Alterations In Brain Circuits Research Articles

Brain connectivity-guided, Optimised theta burst transcranial magnetic stimulation to improve Central Pain Modulation in knee Osteoarthritis Pain (BoostCPM): protocol of a pilot randomised clinical trial in a secondary care setting in the UK

IntroductionChronic pain is a common health problem that is not efficiently managed by standard analgesic treatments. There is evidence that treatment resistance may result from maladaptive brain changes in areas...

M2 Cortex Circuitry and Sensory-Induced Behavioral Alterations in Huntington's Disease: Role of Superior Colliculus.

Early and progressive cortico-striatal circuit alterations have been widely characterized in Huntington's disease (HD) patients. Cortical premotor area, M2 cortex in rodents, is the most affected cortical input to the striatum from early stages in patients and is associated to the motor learning deficits present in HD mice. Yet, M2 cortex sends additional long-range axon collaterals to diverse output brain regions beyond basal ganglia. Here, we aimed to elucidate the contribution of M2 cortex projections to HD pathophysiology in mice. Using fMRI, M2 cortex showed most prominent functional connectivity alterations with the superior colliculus (SC) in symptomatic R6/1 HD male mice. Structural alterations were also detected by tractography, although diffusion weighted imaging measurements suggested preserved SC structure and similar electrophysiological responses were obtained in the SC on optogenetic stimulation of M2 cortical axons. Male and female HD mice showed behavioral alterations linked to SC function, including decreased defensive behavioral responses toward unexpected stimuli, such as a moving robo-beetle, and decreased locomotion on an unexpected flash of light. Additionally, GCamp6f fluorescence recordings with fiber photometry showed that M2 cortex activity was engaged by the presence of a randomly moving robo-bettle, an effect absent in HD male mice. Moreover, acute chemogenetic M2 cortex inhibition in WT mice shift behavioral responses toward an HD phenotype. Collectively, our findings highlight the involvement of M2 cortex activity in visual stimuli-induced behavioral responses, which are deeply altered in the R6/1 HD mouse model.SIGNIFICANCE STATEMENT Understanding brain circuit alterations in brain disorders is critical for developing circuit-based therapeutic interventions. The cortico-striatal circuit is the most prominently disturbed in Huntington's disease (HD); and particularly, M2 cortex has a prominent role. However, the same M2 cortical neurons send additional projections to several brain regions beyond striatum. We characterized new structural and functional circuitry alterations of M2 cortex in HD mouse models and found that M2 cortex projection to the superior colliculus (SC) was deeply impaired. Moreover, we describe differential responses to unexpected sensory stimulus in HD mouse models, which relies on SC function. Our data highlight the involvement of M2 cortex in SC-dependent sensory processing and its alterations in HD pathophysiology.

Medio-dorsal thalamic dysconnectivity in chronic knee pain: A possible mechanism for negative affect and pain comorbidity.

The reciprocal interaction between pain and negative affect is acknowledged but pain-related alterations in brain circuits involved in this interaction, such as the mediodorsal thalamus (MDThal), still require a better understanding. We sought to investigate the relationship between MDThal circuitry, negative affect and pain severity in chronic musculoskeletal pain. For these analyses, participants with chronic knee pain (CKP, n = 74) and without (n = 36) completed magnetic resonance imaging scans and questionnaires. Seed-based MDThal functional connectivity (FC) was compared between groups. Within CKP group, we assessed the interdependence of MDThal FC with negative affect. Finally, post hoc moderation analysis explored whether burden of pain influences affect-related MDThal FC. The CKP group showed altered MDThal FC to hippocampus, ventromedial prefrontal cortex and subgenual anterior cingulate. Furthermore, in CKP group, MDThal connectivity correlated significantly with negative affect in several brain regions, most notably the medial prefrontal cortex, and this association was stronger with increasing pain burden and absent in pain-free controls. In conclusion, we demonstrate mediodorsal thalamo-cortical dysconnectivity in chronic pain with areas linked to mood disorders and associations of MDThal FC with negative affect. Moreover, burden of pain seems to enhance affect sensitivity of MDThal FC. These findings suggest mediodorsal thalamic network changes as possible drivers of the detrimental interplay between chronic pain and negative affect.

