Limbic Circuits Research Articles

Hypersexuality As a Neuropsychiatric Disorder: The Neurobiology and Treatment Options.

Hypersexuality refers to abnormally increased or extreme involvement in any sexual activity. It is clinically challenging, presents trans-diagnostically and there is extensive medical literature addressing the nosology, pathogenesis and neuropsychiatric aspects in this clinical syndrome. Classification includes deviant behaviours, diagnosable entities related to impulsivity, and obsessional phenomena. Some clinicians view an increase in sexual desire as 'normal' i.e. psychodynamic theorists consider it as egodefensive at times alleviating unconscious anxiety rooted in intrapsychic conflicts. We highlight hypersexuality as multi-dimensional involving an increase in sexual activity that is associated with distress and functional impairment. The aetiology of hypersexuality is multi-factorial with differential diagnoses that include major psychiatric disorders (e.g. bipolar disorder), adverse effects of treatments (e.g. levodopatreatment), substance-induced disorders (e.g. amphetamine substance use), neuropathological disorders (e.g. frontal lobe syndrome), among others. Numerous neurotransmitters are implicated in its pathogenesis, with dopamine and noradrenaline playing a crucial role in the neural reward pathways and emotionally- regulated limbic system neural circuits. The management of hypersexuality is determined by the principle of de causa effectu evanescent, if the causes are treated, the effect may disappear. We aim to review the role of pharmacological agents causing hypersexuality and centrally acting agents treating the associated underlying medical conditions. Bio-psycho-social determinants are pivotal in embracing the understanding and guiding management of this complex and multi-determined clinical syndrome.

FMRI-Based Brain Responses to Quinine and Sucrose Gustatory Stimulation for Nutrition Research in the Minipig Model: A Proof-of-Concept Study.

The minipig model is of high interest for brain research in nutrition and associated pathologies considering the similarities to human nutritional physiology, brain structures, and functions. In the context of a gustatory stimulation paradigm, fMRI can provide crucial information about the sensory, cognitive, and hedonic integration of exteroceptive stimuli in healthy and pathological nutritional conditions. Our aims were (i) to validate the experimental setup, i.e., fMRI acquisition and SPM-based statistical analysis, with a visual stimulation; (ii) to implement the fMRI procedure in order to map the brain responses to different gustatory stimulations, i.e., sucrose (5%) and quinine (10 mM), and (ii) to investigate the differential effects of potentially aversive (quinine) and appetitive/pleasant (sucrose) oral stimulation on brain responses, especially in the limbic and reward circuits. Six Yucatan minipigs were imaged on an Avanto 1.5-T MRI under isoflurane anesthesia and mechanical ventilation. BOLD signal was recorded during visual or gustatory (artificial saliva, sucrose, or quinine) stimulation with a block paradigm. With the visual stimulation, brain responses were detected in the visual cortex, thus validating our experimental and statistical setup. Quinine and sucrose stimulation promoted different cerebral activation patterns that were concordant, to some extent, to results from human studies. The insular cortex (i.e., gustatory cortex) was activated with both sucrose and quinine, but other regions were specifically activated by one or the other stimulation. Gustatory stimulation combined with fMRI analysis in large animals such as minipigs is a promising approach to investigate the integration of gustatory stimulation in healthy or pathological conditions such as obesity, eating disorders, or dysgeusia. To date, this is the first intent to describe gustatory stimulation in minipigs using fMRI.

Sub-circuit alterations in dorsal hippocampus structure and function after global neurodevelopmental insult.

Patients with neuropsychiatric and neurological disorders often express limbic circuit abnormalities and deficits in information processing. While these disorders appear to have diverse etiologies, their common features suggest neurodevelopmental origins. Neurodevelopment is a prolonged process of diverse events including neurogenesis/apoptosis, axon pathfinding, synaptogenesis, and pruning, to name a few. The precise timing of the neurodevelopmental insult to these processes likely determines the resulting functional outcome. We used the epilepsy and schizophrenia-related gestational day 17 methylazoxymethanol acetate model to examine the impact of this timed neurodevelopmental insult on principal cell morphology and synaptic network function of the dorsal hippocampus (dHPC) circuit. Our observed structural and functional alterations in dHPC are compartment specific, indicating that adverse global exposure during gestation can produce specific alterations and distort information processing in neural circuits that underlie cognitive abilities.

