Neurological Basis Research Articles

Altered Functional Connectivity of the Primary Visual Cortex in Adult Comitant Strabismus: A Resting-State Functional MRI Study

ABSTRACTPurpose: The aim of this study was to examine the functional connectivity between the primary visual cortex and other cortical areas during rest in normal subjects and patients with comitant strabismus using functional magnetic resonance imaging (fMRI).Methods: A prospective, observational study was conducted. Ten patients with comitant exotropia and eleven matched healthy subjects underwent resting-state fMRI with their eyes closed. Resting-state fMRI was performed using a 3.0 T MR scanner. The primary visual cortex was subdivided into anterior and posterior subdivisions. The resting-state functional connectivities within the primary visual cortex and between the primary visual cortex and other cortical areas were calculated for each group and compared between the strabismic and normal control groups. fMRI data were analyzed using Statistical Parametric Mapping software and Analysis of Functional NeuroImages software.Results: Compared with the normal controls, patients with comitant strabismus had increased functional connectivity between the posterior primary visual cortex and other cortical areas, especially the visual cortex [Brodmann area 19 (BA19)] and other oculomotor regions, such as the frontal eye field (BA6).Conclusions: The fMRI results suggest that ongoing and permanent cortical changes occur in patients with comitant strabismus. Disrupted brain functional connectivities are associated with abnormal eye movement and loss of stereopsis. Our study provides a neurological basis for understanding the pathophysiology of comitant strabismus, which may prompt new areas of research to more precisely define this basis and extend these findings to enhance diagnosis and treatment.

A Moderately Pessimistic Perspective on “Cooperative Naturalism”

Murray Smith’s plea for a “cooperative naturalism” that adopts a “triangulational” approach to issues in film studies is both timely and well-defended. I raise three concerns, however: one is external, relating to this strategy’s limitations, and two are internal, relating to Smith’s application of the strategy. While triangulation seems appropriate when we ask about the nature of film experience, other philosophical questions about film have an ineliminable normative dimension that triangulation cannot address. Empirically informed philosophical reflection upon the arts must be “moderately pessimistic” in recognizing this fact. The internal concerns relate to Smith’s claims about the value and neurological basis of cinematic empathy. First, while empathy plays a central role in film experience, I argue that its neurological underpinnings fail to support the epistemic value he ascribes to it. Second, I question Smith’s reliance, in triangulating, upon the work of the Parma school on “mirror neurons.”

Tourette Syndrome

Tourette syndrome (TS) is a neurodevelopmental disorder. TS was formerly considered to be a psychogenic disease; however, TS has recently been thought to be a heterogeneous disease with neurological bases and involving environmental and genetic factors. For example, it has been suggested that neurotransmitters including dopamine and cortico-striato-thalamo-cortical circuits are suggested to be associated with TS pathogenesis. According to these recent evidence, in addition to pharmacotherapy as the standard treatment, deep brain stimulation is being applied for patients with treatment-refractory TS in clinical settings.

Brain activity associated with social exclusion overlaps with drug-related frontal-striatal circuitry in cocaine users: A pilot study

BackgroundExposure to various types of stress can elevate craving for cocaine and hasten relapse among substance dependent individuals. This investigation evaluated the effects of social exclusion on brain activity in cocaine dependent individuals. MethodForty three individuals (18 crack-cocaine users, 25 controls) were recruited from the community to participate in functional neuroimaging study in which they performed a simulated 3 person ball-tossing game (Cyberball). Each participant was told that the other 2 players were in nearby MRI scanners. Task blocks included: Inclusion (likelihood of our participant receiving the ball = 50%), Exclusion (likelihood gradually decreases to 0%), and Rest. Self-worth variables (e.g self-esteem, locus of control) were measured before and after the ball-tossing game. General linear model-based statistics were used to measure the brain response to inclusion and exclusion within and between the groups with respect to rest. ResultsRelative to controls, cocaine users had significantly more activity during Exclusion versus Inclusion in 3 areas: the right medial frontal gyrus (Brodmann Area 9,10), left ventral lateral frontal gyrus (Brodmann Area 10,47) and right caudate. This was driven by a higher response to social exclusion in the cocaine users. There was no difference between groups in the brain reactivity to social inclusion. ConclusionCocaine dependent individuals have an amplified brain response to social exclusion stress in cortical regions associated with emotional regulation, arousal, craving and perception of physical pain. These data suggest that there may be a neurological basis for the well-established relationship between social stress and addiction.