Brain circuit pathology in Down syndrome: from neurons to neural networks.

Down syndrome (DS), a genetic pathology caused by triplication of chromosome 21, is characterized by brain hypotrophy and impairment of cognition starting from infancy. While studies in mouse models of DS have elucidated the major neuroanatomical and neurochemical defects of DS, comparatively fewer investigations have focused on the electrophysiology of the DS brain. Electrical activity is at the basis of brain functioning. Therefore, knowledge of the way in which brain circuits operate in DS is fundamental to understand the causes of behavioral impairment and devise targeted interventions. This review summarizes the state of the art regarding the electrical properties of the DS brain, starting from individual neurons and culminating in signal processing in whole neuronal networks. The reported evidence derives from mouse models of DS and from brain tissues and neurons derived from individuals with DS. EEG data recorded in individuals with DS are also provided as a key tool to understand the impact of brain circuit alterations on global brain activity.

Obesity - A Matter of Motivation?

Excessive food intake and reduced physical activity have long been established as primary causes of obesity. However, the underlying mechanisms causing this unhealthy behavior characterized by heightened motivation for food but not for physical effort are unclear. Despite the common unjustified stigmatization that obesity is a result of laziness and lack of discipline, it is becoming increasingly clear that high-fat diet feeding and obesity cause alterations in brain circuits that are critical for the control of motivational behavior.In this mini-review, we provide a comprehensive overview of incentive motivation, its neural encoding in the dopaminergic mesolimbic system as well as its metabolic modulation with a focus on derangements of incentive motivation in obesity. We further discuss the emerging field of metabolic interventions to counteract motivational deficits and their potential clinical implications.

Early derailment of firing properties in CA1 pyramidal cells of the ventral hippocampus in an Alzheimer's disease mouse model

Gradual decline in cognitive and non-cognitive functions are considered clinical hallmarks of Alzheimer's Disease (AD). Post-mortem autoptic analysis shows the presence of amyloid β deposits, neuroinflammation and severe brain atrophy. However, brain circuit alterations and cellular derailments, assessed in very early stages of AD, still remain elusive. The understanding of these early alterations is crucial to tackle defective mechanisms.In a previous study we proved that the Tg2576 mouse model of AD displays functional deficits in the dorsal hippocampus and relevant behavioural AD-related alterations. We had shown that these deficits in Tg2576 mice correlate with the precocious degeneration of dopamine (DA) neurons in the Ventral Tegmental Area (VTA) and can be restored by L-DOPA treatment. Due to the distinct functionality and connectivity of dorsal versus ventral hippocampus, here we investigated neuronal excitability and synaptic functionality in the ventral CA1 hippocampal sub-region of Tg2576 mice. We found an age-dependent alteration of cell excitability and firing in pyramidal neurons starting at 3 months of age, that correlates with reduced levels in the ventral CA1 of tyrosine hydroxylase – the rate-limiting enzyme of DA synthesis. Additionally, at odds with the dorsal hippocampus, we found no alterations in basal glutamatergic transmission and long-term plasticity of ventral neurons in 8-month old Tg2576 mice compared to age-matched controls. Last, we used computational analysis to model the early derailments of firing properties observed and hypothesize that the neuronal alterations found could depend on dysfunctional sodium and potassium conductances, leading to anticipated depolarization-block of action potential firing. The present study depicts that impairment of cell excitability and homeostatic control of firing in ventral CA1 pyramidal neurons is a prodromal feature in Tg2576 AD mice.

Circuitry and Synaptic Dysfunction in Alzheimer's Disease: A New Tau Hypothesis.

For more than five decades, the field of Alzheimer's disease (AD) has focused on two main hypotheses positing amyloid-beta (Aβ) and Tau phosphorylation (pTau) as key pathogenic mediators. In line with these canonical hypotheses, several groups around the world have shown that the synaptotoxicity in AD depends mainly on the increase in pTau levels. Confronting this leading hypothesis, a few years ago, we reported that the increase in phosphorylation levels of dendritic Tau, at its microtubule domain (MD), acts as a neuroprotective mechanism that prevents N-methyl-D-aspartate receptor (NMDAr) overexcitation, which allowed us to propose that Tau protein phosphorylated near MD sites is involved in neuroprotection, rather than in neurodegeneration. Further supporting this alternative role of pTau, we have recently shown that early increases in pTau close to MD sites prevent hippocampal circuit overexcitation in a transgenic AD mouse model. Here, we will synthesize this new evidence that confronts the leading Tau-based AD hypothesis and discuss the role of pTau modulating neural circuits and network connectivity. Additionally, we will briefly address the role of brain circuit alterations as a potential biomarker for detecting the prodromal AD stage.

