of NBIA are categorized based on the mutant genes. Although in the last 10 years, the development of whole-exome sequencing (WES) technology has promoted the identification of disease-causing genes, there seem to be some unknown genes and our knowledge about the molecular aspects and pathogenesis of NBIA is not complete yet. There is currently no comprehensive study about the NBIA in Iran; however, one of the latest discovered NBIA genes, GTP-binding protein 2 (GTPBP2), has been identified in an Iranian family, and there are some patients who have genetically remained unknown.
The symptoms of obsessive–compulsive disorder (OCD) are suggestive of cognitive rigidity, and previous work identified impaired flexible responding on set-shifting tasks in such patients. The basal ganglia are central to habit learning and are thought to be abnormal in OCD, contributing to inflexible, rigid habitual patterns of behaviour. Here, we demonstrate that increased cognitive inflexibility, indexed by poor performance on the set-shifting task, correlated with putamen morphology, and that patients and their asymptomatic relatives had common curvature abnormalities within this same structure. The association between the structure of the putamen and the extradimensional errors was found to be significantly familial in OCD proband–relative pairs. The data implicate changes in basal ganglia structure linked to cognitive inflexibility as a familial marker of OCD. This may reflect a predisposing heightened propensity toward habitual response patterns and deficits in goal-directed planning.
The context-based selection of semantic representations is presented as an essential issue in understanding the interpretation of speech meaning. Clinical findings serve to illustrate the role of the thalamus, the basal ganglia, and the cerebellum in processing subtle context-related differences in meaning. The paucity of findings relating to spoken language is emphasized along with the need to specify neuropragmatic principles of context-based activations of semantic and episodic representations. With a view on developing such principles, several relevant findings are reviewed relating to cortico-thalamic interactions and the pivotal role of the motor thalamus in integrating multisensory information from basal-ganglia circuits and the cerebellum. The on-line selection of semantic and episodic representations is also discussed in terms of experiments on the role of the hippocampus and frontal circuits suggesting some parallels with navigation, but the on-line processing of speech requires a chunking of action-related sequences which appears to involve the basal ganglia and critical cortico-thalamic loops.
Why do we run toward people we love, but only walk toward others? Why do people in New York seem to walk faster than other cities? Why do our eyes linger longer on things we value more? There is a link between how the brain assigns value to things, and how it controls our movements. This link is an ancient one, developed through shared neural circuits that on one hand teach us how to value things, and on the other hand control the vigor with which we move. As a result, when there is damage to systems that signal reward, like dopamine and serotonin, that damage not only affects our mood and patterns of decision-making, but how we move. In this book, we first ask why, in principle, evolution should have developed a shared system of control between valuation and vigor. We then focus on the neural basis of vigor, synthesizing results from experiments that have measured activity in various brain structures and neuromodulators, during tasks in which animals decide how patiently they should wait for reward, and how vigorously they should move to acquire it. Thus, the way we move unmasks one of our well-guarded secrets: how much we value the thing we are moving toward.
To investigate the frequency of bradykinesia in patients with obsessive-compulsive disorder (OCD) and to see whether patients with OCD who also have bradykinesia display distinctive neuropsychological and neuropsychiatric features.
We studied 23 antipsychotic-free patients with OCD and 13 healthy controls. Bradykinesia was assessed with section III of the Unified Parkinson Disease Rating Scale. The Wechsler Adult Intelligent Scales-Revised (WAIS-R) was used to assess the Full Scale IQ and to measure visuospatial, visuoconstructional ability and psychomotor speed/mental slowness.
Of the 23 patients with OCD studied, 8 (34%) had mild symptoms of bradykinesia. No relationship was found between bradykinesia and the sociodemographic variables assessed but this motor symptom was significantly associated with the severity of compulsions. Patients with bradykinesia differed from those without: they had a higher frequency of repeating compulsions, and lower IQ scores, performance scores, and WAIS-R subtest scores for similarities and picture completion. No significant differences were found between patients without bradykinesia and healthy controls in any test.
Clinical assessment of motor symptoms in adult patients with OCD often discloses mild bradykinesia sometimes associated with repeating compulsions and poor WAIS-R performance scores.