Music Treatment for Anhedonia in Major Depressive Disorder: Implications for Therapeutic Interventions

This is a literature review examining the prospect of music as a treatment for anhedonia in major depressive disorder. It delves into the neural circuitry and neurological basis for pleasure, music, and anhedonia. Using the literature, it then explores the relationship among the three and the implications that these connections could have.

A Novel FES Strategy for Poststroke Rehabilitation Based on the Natural Organization of Neuromuscular Control.

The past decades have witnessed remarkable progress in neural technologies such as functional electrical stimulation (FES) and their applications in neurorehabilitation and neuromodulation. These advances are powered by new neuroscientific understandings of the organization and compositionality of neuromuscular control illuminating how muscle groups may be activated together as discrete units known as muscle synergies. These parallel developments have promoted novel approaches to clinical rehabilitation for neurological disorders that are insurmountable to current treatments. One such breakthrough is the evolution of FES as a therapeutic tool in poststroke rehabilitation with an interventional strategy particularly inspired by the concept that muscles in humans may be purposefully coordinated through neuromotor modules represented as muscle synergies. This paper will review recent advances in multichannel FES technology, its potential applications in poststroke rehabilitation, new findings that support the neurological basis of the muscle synergies for generating natural motor tasks, and the application of the muscle-synergy concept in poststroke assessment and rehabilitation of motor impairment. Finally, we will recommend future directions of development in relation to assistive FES and synergy-driven adaptive training for poststroke rehabilitation.

Is there a burden attached to synaesthesia? Health screening of synaesthetes in the general population

Synaesthesia has long been considered a benign alternative form of perception most often associated with positive rather than negative outcomes. The condition has been associated with a variety of cognitive and perceptual advantages, including benefits in memory, processing speed, and creativity. It is not currently recognized in the DSM-IV. Recently, however, several studies have raised the question of a possible link between synaesthesia and clinical conditions. Here, we present the first large-scale screening of the general population in which we (1) objectively identified grapheme-colour synaesthetes and (2) elicited information from our participants about a range of clinical conditions. We compared the prevalence rates of these conditions in synaesthetes versus non-synaesthetes to establish whether any conditions were found at a higher rate among synaesthetes. In our initial study, screening 3,742 people (95 synaesthetes and 3,647 controls), we found initially that grapheme-colour was significantly comorbid with two conditions (anxiety disorder and obsessive compulsive disorder). In our second study, screening a new population of 120 synaesthetes and 166 non-synaesthetes, we replicated our finding that grapheme-colour synaesthesia is comorbid with anxiety disorder. At the same time, we also addressed a methodological concern that likely elevated rates of OCD in Study 1. We consider the aetiology of synaesthesia to determine whether there may be a shared genetic or neurological basis with anxiety disorder, and we question the status of synaesthesia within a mental health framework.

Neuroprogression: the hidden mechanism of depression.

For many years, depressive disorder (DD) was considered a transient and natural disease of people’s mood. Its etiology had been attributed mainly to biochemical alterations of the monoamines and their receptors. Nevertheless, its prevalence and considerable impact on the family and social environment of those afflicted by it have placed the disease as a global public health problem. Neuroprogression is the term used to describe the changes in several psychiatric conditions evidenced and observed in the clinical manifestations, biochemical markers, and cerebral structures of the patients with major depressive disorder (MDD), which frequently overlap with neurodegenerative disorders. DD is considered a potentially aggressive state of neuronal deterioration involving apoptosis, reduced neurogenesis, decreased neuronal plasticity, and increased immune response. Clinically, it encompasses a poor response to treatment and an increase in depressive episodes, both of which bring about vulnerability and decline of functions associated with structural changes in the brain. The interest of this work is to review the metabolic processes involved in the morphologic alterations in the limbic system reported in patients with MDD, as well as the neurologic bases of this complex pathology that include environmental stress, genetic vulnerability, alterations in the neurotransmission, and changes in the neuroplasticity, all of which today bring into limelight a mechanism of progressive neuronal damage.