Yakovlev's Basolateral Limbic Circuit in Multiple Sclerosis Related Cognitive Impairment.

In 1948, Paul Yakovlev described an additional limbic circuit located basolateral to James Papez's circuit (1937) and included orbitofrontal cortex, amygdala, and dorsomedial nucleus of thalamus. This circuit is shown to be an important component of subcortical cognitive abilities. We aimed to demonstrate this circuit in a multiple sclerosis (MS) cohort using diffusion tensor imaging (DTI) and evaluate its role in MS-related cognitive impairment (CI). We enrolled cognitively intact (n = 10) and impaired (n = 36) MS patients who underwent a comprehensive cognitive assessment; the minimal assessment of cognitive function in MS (MACFIMS) and structural magnetic resonance imaging. Correlation analyses between volumetric and DTI-derived values of the orbitofrontothalamic (OFT), amygdalothalamic tracts (ATTs), and dorsomedial nucleus of thalamus and CI index derived from MACFIMS were computed after adjustment for age, education, and lesion load. We observed a consistent trend between CI index and bilateral dorsomedial nucleus' mean diffusivity (MD) (r = .316; P = .02), left OFT Fractional anisotropy (FA) (r = -.302; P = .02), MD (r = .380; .006), and radial diffusivities (RDs) (r = .432; P = .002), also with right ATT FA (r = -.475; P = .0006) and left ATT FA ( = -.487; P = .0005). After Bonferroni correction, correlations of left OFT RD and right and left ATT FA with CI were found to be significant. Our study provides in vivo DTI delineation of Yakovlev's historical basolateral limbic circuit and establishes a role in MS-related CI. These findings may potentially pave the way for future clinical studies using targeted invasive and noninvasive neurostimulation modalities for CI in MS.

Closed Loop Deep Brain Stimulation for PTSD, Addiction, and Disorders of Affective Facial Interpretation: Review and Discussion of Potential Biomarkers and Stimulation Paradigms.

The treatment of psychiatric diseases with Deep Brain Stimulation (DBS) is becoming more of a reality as studies proliferate the indications and targets for therapies. Opinions on the initial failures of DBS trials for some psychiatric diseases point to a certain lack of finesse in using an Open Loop DBS (OLDBS) system in these dynamic, cyclical pathologies. OLDBS delivers monomorphic input into dysfunctional brain circuits with modulation of that input via human interface at discrete time points with no interim modulation or adaptation to the changing circuit dynamics. Closed Loop DBS (CLDBS) promises dynamic, intrinsic circuit modulation based on individual physiologic biomarkers of dysfunction. Discussed here are several psychiatric diseases which may be amenable to CLDBS paradigms as the neurophysiologic dysfunction is stochastic and not static. Post-Traumatic Stress Disorder (PTSD) has several peripheral and central physiologic and neurologic changes preceding stereotyped hyper-activation behavioral responses. Biomarkers for CLDBS potentially include skin conductance changes indicating changes in the sympathetic nervous system, changes in serum and central neurotransmitter concentrations, and limbic circuit activation. Chemical dependency and addiction have been demonstrated to be improved with both ablation and DBS of the Nucleus Accumbens and as a serendipitous side effect of movement disorder treatment. Potential peripheral biomarkers are similar to those proposed for PTSD with possible use of environmental and geolocation based cues, peripheral signs of physiologic arousal, and individual changes in central circuit patterns. Non-substance addiction disorders have also been serendipitously treated in patients with OLDBS for movement disorders. As more is learned about these behavioral addictions, DBS targets and effectors will be identified. Finally, discussed is the use of facial recognition software to modulate activation of inappropriate responses for psychiatric diseases in which misinterpretation of social cues feature prominently. These include Autism Spectrum Disorder, PTSD, and Schizophrenia—all of which have a common feature of dysfunctional interpretation of facial affective clues. Technological advances and improvements in circuit-based, individual-specific, real-time adaptable modulation, forecast functional neurosurgery treatments for heretofore treatment-resistant behavioral diseases.