It has been shown these last years that optogenetic tool, that uses a combination of optics and genetics technics to control neuronal activity with light on behaving animals, allows to establish causal relationship between brain activity and normal or pathological behaviors . In combination with animal model of neuropsychiatric disorder, optogenetic could help to identify deficient circuitry in numerous pathologies by exploring functional connectivity, with a specificity never reached before, while observing behavioral and/or physiological correlates. To illustrate the promising potential of these tools for the understanding of psychiatric diseases, we will present our recent study where we used optogenetic to block abnormal repetitive behavior in a mutant mouse model of obsessive-compulsive disorder . Using a delay-conditioning task we showed that these mutant mouse model had a deficit in response inhibition that lead to repetitive behaviour. With optogenetic, we could stimulate a specific circuitry in the brain that connect the orbitofrontal cortex with the basal ganglia; a circuitry that has been shown to be dysfunctional in compulsive behaviors. We observed that these optogenetic stimulations, through their effect on inhibitory neurons of the basal ganglia, could restore the behavioral response inhibition and alleviate the compulsive behavior. These findings raise promising potential for the design of targeted deep brain stimulation therapy for disorders involving excessive repetitive behavior and/or for the optimization of already existing stimulation protocol .
The polymorphism rs1006737 within the CACNA1C gene is associated with increased risk for bipolar disorder (BD) and variations in brain morphology and function of subcortical regions. Here we sought to investigate the influence of CACNA1C polymorphism on key subcortical brain structures implicated in the pathophysiology of BD.
Structural magnetic resonance imaging scans were acquired from 41 euthymic patients with BD and 40 healthy controls, who were also genotyped for the CACNA1C rs1006737 polymorphism. The effect of diagnosis, genotype and their interaction was examined in predefined volumes of interest in the basal ganglia, hypothalamus and amygdala extracted using SPM5.
Carriers of the CACNA1C rs1006737 risk allele showed increased grey matter density in the right amygdala and right hypothalamus irrespective of diagnosis. An interaction between genotype and diagnosis was observed in the left putamen which was smaller in BD patients carrying the risk allele than in healthy controls.
The CACNA1C rs1006737 polymorphism influences anatomical variation within subcortical regions involved in emotional processing.
Deep Brain Stimulation (DBS) has gained a revival for psychiatric disorders after its application in the SubThalamic Nucleus (STN) for neurological disorders such as Parkinson's disease. The involvement of STN in non-motor processes has also been demonstrated and led to target it for the treatment of obsessive-compulsive disorders. In the context of another disease related to loss of impulse control, addiction, we suggest STN to be an appropriate target. We have tested the effects of STN “inactivation” by lesions or DBS in rats on motivation for food (sucrose), cocaine, heroin, alcohol and nicotine. Inactivation of the STN does not affect consummatory processes, but seems to act on incentive motivation (responses to cues associated with a given reward). STN inactivation can induce opposite effects on motivation for natural reward or for various drugs of abuse, decreasing motivation for drugs, while increasing motivation for sweet food reward [1,2]. STN inactivation by either lesion or DBS can also prevent the loss of control over cocaine or alcohol intake, as assessed in the model of escalation of drug intake. These data, in line with clinical observation in Parkinsonian patients suffering from addiction to their dopaminergic treatment, support our hypothesis that STN could be an interesting target for the treatment of addiction and DBS could be the appropriate surgical tool.
The basal ganglia represents a key component of the pathophysiological model for obsessive-compulsive disorder (OCD). This brain region is part of several neural circuits, including the orbitofronto-striatal circuit and dorsolateral prefronto-striatal circuit. There are, however, no published studies investigating those circuits at a network level in non-medicated patients with OCD. Resting state functional magnetic resonance imaging scans were obtained from 20 non-medicated patients with OCD and 23 matched healthy volunteers. Voxelwise statistical parametric maps testing strength of functional connectivity of three striatal seed regions of interest (ROIs) with remaining brain regions were calculated and compared between groups. We performed additional correlation analyses between strength of connectivity and the severity scores for obsessive-compulsive symptoms, depression, and anxiety in the OCD group. Positive functional connectivity with the ventral striatum was significantly increased (Pcorrected <.05) in the orbitofrontal cortex, ventral medial prefrontal cortex and dorsal lateral prefrontal cortex of subjects with OCD. There was no significant correlation between measures of symptom severity and the strength of connectivity (Puncorrected <.001). This is the first study to investigate the corticostriatal connectivity in non-medicated patients with OCD. These findings provide the first direct evidence supporting a pathophysiological model involving basal ganglia circuitry in OCD.