Brain Circuit Alterations and Cognitive Disability in Late-Onset Cobalamin D Disorder.

Neuroimaging studies describing brain circuits’ alterations in cobalamin (vitamin B12)-deficient patients are limited and have not been carried out in patients with inborn errors of cobalamin metabolism. The objective of this study was to assess brain functionality and brain circuit alterations in a patient with an ultra-rare inborn error of cobalamin metabolism, methylmalonic aciduria, and homocystinuria due to cobalamin D disease, as compared with his twin sister as a healthy control (HC). We acquired magnetic resonance imaging (including structural, functional, and diffusion images) to calculate brain circuit abnormalities and combined these results with the scores after a comprehensive neuropsychological evaluation. As compared with HC, the patient had severe patterns of damage, such as a 254% increment of ventricular volume, pronounced subcortical and cortical atrophies (mainly at striatum, cingulate cortex, and precuneus), and connectivity alterations at fronto-striato-thalamic circuit, cerebellum, and corpus callosum. In agreement with brain circuit alterations, cognitive deficits existed in attention, executive function, inhibitory control, and mental flexibility. This is the first study that provides the clinical, genetic, neuroanatomical, neuropsychological, and psychosocial characterization of a patient with the cobalamin D disorder, showing functional alterations in central nervous system motor tracts, thalamus, cerebellum, and basal ganglia, that, as far as we know, have not been reported yet in vitamin B12-related disorders.

Atrophy of right inferior frontal orbital gyrus and frontoparietal functional connectivity abnormality in depressed suicide attempters.

Although structural and functional brain abnormalities have been observed in depressed suicide attempters (DS), structural deficits and functional impairments together with their relationship in DS remain unclear. To clarify this issue, we aimed to examine the differences in gray matter (GM) alteration, corresponding functional connectivity (FC) change, and their relationship between DS and depressed non-suicide attempters (NDS). Sixty-eight DS, 119 NDS and 103 healthy controls were enrolled and subjected to magnetic resonance imaging scans. The patients were evaluated using the 17-item Hamilton Rating Scale for Depression (HRSD) and Nurses' Global Assessment of Suicide Risk (NGASR) scale. Both voxel-based morphometry and resting-state FC analyses were performed based on functional and structural imaging data. Compared with NDS, the DS group showed reduced GM volume in the right inferior frontal orbital gyrus (IFOG) and left caudate (CAU) but increased GM volume in the left calcarine fissure, weaker negative right IFOG-left rectus gyrus (REG) FC, and weaker positive right IFOG-left inferior parietal lobule (IPL) FC. In DS, the GM volume of the right IFOG and left CAU was negatively correlated with NGASR and HRSD scores, respectively; the right IFOG-left IPL FC was negatively correlated with cognitive factor scores; and the GM volume of the right IFOG was positively correlated with IFOG-REG and IFOG-IPL FC. Our findings indicate that structural deficit with its related functional alterations in brain circuits converged in right IFOG centralized pathways and may play a central role in suicidal behaviors in depression.

Abnormal Alterations of Regional Spontaneous Neuronal Activity in Inferior Frontal Orbital Gyrus and Corresponding Brain Circuit Alterations: A Resting-State fMRI Study in Somatic Depression.