Intrinsic connectivity networks underlying individual differences in control-averse behavior.

When people sense that another person tries to control their decisions, some people will act against the control, whereas others will not. This individual tendency to control-averse behavior can have far-reaching consequences, such as engagement in illegal activities or noncompliance with medical treatments. Although individual differences in control-averse behavior have been well documented in behavioral studies, their neurological basis is less well understood. Here, we use a neural trait approach to examine whether individual differences in control-averse behavior might be linked to stable brain-based characteristics. To do so, we analyze the association between intrinsic connectivity networks as measured by resting state functional magnetic resonance imaging and control-averse behavior in an economic exchange game. In this game, subjects make choices that are either free or controlled by another person, with real consequences to both interaction partners. We find that the individual level of control-averse behavior can be positively predicted by intrinsic connectivity within the salience network, but not the central executive network or the default mode network. Specifically, subjects with a more prominent connectivity hub in the dorsal anterior cingulate cortex show greater levels of control-averse behavior. This finding provides the first evidence that the heterogeneity in control-averse behavior might originate in systematic differences of the stable functional brain organization.

Evaluating Functional Connectivity Alterations in Autism Spectrum Disorder Using Network-Based Statistics.

The study of resting-state functional brain networks is a powerful tool to understand the neurological bases of a variety of disorders such as Autism Spectrum Disorder (ASD). In this work, we have studied the differences in functional brain connectivity between a group of 74 ASD subjects and a group of 82 typical-development (TD) subjects using functional magnetic resonance imaging (fMRI). We have used a network approach whereby the brain is divided into discrete regions or nodes that interact with each other through connections or edges. Functional brain networks were estimated using the Pearson’s correlation coefficient and compared by means of the Network-Based Statistic (NBS) method. The obtained results reveal a combination of both overconnectivity and underconnectivity, with the presence of networks in which the connectivity levels differ significantly between ASD and TD groups. The alterations mainly affect the temporal and frontal lobe, as well as the limbic system, especially those regions related with social interaction and emotion management functions. These results are concordant with the clinical profile of the disorder and can contribute to the elucidation of its neurological basis, encouraging the development of new clinical approaches.

Reduced structural complexity of the right cerebellar cortex in male children with autism spectrum disorder.

The cerebellum contains 80% of all neurons in the human brain and contributes prominently to implicit learning and predictive processing across motor, sensory, and cognitive domains. As morphological features of the cerebellum in atypically developing individuals remain unexplored in-vivo, this is the first study to use high-resolution 3D fractal analysis to estimate fractal dimension (FD), a measure of structural complexity of an object, of the left and right cerebellar cortex (automatically segmented from Magnetic Resonance Images using FreeSurfer), in male children with Autism Spectrum Disorders (ASD) (N = 20; mean age: 8.8 years old, range: 7.13–10.27) and sex, age, verbal-IQ, and cerebellar volume-matched typically developing (TD) boys (N = 18; mean age: 8.9 years old, range: 6.47–10.52). We focus on an age range within the ‘middle and late childhood’ period of brain development, between 6 and 12 years. A Mann-Whitney U test revealed a significant reduction in the FD of the right cerebellar cortex in ASD relative to TD boys (P = 0.0063, Bonferroni-corrected), indicating flatter and less regular surface protrusions in ASD relative to TD males. Consistent with the prediction that the cerebellum participates in implicit learning, those ASD boys with a higher (vs. lower) PIQ>VIQ difference showed higher, more normative complexity values, closer to TD children, providing new insight on our understanding of the neurological basis of differences in verbal and performance cognitive abilities that often characterize individuals with ASD.