Motion is a behavior involving a motor act programmed and executed in a particular cognitive and emotional context. Deep structures of the brain, including the basal ganglia, appear to play a crucial role in the integration of these three kinds of cortex information (motion, cognition, emotion). Through its organization, the basal ganglia system enables learning and memorization of behavioral sequences, which can then be executed as routines. Their dysfunctions seem to be associated with many psychopathological situations. Thus, tics in Tourette's syndrome (TS) can be seen as a control routines defect that may result from wiring anomaly between the cortex and the basal ganglia. By precisely targeting deep brain circuits implicated in psychiatric disorders, deep brain stimulation (DBS) offers hope for the alleviation of severe illnesses resistant to drug therapies and provides a novel tool to investigate the neuroanatomic and physiological bases of certain disorders, including Obsessive-Compulsive Disorder (OCD) and TS, for which early results indicate positive therapeutic outcomes, even during the long-term follow-up. The pathophysiologies of OCD and of TS share dysfunctions of the associative and limbic circuits running between cortical and sub-cortical structures. Recent pathophysiological hypotheses suggest that TS symptoms result from a dysfunction of the basal ganglia circuitry, notably of the ventral striatum. These data are consistent with the supposed function of cortico-basal ganglia circuits in habit learning and routine performance of habits. Based on early reports indicating that high-frequency stimulation of structures along the cortico-basal ganglia axis might be effective in alleviating TS symptoms, DBS is being tested across the world at several nodes of this circuit, including the pallidum, and thalamus. Increasing our knowledge of the functional organization of the cortico-basal ganglia circuits and of their dysfunction in pathological repetitive behaviors would certainly contribute to better define the surgical therapeutic targets, thereby improving available treatments.
Science explains how marijuana produces the experience of being high after Herkenham mapped location of the densest concentrations of CB1 receptors. The hippocampus, amygdala, and basal ganglia/cerebellum have especially dense cannabinoid receptors and THC impacts the functions produced by these areas in conspicuously noticeable ways. The hippocampus produces short term memory, an important element in learning. Reduced working memory is the most documented cognitive impairment caused by acute marijuana use. The endocannabinoid system is also uniquely responsible for forgetting negative experiences. The amygdala modulates anxiety, appetites, the sense of novelty and the hypothalamus. When THC stimulates the amygdala, most people experience relaxation, hunger (“munchies”) and altered sensory experience due to dishabituation to stimuli. Hypothalamic modulation by the amygdala results in reduction of the stress response, leading to the “chill” of being high. And genetic differences in CB1 density determines aspects of temperament. Supranormal stimulation of CB1 receptors in the basal ganglia reduces spontaneous motor activity and THC stimulation of the cerebellum reduces fine motor control and alters the sense of time and driving skills. The experience of being high is the culmination of altered brain function in the above areas with the highest CB1 density.
Obsessive compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive ritualistic behaviors and has been associated with diverse functional brain abnormalities. We sought to synthesize current evidence from functional magnetic resonance imaging (fMRI) studies and examine their alignment to pathogenetic models of OCD. Following systematic review, we identified 54 task-fMRI studies published in the last decade comparing adults with OCD (n = 1186) to healthy adults (n = 1159) using tasks of affective and non-affective cognition. We used voxel-based quantitative meta-analytic methods to combine primary data on anatomical coordinates of case-control differences, separately for affective and non-affective tasks. We found that functional abnormalities in OCD cluster within cortico-striatal thalamic circuits. Within these circuits, the abnormalities identified showed significant dependence on the affective or non-affective nature of the tasks employed as circuit probes. In studies using affective tasks, patients overactivated regions involved in salience, arousal and habitual responding (anterior cingulate cortex, insula, caudate head and putamen) and underactivated regions implicated in cognitive and behavioral control (medial prefrontal cortex, posterior caudate). In studies using non-affective cognitive tasks, patients overactivated regions involved in self-referential processing (precuneus, posterior cingulate cortex) and underactivated subcortical regions that support goal-directed cognition and motor control (pallidum, ventral anterior thalamus, posterior caudate). The overall pattern suggests that OCD-related brain dysfunction involves increased affective and self-referential processing, enhanced habitual responding and blunted cognitive control.
The exact role of the basal ganglia in both the motor and non-motor domains has proven elusive since it is virtually impossible to refer to its function in isolation of cortical, and especially frontal cortical circuits. The result is that we often speak of frontal-striatal circuits and functions but this still leaves us in the dark when trying to specify basal ganglia information processing. A critical review of the data from both basic science and clinical studies suggests that we should break down processing along a temporal continuum, including the domains of context, sequential information processing, and feedback or reinforcement (i.e., the consequences of action). This analysis would cut across other theoretical constructs, such as attention, central executive, memory, and learning functions, traditionally employed in the neuropsychological literature. Under specified behavioral constraint, the basal ganglia can then be seen to be involved in fundamental aspects of attentional control (often covert), in the guidance of the early stages of learning (especially reinforcement-based, but also encoding strategies in explicit paradigms), and in the associative binding of reward to cue salience and response sequences via dopaminergic mechanisms. Parkinson’s disease is considered to offer only a limited view of basal ganglia function due to partial striatal depletion of dopamine and the potential involvement of other structures and transmitters in its pathology. It is hoped that the present formulation will suggest new heuristic research strategies for basal ganglia research, permitting a closer link to be established between neurophysiological, functional imaging and neuropsychological paradigms. (JINS, 2003, 9, 103–127.)