Background: Major depressive disorders often involve somatic symptoms and have been found to have fundamental differences from non-somatic depression (NSD). However, the neural basis of this type of somatic depression (SD) is unclear. The aim of this study is to use the amplitude of low-frequency fluctuation (ALFF) and functional connectivity (FC) analyses to examine the abnormal, regional, spontaneous, neuronal activity and the corresponding brain circuits in SD patients. Methods: 35 SD patients, 25 NSD patients, and 27 matched healthy controls were selected to complete this study. The ALFF and seed-based FC analyses were employed, and the Pearson correlation was determined to observe possible clinical relevance. Results: Compared with NSD, the SD group showed a significant ALFF increase in the right inferior temporal gyrus; a significant ALFF decrease in left hippocampus, right inferior frontal orbital gyrus and left thalamus; and a significant decrease in the FC value between the right inferior frontal orbital gyrus and the left inferior parietal cortex (p < 0.05, corrected). Within the SD group, the mean ALFF value of the right inferior frontal orbital gyrus was associated with the anxiety factor scores (r = –0.431, p = 0.010, corrected). Conclusions: Our findings suggest that abnormal differences in the regional spontaneous neuronal activity of the right inferior frontal orbital gyrus were associated with dysfunction patterns of the corresponding brain circuits during rest in SD patients, including the limbic-cortical systems and the default mode network. This may be an important aspect of the underlying mechanisms for pathogenesis of SD at the neural level.

Translating Developmental Neuroscience to Understand Risk for Psychiatric Disorders.

The transition from childhood to adulthood represents the developmental time frame in which the majority of psychiatric disorders emerge. Recent efforts to identify risk factors mediating the susceptibility to psychopathology have led to a heightened focus on both typical and atypical trajectories of neural circuit maturation. Mounting evidence has highlighted the immense neural plasticity apparent in the developing brain. Although in many cases adaptive, the capacity for neural circuit alteration also induces a state of vulnerability to environmental perturbations, such that early-life experiences have long-lasting implications for cognitive and emotional functioning in adulthood. The authors outline preclinical and neuroimaging studies of normative human brain circuit development, as well as parallel efforts covered in this issue of the Journal, to identify brain circuit alterations in psychiatric disorders that frequently emerge in developing populations. Continued translational research into the interactive effects of neurobiological development and external factors will be crucial for identifying early-life risk factors that may contribute to the emergence of psychiatric illness and provide the key to optimizing treatments.

Prenatal stress increases adult vulnerability to cocaine reward without affecting pubertal anxiety or novelty response

Prenatal stress (PS) induces long-lasting molecular alterations in brain circuits of the offspring and increases the propensity to develop neuropsychiatric diseases during adulthood, including mood disorders and drug addiction. A major goal of this study was to assess the impact of PS on pubertal behaviour and adult vulnerability to cocaine-induced conditioning place preference (CPP). We therefore evaluated pubertal novelty response and anxiety-like behaviour in control (C) and PS rats, and then, we examined cocaine-induced CPP in those animals during adulthood. We found no differences between C and PS groups on pubertal behaviour, however, only PS rats showed a significant cocaine-induced CPP. To further analyze our results, we classified cocaine-treated rats regarding their CPP score in Low CPP or High CPP and we then analysed their pubertal behaviour. We found different relations of anxiety-like behaviour to cocaine reward as a function of PS exposure: for C group, High CPP and Low CPP had shown similar levels of anxiety-like behaviour at puberty; on the contrary, for PS group, High CPP had shown lower anxiety-like behaviour than Low CPP rats. This study underscores the importance of considering prenatal exposure to stress when analysing the relationship between anxiety and cocaine vulnerability. Moreover, the evaluation of behavioural traits at puberty opens the possibility of early intervention and will allow the development of specific prevention strategies to avoid the devastating consequences of drug addiction later in life.

Amyloid-Beta Deposition is Associated with Increased Medial Temporal Lobe Activation during Memory Encoding in the Cognitively Normal Elderly

Much is unknown about changes that occur in the brain in the years preceding the cognitive and functional impairment associated with Alzheimer disease (AD). This period before mild cognitive impairment is present has been referred to as preclinical AD, and is thought to begin with amyloid-beta deposition and then progress to neurodegeneration and functional brain circuit alterations. Prior studies have shown that there is increased medial temporal lobe activation on functional magnetic resonance imaging (fMRI) early in the course of mild cognitive impairment. It is unknown, however, whether this altered fMRI activity precedes cognitive impairment. The purpose of this study is to address this question using Pittsburgh Compound-B (PiB) imaging and fMRI in a sample of cognitively normal older adults. Forty-four cognitively normal older adults underwent both PiB imaging and fMRI with a face-name memory task: 21 were classified as PiB(+) and 23 were PiB(-). Additionally, thorough cognitive and neuropsychological test batteries were administered outside the scanner. The main outcome measure in this study is fMRI activation in the medial temporal lobe during a face-name memory-encoding task. PiB(+) subjects showed higher fMRI activation during the memory task in the hippocampus relative to PiB(-) participants. The increased medial temporal lobe activation in preclinical AD, observed in this study, may serve as an early biomarker of neurodegeneration. Future studies are needed to clarify whether this functional biomarker can stratify AD risk among PiB(+) older adults.