MARCKSL1 Regulates Spine Formation in the Amygdala and Controls the Hypothalamic-Pituitary-Adrenal Axis and Anxiety-Like Behaviors

Abnormalities in limbic neural circuits have been implicated in the onset of anxiety disorders. However, the molecular pathogenesis underlying anxiety disorders remains poorly elucidated. Here, we demonstrate that myristoylated alanine-rich C-kinase substrate like 1 (MARCKSL1) regulates amygdala circuitry to control the activity of the hypothalamic-pituitary-adrenal (HPA) axis, as well as induces anxiety-like behaviors in mice. MARCKSL1 expression was predominantly localized in the prefrontal cortex (PFC), hypothalamus, hippocampus, and amygdala of the adult mouse brain. MARCKSL1 transgenic (Tg) mice exhibited anxiety-like behaviors dependent on corticotropin-releasing hormone. MARCKSL1 increased spine formation in the central amygdala, and downregulation of MARCKSL1 in the amygdala normalized both increased HPA axis activity and elevated anxiety-like behaviors in Tg mice. Furthermore, MARCKSL1 expression was increased in the PFC and amygdala in a brain injury model associated with anxiety-like behaviors. Our findings suggest that MARCKSL1 expression in the amygdala plays an important role in anxiety-like behaviors.

Altered anatomical connections of associative and limbic cortico-basal-ganglia circuits in obsessive-compulsive disorder

BackgroundCurrent neurocognitive models suppose dysfunctions of associative and limbic cortico-basal ganglia circuits to be at the core of obsessive-compulsive disorder (OCD). As little is known about the state of underlying anatomical connections, we investigated whether these connections were reduced and/or not properly organised in OCD patients compared to control. MethodsDiffusion magnetic resonance images were obtained in 37 OCD patients with predominant checking symptoms and 37 matched healthy controls. We developed indices to characterise the quantity (spatial extent and density) and the organisation (topography and segregation) of 24 anatomical connections between associative and limbic cortical (anterior cingulate, dorsolateral prefrontal, orbitofrontal cortices and the frontal pole), and subcortical (caudate nucleus, putamen and thalamus) areas in each hemisphere. ResultsAssociative and limbic cortico-basal-ganglia connections were reduced in OCD patients compared to controls: 19/24 connections had a reduced subcortical spatial extent, 9/24 had a reduced density. Moreover, while the general topography was conserved, the different cortical projection fields in the striatum and thalamus were hyper-segregated in OCD patients compared to controls. ConclusionThese quantitative and qualitative differences of anatomical connections go beyond the current model of a reduced cortical control of automatic behaviour stored in the basal ganglia. The hyper-segregation in OCD could also impair the integration of cortical information in the thalamus and striatum and distort the subsequent behavioural selection process. This provides new working hypotheses for functional and behavioural studies on OCD.

Anatomy of the Limbic White Matter Tracts as Revealed by Fiber Dissection andTractography.