The putative glymphatic signature of chronic fatigue syndrome: A new view on the disease pathogenesis and therapy

The underlying pathophysiology of chronic fatigue syndrome remains incompletely understood and there are no curative treatments for this disorder at present. However, increasing neuroimaging evidence indicates that functional and structural abnormalities exist in the brains of chronic fatigue syndrome patients, suggesting that the central nervous system is involved in this disorder and that at least some chronic fatigue syndrome patients may have an underlying neurological basis for their illness. In the present paper, we speculate that glymphatic dysfunction, causing toxic build up within the central nervous system, may be responsible for at least some cases of chronic fatigue syndrome. We further postulate that cerebrospinal fluid diversion such as lumboperitoneal shunting may be beneficial to this subgroup of patients by restoring glymphatic transport and waste removal from the brain. Although recent evidence indicates that at least some chronic fatigue syndrome patients may benefit from cerebrospinal fluid drainage, further studies are needed to confirm this finding and to determine whether this can be attributed to enhancement of glymphatic fluid flow and interstitial fluid clearance. If confirmed, this could offer promising avenues for the future treatment of chronic fatigue syndrome. Clearly, given the relative invasive nature of cerebrospinal fluid diversion, such procedures should be reserved for chronic fatigue syndrome patients who are severely debilitated, or for those with severe headaches. Anyhow, it seems worthwhile to make every effort to identify new therapies for patients who suffer from this devastating disease, especially given that there are currently no effective treatments for this condition.

Long-term effects of curcumin in the non-human primate brain

Curcumin has recently been shown to be a potential treatment for slowing or ameloriating cognitive decline during aging in our nonhuman primate model of normal aging. In these same monkeys, we studied for the first time the neurological impacts of long-term curcumin treatments using longitudinal magnetic resonance imaging (MRI). Sixteen rhesus monkeys received curcumin or a vehicle control for 14–18 months. We applied a combination of structural and diffusion MRI to determine whether the curcumin resulted in structural or functional changes in focal regions of the brain. The longitudinal imaging revealed decreased microscale diffusivity (mD) measurements mainly in the hippocampus and basal forebrain structures of curcumin treated animals. Changes in generalized fractional anisotropy (GFA) and grey matter density (GMd) measurements indicated an increased grey matter density in cortical ROIs with improved white matter integrity in limbic, cerebellar, and brain stem regions. These findings suggest that noticeable changes in the neuronal environment could be induced from long-term curcumin treatments. Results may provide a neurological basis on the recent findings demonstrating improved spatial working memory and motor function in nonhuman primates.

Causal and functional interpretation of mu- and delta-opioid receptor profiles in mesoaccumbens and nigrostriatal pathways of an oral stereotypy phenotype

Spontaneous stereotypic behaviours are repetitive, compulsive, topographically invariant response patterns commonly observed in captive or domestic animals, which have been linked to dysfunction of basal ganglia input/output pathways. There is evidence that endogenous opioids play a key regulatory role in basal ganglia direct and indirect pathways, but their precise role, both causally and functionally, in spontaneous stereotypic behaviour is unclear. Here we examined the profile of mu- and delta-opioid receptors (density [Bmax] and affinity [Kd]) of basal ganglia structures in stereotypy (n = 10) and non-stereotypy (n = 10) animals using a competitive ligand binding approach. Mu receptor densities were significantly higher in the nucleus accumbens (p < 0.001), ventral tegmentum area (p < 0.001) and caudate nuclei (p < 0.001) of stereotypy compared to control animals. No differences were observed for delta Bmax values in any of the brain regions studied (p > 0.15). Receptor binding affinity was only found to be significantly different between control and stereotypy animals for mu receptors on the caudate region; (p < 0.001). Our findings suggest that increased inhibition (via mu-opioid receptors) of the indirect (dorsal striatopallidal) pathways are associated with spontaneous stereotypy development. Data also suggested that different types of spontaneous stereotypies (e.g. oral versus locomotor) within or a cross species may have a different neurological basis. This may have important implications for understanding the aetiology and function of these behaviours. In some instances (oral stereotypy), the behaviour may be associated with allostasis, a process that could enhance the reward value of appetitive behaviour performance (as a starting point of stereotypy development).