Estudio sinomédico de los circuitos subyacentes a los síntomas depresivos y una propuesta de tratamiento con craneoacupuntura

Depression is the most common psychiatric disorder and is characterized by a deeply negative view of the world, oneself and the future, and this has been linked to negative ways in attention and comprehension and memory. Acupuncture has proven to have clinical efficacy in the treatment of depression, however, even with resources available for the treatment of this disorder, there are more difficult to eradicate symptoms, are expression of alterations in brain circuits, one of the most important factors for the expression of depression is stress, which has deleterious effects on vulnerable brain structures that impacts the neural circuits involved in chronic way, these neurobiological changes manifest themselves as characteristic behavioural and cognitive depression. In this study the neuroanatomical abnormalities, neural function and alteration of neurobiological circuits are described and analyzed its correspondence to the pathophysiology, organic phenomenology and syndromatic differentiation in traditional chinese medicine and based on this analysis is proposed treatment in scalp-acupuncture specific areas.

Fear and Reward Circuit Alterations in Pediatric CRPS.

In chronic pain, a number of brain regions involved in emotion (e.g., amygdala, hippocampus, nucleus accumbens, insula, anterior cingulate, and prefrontal cortex) show significant functional and morphometric changes. One phenotypic manifestation of these changes is pain-related fear (PRF). PRF is associated with profoundly altered behavioral adaptations to chronic pain. For example, patients with a neuropathic pain condition known as complex regional pain syndrome (CRPS) often avoid use of and may even neglect the affected body area(s), thus maintaining and likely enhancing PRF. These changes form part of an overall maladaptation to chronic pain. To examine fear-related brain circuit alterations in humans, 20 pediatric patients with CRPS and 20 sex- and age-matched healthy controls underwent functional magnetic resonance imaging (fMRI) in response to a well-established fearful faces paradigm. Despite no significant differences on self-reported emotional valence and arousal between the two groups, CRPS patients displayed a diminished response to fearful faces in regions associated with emotional processing compared to healthy controls. Additionally, increased PRF levels were associated with decreased activity in a number of brain regions including the right amygdala, insula, putamen, and caudate. Blunted activation in patients suggests that (a) individuals with chronic pain may have deficits in cognitive-affective brain circuits that may represent an underlying vulnerability or consequence to the chronic pain state; and (b) fear of pain may contribute and/or maintain these brain alterations. Our results shed new light on altered affective circuits in patients with chronic pain and identify PRF as a potentially important treatment target.

Uncovering the etiology of conversion disorder: insights from functional neuroimaging.

Conversion disorder (CD) is a syndrome of neurological symptoms arising without organic cause, arguably in response to emotional stress, but the exact neural substrates of these symptoms and the underlying mechanisms remain poorly understood with the hunt for a biological basis afoot for centuries. In the past 15 years, novel insights have been gained with the advent of functional neuroimaging studies in patients suffering from CDs in both motor and nonmotor domains. This review summarizes recent functional neuroimaging studies including functional magnetic resonance imaging (fMRI), single photon emission computerized tomography (SPECT), and positron emission tomography (PET) to see whether they bring us closer to understanding the etiology of CD. Convergent functional neuroimaging findings suggest alterations in brain circuits that could point to different mechanisms for manifesting functional neurological symptoms, in contrast with feigning or healthy controls. Abnormalities in emotion processing and in emotion-motor processing suggest a diathesis, while differential reactions to certain stressors implicate a specific response to trauma. No comprehensive theory emerges from these clues, and all results remain preliminary, but functional neuroimaging has at least given grounds for hope that a model for CD may soon be found.