The limbic tracts are involved in crucial cerebral functions such as memory, emotion, and behavior. The complex architecture of the limbic circuit makes it harder to approach compared with other white matter networks. Our study aims to describe the 3-dimensional anatomy of the limbic white matter by the use of 2 complementary study methods, namely exvivo fiber dissection and invivo magnetic resonance imaging-based tractography. Three fiber dissection protocols were performed using blunt wooden instruments and a surgical microscope on formalin-fixed brains prepared according to the Klingler method. Diffusion tensor imaging acquisitions were done with a 3-Tesla magnetic resonance scanner on patients with head and neck pathology that did not involve the brain. Fiber tracking was performed with manually selected regions of interest. Cingulum, fornix, the anterior thalamic peduncle, the accumbofrontal bundle, medial forebrain bundle, the uncinate fasciculus, the mammillothalamic tract, ansa peduncularis, and stria terminalis were dissected and fiber tracked. For each tract, location, configuration, segmentation, dimensions, dissection and tractography particularities, anatomical relations, and terminations are described. The limbic white matter tracts were systematized as 2 concentric rings around the thalamus. The inner ring is formed by fornix, mammillothalamic tract, ansa peduncularis, stria terminalis, accumbofrontal fasciculus, and medial forebrain bundle and anterior thalamic peduncle, and the outer ring is formed by the cingulum and uncinate fasciculus. This paper proposes a fiber-tracking protocol for the limbic tracts inspired and validated by fiber dissection findings that can be used routinely in the clinical practice.

Longitudinal hippocampal and extra-hippocampal microstructural and macrostructural changes following temporal lobe epilepsy surgery

Objectives1) Characterize the evolution of microstructural changes in the contralateral, non-operated hippocampus—using longitudinal diffusion tensor imaging (DTI)—following surgery for temporal lobe epilepsy (TLE). 2) Characterize the downstream extra-hippocampal volumetric changes of the fornix and mammillary bodies after TLE surgery. 3) Examine the relationship between these measures and seizure/cognitive outcome. MethodsSerial structural and DTI brain MRI scans were collected in 25 TLE patients pre- and post-surgery (anterior temporal lobectomy, ATL – 13; selective amygdalohippocampectomy, SelAH – 12) and in 12 healthy controls. Contralateral hippocampal fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were computed with manual hippocampal tracings as volumes of interest following co-registration to anatomical images. Fornix and mammillary body volumetry was performed by manual segmentation. ResultsAfter surgery, the non-resected hippocampus showed significant postoperative decline in FA (p = 0.0001), with increase of MD (p = 0.01) and RD (p = 0.0001). In contrast to the timing of our previously reported volume changes where atrophy is observed in the first week, diffusion changes occurred late, taking 1–3 years to develop and are not significant at one week after surgery. Diffusion changes are accompanied by delayed limbic circuit volume loss in the mammillary bodies (35%; p < 0.0001) and fornix (24%; p < 0.0001) compared to baseline. There was no correlation between postoperative diffusion or structural changes and memory score nor did the degree of postoperative change in hippocampal DTI parameters, mammillary body volume or fornix volume vary significantly based on seizure outcome. SignificanceDifferences observed in the timing of postoperative volume (first week) and FA/MD (one year) changes would suggest that early contralateral hippocampal atrophy is not secondary to fluid shifts (dehydration) while the late DTI changes suggest ongoing microstructural changes extending beyond the early postoperative period. Postoperative hippocampal diffusion changes are accompanied by delayed mammillary body and fornix volume loss which did not differ when stratified by seizure outcome nor was correlated with degree of hippocampal diffusion change. Finally, we did not identify any significant correlation between postoperative diffusion parameter change and memory performance.

Neurological, nutritional and alcohol consumption factors underlie cognitive and motor deficits in chronic alcoholism.