Bayesian Semiparametric Mixed Effects Markov Models With Application to Vocalization Syntax

ABSTRACTStudying the neurological, genetic, and evolutionary basis of human vocal communication mechanisms using animal vocalization models is an important field of neuroscience. The datasets typically comprise structured sequences of syllables or “songs” produced by animals from different genotypes under different social contexts. It has been difficult to come up with sophisticated statistical methods that appropriately model animal vocal communication syntax. We address this need by developing a novel Bayesian semiparametric framework for inference in such datasets. Our approach is built on a novel class of mixed effects Markov transition models for the songs that accommodate exogenous influences of genotype and context as well as animal-specific heterogeneity. Crucial advantages of the proposed approach include its ability to provide insights into key scientific queries related to global and local influences of the exogenous predictors on the transition dynamics via automated tests of hypotheses. The methodology is illustrated using simulation experiments and the aforementioned motivating application in neuroscience. Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.

Regional alterations of cerebral [18F]FDG metabolism in the chronic unpredictable mild stress- and the repeated corticosterone depression model in rats.

Preclinical research has been indispensable in the exploration of the neurological basis of major depressive disorder (MDD). The present study aimed to examine effects on regional brain activity of two frequently used depression models, the chronic unpredictable mild stress (CUMS)- and the chronic corticosterone (CORT) depression model. The CUMS and CORT depression model were induced by exposing male Long-Evans rats to a 4-week procedure of unpredictable mild stressors or a 3-week procedure of chronic corticosterone, respectively. Positron emission tomography with [18F]FDG was performed to determine alterations in regional brain activity. In addition, depressive- and anxiety-like behaviour was assessed via the forced swim test and the open field test, respectively. The chronic CORT administration, but not the CUMS model, significantly induced depressive-like behaviour and elevated plasma corticosterone levels. Compared to control, induction of the CORT depression model resulted in a significantly reduced glucose consumption in the insular cortex and the striatum, and a significantly elevated consumption in the cerebellum and the midbrain. Induction of the CUMS model replicated the findings with respect to the activity in the striatum region, and cerebellum, but missed significance in the insular cortex and the midbrain. Based on the alterations in behaviour and regional [18F]FDG uptake, a superior face validity and construct validity can be observed after induction of depression via chronic CORT injections, compared to the used CUMS paradigm.

Segregating polymorphism in the NMDA receptor gene GRIN2A, schizotypy, and mental rotation among healthy individuals

Common alleles associated with psychiatric disorders are often regarded as deleterious genes that influence vulnerability to disease, but they may also be considered as mediators of variation in adaptively structured cognitive phenotypes among healthy individuals. The schizophrenia-associated gene GRIN2A (glutamate ionotropic receptor NMDA type subunit 2a) codes for a protein subunit of the NMDA (N-methyl-D-aspartate) receptor that underlies central aspects of human cognition. Pharmacological NMDA blockage recapitulates the major features of schizophrenia in human subjects, and represents a key model for the neurological basis of this disorder. We genotyped two functional GRIN2A polymorphisms in a large population of healthy individuals who were scored for schizotypy and mental imagery/manipulation (the mental rotation test). Rare-allele homozygosity of the promoter microsatellite rs3219790 was associated with high total schizotypy (after adjustment for multiple comparisons) and with enhanced mental rotation ability (nominally, but not after adjustment for multiple comparisons), among males. These findings provide preliminary evidence regarding a genetic basis to previous reports of enhanced mental imagery in schizophrenia and schizotypy. The results also suggest that some schizophrenia-related alleles may be subject to cognitive tradeoffs involving both positive and negative effects on psychological phenotypes, which may help to explain the maintenance of psychiatric-disorder risk alleles in human populations.

The Soliton and the Action Potential - Primary Elements Underlying Sentience.