Brain Connectivity as Potential Biomarker for Alzheimer's Disease

One important challenge for the Alzheimer's disease research field is developing new and efficacious biomarkers. In this regard we have devoted significant efforts towards finding biomarkers that are able to detect the prodromal pathological stage at an early phase. The idea behind this picture is to detect early stage points in order to provide better treatment options. Here, we firmly believe that this strategy will offer better hope for patients. With this in mind, we discuss the use of brain circuit alterations as a potential tool for early time point detection. Additionally, we briefly discuss the combination of powerful new techniques, like optogenetics and magnetic resonance imaging, for new diagnosis and treatment strategies. The short document will be an important contribution towards exploring new strategies for AD diagnosis and treatment. Given the practical application of these data, we feel that this manuscript will be of significant interest to the audience of Journal of Neurology and Neuroscience.

Neurological soft signs in primary headache patients

Neurological soft signs (NSS) are semeiotic anomalies not assessed by the standard neurological examination, primarily developed in psychiatric settings and recently proposed as potential markers of minor brain circuit alterations, especially the cerebellar–thalamic–prefrontal network. Primary headache patients present with normal neurological examination and frequent psychiatric comorbidity. Aim of this exploratory study consisted in assessing NSS in 20 episodic frequent migraine (MH) and in 10 tension-type headache (ETTH) outpatients compared to 30 matched healthy controls. NSS were assessed by the Heidelberg scale; clinical characteristics and brain MRI were additionally obtained in all patients. NSS were increased by ∼70 and ∼90% in ETTH and MH, respectively, with respect to controls (p<0.001) and the difference remained significant even after controlling for age and education. Headache type and characteristics did not influence NSS presentation, while headache patients with white matter hyperintensities (WMH) at brain MRI had higher NSS scores compared both to normal controls and patients without WMH. NSS identify a subset of primary headache patients sharing the same comorbidities or minimal brain anomalies, suggesting that tailored prophylactic options might apply.

An integrative neurocircuit perspective on psychogenic nonepileptic seizures and functional movement disorders: neural functional unawareness.

Functional neurological disorder (conversion disorder) is a neurobehavioral condition frequently encountered by neurologists. Psychogenic nonepileptic seizure (PNES) and functional movement disorder (FMD) patients present to epileptologists and movement disorder specialists respectively, yet neurologists lack a neurobiological perspective through which to understand these enigmatic groups. Observational research studies suggest that PNES and FMD may represent variants of similar (or the same) conditions given that both groups exhibit a female predominance, have increased prevalence of mood-anxiety disorders, frequently endorse prior abuse, and share phenotypic characteristics. In this perspective article, neuroimaging studies in PNES and FMD are reviewed, and discussed using studies of emotional dysregulation, dissociation and psychological trauma in the context of motor control. Convergent neuroimaging findings implicate alterations in brain circuits mediating emotional expression, regulation and awareness (anterior cingulate and ventromedial prefrontal cortices, insula, amygdala, vermis), cognitive control and motor inhibition (dorsal anterior cingulate, dorsolateral prefrontal, inferior frontal cortices), self-referential processing and perceptual awareness (posterior parietal cortex, temporoparietal junction), and motor planning and coordination (supplementary motor area, cerebellum). Striatal-thalamic components of prefrontal-parietal networks may also play a role in pathophysiology. Aberrant medial prefrontal and amygdalar neuroplastic changes mediated by chronic stress may facilitate the development of functional neurological symptoms in a subset of patients. Improved biological understanding of PNES and FMD will likely reduce stigma and aid the identification of neuroimaging biomarkers guiding treatment development, selection, and prognosis. Additional research should investigate neurocircuit abnormalities within and across functional neurological disorder subtypes, as well as compare PNES and FMD with mood-anxiety-dissociative disorders.

Optogenetics in psychiatric animal models

Optogenetics is the optical control of neuronal excitability by genetically delivered light-activated channels and pumps and represents a promising tool to fuel the study of circuit function in psychiatric animal models. This review highlights three developments. First, we examine the application of optogenetics in one of the neuromodulators central to the pathophysiology of many psychiatric disorders, the dopaminergic system. We then discuss recent work in translating functional magnetic resonance imaging in small animals (in which optogenetics can be employed to reveal physiological mechanisms underlying disease-related alterations in brain circuits) to patients. Finally, we describe emerging technological developments for circuit manipulation in freely behaving animals.