Variations in pattern and extent of cognitive and motor impairment occur in alcoholism (ALC). Causes of such heterogeneity are elusive and inconsistently accounted for by demographic or alcohol consumption differences. We examined neurological and nutritional factors as possible contributors to heterogeneity in impairment. Participants with ALC (n=96) and a normal comparison group (n=41) were examined on six cognitive and motor domains. Signs of historically determined subclinical Wernicke's encephalopathy were detected using the Caine et al. criteria, which were based on postmortem examination and chart review of antemortem data of alcoholic cases with postmortem evidence for Wernicke's encephalopathy. Herein, four Caine criteria provided quantification of dietary deficiency, cerebellar dysfunction, low general cognitive functioning and oculomotor abnormalities in 86 of the 96 ALC participants. Subgroups based on Caine criteria yielded a graded effect, where those meeting more criteria exhibited greater impairment than those meeting no to fewer criteria. These results could not be accounted for by history of drug dependence. Multiple regression indicated that compromised performance on ataxia, indicative of cerebellar dysfunction, predicted non-mnemonic and upper motor deficits, whereas low whole blood thiamine level, consistent with limbic circuit dysfunction, predicted mnemonic deficits. This double dissociation indicates biological markers that contribute to heterogeneity in expression of functional impairment in ALC. That non-mnemonic and mnemonic deficits are subserved by the dissociable neural systems of frontocerebellar and limbic circuitry, both commonly disrupted in ALC, suggests neural mechanisms that can differentially affect selective functions, thereby contributing to heterogeneity in pattern and extent of dysfunction in ALC.

Cortical and Subcortical Brain Changes in Children and Adolescents With Narcolepsy Type 1.

Neuroimaging studies on structural alterations in patients with type 1 narcolepsy (NT1) have shown controversial and heterogeneous results. The purpose of this study was to investigate microstructural brain changes in patients with NT1 close to disease onset. We examined cortical and subcortical grey matter volumes in 20 drug-naïve children and adolescents with NT1 compared with 19 healthy controls; whole-brain voxel-based morphometry, shape and volumetric analyses, and cortical thickness analysis were used. When compared with controls, NT1 patients revealed reduced grey matter volume in cerebellum and medial prefrontal cortex and increased volume in right hippocampus. Cortical thickness in frontal lobe was also reduced in patients compared with controls. Increased volume and shape expansion in right hippocampus in patients compared with controls were also confirmed by both vertex and volumetric analyses. Our results indicate that subtle structural brain changes involving attentional and limbic circuits are detectable in children and adolescents with NT1. Cerebellum involvement might be related to the childhood NT1 clinical phenotype.

Altered Brain Complexity in Women with Primary Dysmenorrhea: A Resting-State Magneto-Encephalography Study Using Multiscale Entropy Analysis

How chronic pain affects brain functions remains unclear. As a potential indicator, brain complexity estimated by entropy-based methods may be helpful for revealing the underlying neurophysiological mechanism of chronic pain. In this study, complexity features with multiple time scales and spectral features were extracted from resting-state magnetoencephalographic signals of 156 female participants with/without primary dysmenorrhea (PDM) during pain-free state. Revealed by multiscale sample entropy (MSE), PDM patients (PDMs) exhibited loss of brain complexity in regions associated with sensory, affective, and evaluative components of pain, including sensorimotor, limbic, and salience networks. Significant correlations between MSE values and psychological states (depression and anxiety) were found in PDMs, which may indicate specific nonlinear disturbances in limbic and default mode network circuits after long-term menstrual pain. These findings suggest that MSE is an important measure of brain complexity and is potentially applicable to future diagnosis of chronic pain.

Frontal Alpha Asymmetry, a Potential Biomarker for the Effect of Neuromodulation on Brain's Affective Circuitry-Preliminary Evidence from a Deep Brain Stimulation Study.