At present the neurological basis of sentience is poorly understood and this problem is exacerbated by only a partial knowledge of how one of the primary elements of sentience, the action potential, actually works. This has consequences for our understanding of how communication within the brain and in artificial brain neural networks (BNNs). Reverse engineering models of brain activity assume processing works like a conventional binary computer and neglects speed of cognition, latencies, error in nerve conduction and the true dynamic structure of neural networks in the brain. Any model of nerve conduction that claims inspiration from nature must include these prerequisite parameters, but current western computer modeling of artificial BNNs assumes that the action potential is binary and binary mathematics has been assumed by force of popular acceptance to mediate computation in the brain. Here we present evidence that the action potential is a temporal compound ternary structure, described as the computational action potential (CAP). The CAP contains the refractory period, an analog third phase capable of phase-ternary computation via colliding action potentials. This would best fit a realistic BNN and provides a plausible mechanism to explain transmission, in preference to Cable Theory. The action potential pulse (APPulse), is made up of the action potential combined with a coupled synchronized soliton pressure pulse in the cell membrane. We describe a model of an ion channel in a membrane where a soliton deforms the channel sufficiently to destroy the electrostatic insulation thereby instigating a mechanical contraction across the membrane by electrostatic forces. Such a contraction has the effect of redistributing the force lengthways thereby increasing the volume of the ion channel in the membrane. Na ions, once attracted to the interior, balance the forces and the channel reforms to its original shape. A refractory period then occurs until the Na ions diffuse from the adjacent interior space. Finally, a computational model of the action potential (the CAP) is proposed with single action potentials significantly including the refractory period as a computational element capable of computation between colliding action potentials.

Memantine rescues prenatal citalopram exposure-induced striatal and social abnormalities in mice

Prenatal exposure to citalopram (CTM), an antidepressant drug, has been associated with altered behavior, including autism-like symptoms in both human and rodent offspring. However, the neurological basis underlying these abnormal behaviors is not well understood. Here, we examined behavioral, morphological, and biochemical alterations in the male and female offspring of C57BL/6 mouse mothers that had been exposed to CTM during the last trimester of gestation. We observed abnormal behavior such as anxiety, altered locomotion and disordered social interactions in 2–5 months old offspring with prenatal CTM exposure. Using Golgi-Cox staining, we found that CTM caused significantly reduced dendritic length and number of dendritic branches in striatal neurons, as well as altered subunit levels of N-methyl-d-aspartate receptors (NMDARs) and calcium/calmodulin-dependent protein kinase II (CaMKII). Memantine, a selective NMDAR antagonist, improved prenatal CTM-induced abnormal protein levels and social interaction deficits. These results highlight potential mechanisms underlying the abnormal behavior observed in children who are prenatally exposed to CTM.

Abnormal spontaneous brain activity is associated with impaired emotion and cognition in hyperthyroidism: A rs-fMRI study

Hyperthyroid patients undergo emotional and cognitive dysfunction. However, the neurological basis for it remains ambiguous. Amplitude of low frequency fluctuation (ALFF) and regional homogeneity (ReHo) were used to investigate abnormal spontaneous activity in hyperthyroidism for the first time. 29 hyperthyroid patients and 29 healthy controls (HC) received 3.0T magnetic resonance imaging (MRI) scans and neuropsychological assessments. Compared with HC, hyperthyroid patients showed decreased ALFF in left medial frontal gyrus (MeFG) and left posterior cingulate cortex (PCC). Hyperthyroidism group exhibited decreased ReHo in left MeFG. Within hyperthyroidism group, ALFF values in left MeFG were positively correlated with Hamilton Anxiety Rating Scale (HARS) Z-scores, but negatively correlated with processing speed Z-scores. Besides, ALFF values in left precuneus had a positive correlation with HARS Z-scores. As a result, abnormal brain spontaneous activity mainly in default mode network (DMN) implicated the neuro-pathological substrate of relevant emotional and cognitive dysfunction in hyperthyroid patients.