Neuromodulation techniques targeting limbic circuits can be used to treat refractory psychiatric or neurological disorders. However, objective measure for the impact of neuromodulation on affective brain circuits is lacking. Deep brain stimulation at a key node of the limbic circuit, the anterior thalamic nuclei (ANT-DBS), is used to treat refractory epilepsy. While effective in reducing seizures, patients have reported subjective depressive symptoms as a side effect. In line with potential vulnerability to depression, we have previously shown ANT-DBS to increase attention allocation to threat evidenced by behavior and brain physiology. Rightward frontal alpha asymmetry with greater right hemispheric activation is thought to reflect brain physiology linked with depression and anxiety. To that end, we investigated whether high-frequency electric stimulation at ANT influences frontal alpha asymmetry. Furthermore, we explored the impact of DBS on emotional modulation of frontal alpha asymmetry and whether it is linked with emotional modulation of response speed. Electrical stimulation at ANT led to an increased rightward frontal alpha asymmetry compared to situations where stimulation was off (F(1,12) = 14.09, p = 0.003) or the thalamic control location was stimulated (F(1,12) = 10.19, p = 0.008), along with prolonged reaction times in the context of emotional distractors (F(1,7) = 16.66, p = 0.005). The change was specifically driven by increased activity in the right hemisphere. Furthermore, we found a correlation between the emotional modulation of frontal alpha asymmetry and emotional interference of response speed due to ANT stimulation (r = 0.78, p = 0.02). In conclusion, DBS at ANT increased relative right hemispheric activity and this was linked with emotional modulation of behavior. Previous studies have linked frontal alpha asymmetry with emotion related symptoms and furthermore, Vagus Nerve Stimulation (VNS) has been shown to modulate alpha asymmetry. Thus, in the light of the previous literature and the current findings, we suggest that frontal alpha asymmetry along with emotional interference of response speed might be a feasible biomarker for the effects of neuromodulation on brain’s affective circuitry in general.

Developing Repetitive Transcranial Magnetic Stimulation (rTMS) as a Treatment Tool for Cocaine Use Disorder: a Series of Six Translational Studies.

Cocaine dependence is a chronic and relapsing disorder which is particularly resistant to behavioral or pharmacologic treatment, and likely involves multiple dysfunctional frontal-striatal circuits. Through advances in preclinical research in the last decade, we now have an unprecedented understanding of the neural control of drug-taking behavior. In both rodent models and human clinical neuroimaging studies, it is apparent that medial frontal-striatal limbic circuits regulate drug cue-triggered behavior. While non-human preclinical studies can use invasive stimulation techniques to inhibit drug cue-evoked behavior, in human clinical neuroscience, we are pursuing non-invasive theta burst stimulation (TBS) as a novel therapeutic tool to inhibit drug cue-associated behavior. Our laboratory and others have spent the last 7 years systematically and empirically developing a non-invasive, neural circuit-based intervention for cocaine use disorder. Utilizing a multimodal approach of functional brain imaging and brain stimulation, we have attempted to design and optimize a repetitive transcranial magnetic stimulation treatment protocol for cocaine use disorder. This manuscript will briefly review the data largely from our own lab that motivated our selection of candidate neural circuits, and then summarize the results of six studies, culminating in the first double-blinded, sham-controlled clinical trial of TMS as a treatment adjuvant for treatment-engaged cocaine users (10 sessions, medial prefrontal cortex, 110% resting motor threshold, continuous theta burst stimulation, 3600 pulses/session). The intent of this review is to highlight one example of a systematic path for TMS treatment development in patients. This path is not necessarily optimal, exclusive, or appropriate for every neurologic or psychiatric disease. Rather, it is one example of a reasoned, empirically derived pathway which we hope will serve as scaffolding for future investigators seeking to develop TMS treatment protocols.

Failure to Recover from Proactive Semantic Interference and Abnormal Limbic Connectivity in Asymptomatic, Middle-Aged Offspring of Patients with Late-Onset Alzheimer's Disease.

We have obtained previous evidence of limbic dysfunction in middle-aged, asymptomatic offspring of late-onset Alzheimer's disease (LOAD) patients, and failure to recover from proactive semantic interference has been shown to be a sensitive cognitive test in other groups at risk for LOAD. To assess the effects of specific proactive semantic interference deficits as they relate to functional magnetic resonance imaging (fMRI) neocortical and limbic functional connectivity in middle aged offspring of individuals with LOAD (O-LOAD) and age-equivalent controls. We examined 21 O-LOAD and 20 controls without family history of neurodegenerative disorders (CS) on traditional measures of cognitive functioning and the LASSI-L, a novel semantic interference test uniquely sensitive to the failure to recover from proactive interference (frPSI). Cognitive tests then were correlated to fMRI connectivity of seeds located in entorhinal cortex and anterodorsal thalamic nuclei among O-LOAD and CS participants. Relative to CS, O-LOAD participants evidenced lower connectivity between entorhinal cortex and orbitofrontal, anterior cingulate, and anterior temporal cortex. In the offspring of LOAD patients, LASSI-L measures of frPSI were inversely associated with connectivity between anterodorsal thalamus and contralateral posterior cingulate. Intrusions on the task related to frPSI were inversely correlated with a widespread connectivity network involving hippocampal, insular, posterior cingulate, and dorsolateral prefrontal cortices, along with precunei and anterior thalamus in this group. Different patterns of connectivity associated with frPSI were observed among controls. The present results suggest that both semantic interference deficits and connectivity abnormalities might reflect limbic circuit dysfunction as a very early clinical signature of LOAD pathology, as previously demonstrated for other limbic phenotypes, such as sleep and circadian alterations.

The role of vagus nerve stimulation in refractory epilepsy.

Vagus nerve stimulation is an adjunctive therapy used to treat patients with refractory epilepsy who are not candidates for resective surgery or had poor results after surgical procedures. Its mechanism of action is not yet fully comprehended but it possibly involves modulation of the locus coeruleus, thalamus and limbic circuit through noradrenergic and serotonergic projections. There is sufficient evidence to support its use in patients with focal epilepsy and other seizure types. However, it should be recognized that improvement is not immediate and increases over time. The majority of adverse events is stimulation-related, temporary and decreases after adjustment of settings. Future perspectives to improve efficacy and reduce side effects, such as different approaches to increase battery life, transcutaneous stimulation and identification of prognostic factors, should be further investigated.

Imaging the Etiology of Apathy, Anxiety, and Depression in Parkinson's Disease: Implication for Treatment.

Apathy, depression, and anxiety are among the most important non-motor signs of Parkinson's disease (PD). This may be encountered at early stages of illness and represent a major source of burden. Understanding their pathophysiology is a major prerequisite for efficient therapeutic strategies. Anatomical and metabolic imaging studies have enabled a breakthrough by demonstrating that widespread abnormalities within the limbic circuits notably the orbitofrontal and anterior cingulate cortices, amygdala, thalamus, and ventral striatum are involved in the pathophysiology of depression, anxiety, and apathy in PD. Functional imaging has further shown that mesolimbic dopaminergic but also serotonergic lesions play a major role in the mechanisms of these three neuropsychiatric manifestations, which has direct therapeutic implications.

Interoceptive sensitivity in patients with cervical dystonia

IntroductionInteroceptive sensitivity (IS) is the ability to perceive sensations arising from the inner body. One method used to measure IS is the heartbeat detection task. The aim of this study was to investigate IS in patients with cervical dystonia (CD) and compare the results with those obtained in healthy controls (HC). We also sought possible correlations between IS and demographic, clinical and emotional features in CD. To evaluate the reliability of IS in a subgroup of CD patients and HC, we retested IS 4–6 months after the first evaluation. We also investigated whether dystonic posture affects IS values in HC. MethodsTwenty CD patients and 20 HC were investigated. The heartbeat detection task was performed according to a standardized protocol. All the participants underwent a clinical, emotional and psychiatric evaluation. ResultsIS was lower in CD patients than in HC. The ROC curve analysis showed that an IS value of 0.52 differentiates CD patients from healthy controls. No correlations emerged in CD patients between IS and the demographic, clinical and emotional features. No differences were observed in either CD patients or healthy subjects when IS was retested 4–6 months after the first evaluation. When IS was tested in HC mimicking a dystonic posture, the results were similar to those obtained when they held their heads in a neutral position. ConclusionsThe study shows that IS is reduced in CD patients possibly due to an altered functional connection between basal ganglia and limbic circuit, including the insula.

35 Mania after sub thalamic stimulation for parkinson’s disease

Objective Deep brain stimulation of the sub thalamic nucleus (STN-DBS) is an effective treatment for the motor symptoms in advanced Parkinson’s disease (PD). However, important neuropsychiatric complications have been described after this procedure, including mania, depression, impulsiveness or suicide. Acute hippomania and mania have been described in 4% to 15% of cases, mostly in the first weeks of stimulation. The occurrence of mood changes appears to be influenced by the exact stimulation target within the STN, as well as by polarity and voltage of the stimulation. Concomitant dopaminergic medication and pre-existing subsyndromal bipolar disorder may also increase this risk. Here we report two cases of mania after STN-DBS, and review the literature regarding this complication. Method Systematic review of the literature on mania after STN-DBS for Parkinson’s disease. Detailed report of two cases of post-STN-DBS new-onset mania. Results Case 1: 64-year-old man, with a history of depression, medicated with sertraline 100 mg id. Manic episode starting 3 days after stimulation onset. Switching from a ventromedial monopolar to a dorsolateral bipolar stimulation contact, and voltage reduction led to remission of the manic syndrome. Four weeks later the original parameters were reset due to worsening motor symptoms. This led to a recurrence of manic behavioural changes that only remitted after a new reduction of the stimulation voltage, adjustment of dopaminergic therapy, and and introduction of quetiapine 25 mg and valproic acid 1500 mg. Case 2: 62-year-old female, with a history of depression treated with sertraline 150 mg id. Hypomanic episode manifesting on the second day of stimulation, but fully remitting after introduction of quetiapine 25 mg id and suspension of sertraline. Two weeks later the manic episode recurred. Voltage reduction, switching to a dorsolateral target and introduction of valproic acid 300 mg bid led to sustained euthermia. Literature review: we found 21 case-reports and case-series of STN-DBS induced mania, amounting to 49 patients. Risk appears to increase with higher voltages, monopolar stimulation and ventromedial STN targets. Conclusion Mania is an acute and serious complication of DBS-STN. Ventromedial, monopolar, high-voltage stimulation appears to increase the risk of mania, probably because of potential extension to the cortical-striatal limbic circuit. Early recognition and treatment of this complication is critical to the prognosis.

Inhibition of TrkB at the nucleus accumbens, using ANA-12, regulates basal and stress-induced orexin A expression within the mesolimbic system and affects anxiety, sociability and motivation

Repeated stress exposure can lead to the development of anxiety and mood disorders. An emerging biological substrate of depression and associated pathology is the nucleus accumbens (NAc), which through interactions with limbic, cognitive and motor circuits can regulate a variety of stress responses. Within these circuits, orexin neurons are involved in arousal and stress adaptability, effects proposed mediated via brain-derived neurotrophic factor signaling. This study tested the hypotheses that 1) repeated exposure to heterotypic stress alters social ability and preference and passive avoidant behaviors, 2) TrkB receptors at the NAc shell regulates stress-induced behavioral responses and orexin expression within the mesocorticolimbic system. Our findings indicate that ANA-12 (0.25 μg/0.5 μl) enhanced sociability during the social interaction test, although treatment had no effect on social preference. The development of conditioned place preference, and fear retention in the passive avoidance test were also facilitated by ANA-12. Biochemical assessments on brain tissues collected within 2 h of a forced swim exposure revealed that ANA-12 increased orexin A immunoreactivity (ir) in the hypothalamic perifornical area, while expression was reduced in the ventral portion of the hippocampal CA1 layer, irrespective of the stress condition. This contrasts changes at the VTA characterized by elevated versus reduced orexin A-ir in ANA-12-treated stress and non-stress rats, respectively. Colocalized orexin A- and tyrosine hydroxylase (TH)-ir at the VTA supports a different temporal expression post stress, TH-ir being unaffected 9 days post stress. These findings support a role for TrkB receptors in regulating basal and stress-induced social, cognitive and motivational behavior, and modulatory actions of BDNF, via TrkB signaling, on orexin A signaling upon stress exposure.