Neuropsychological Profile of a Patient with Acquired Brain Damage Following Vascular Lesion of the Left Anterior Cingulate Cortex

Stroke is a physiological alteration associated with changes in blood flow that can result in sudden-onset cognitive impairment. It has a heterogenous clinical presentation with varying degrees of severity correlated with specific central nervous system zones or areas, and its prognosis is uncertain. This case study describes a 62-year-old male patient with acquired brain damage of the anterior cingulate cortex as a result of an ischemic event in the territory of the left anterior cerebral artery. Cognitive function was assessed using the neuropsychological executive function and frontal lobe test battery (BANFE-2) as well as other neuropsychological tests. The results show a profile of higher mental functions characterized by the presence of dysexecutive syndrome with marked behavioral alteration and diencephalic amnesia. .

Activation of glycine site and GluN2B subunit of NMDA receptors is necessary for ERK/CREB signaling cascade in rostral anterior cingulate cortex in rats:Implications for affective pain

Objective The rostral anterior cingulate cortex （rACC） is implicated in processing the emotional component of pain. N-methyl-D-aspartate receptors （NMDARs） are highly expressed in the rACC and mediate painrelated affect by activating a signaling pathway that involves cyclic adenosine monophosphate （cAMP）/protein ki- nase A （PKA） and/or extracellular regulated kinase （ERK）/cAMP-response element-binding protein （CREB）. The present study investigated the contributions of the NMDAR glycine site and GluN2B subunit to the activation of ERK and CREB both in vitro and in vivo in rat rACC. Methods Immunohistochemistry and Western blot analy- sis were used to separately assess the expression of phospho-ERK （pERK） and phospho-CREB （pCREB） in vitro and in vivo. Double immunostaining was also used to determine the colocalization of pERK and pCREB. Results Both bath application of NMDA in brain slices in vitro and intraplantar injection of formalin into the rat hindpaw in vivo induced significant up-regulation of pERK and pCREB in the rACC, which was inhibited by the NMDAR antago- nist DL-2-amino-5-phospho-novaleric acid. Selective blockade of the NMDAR GluN2B subunit and the glycine- binding site, or degradation of endogenous D-serine, a co-agonist for the glycine site, significantly decreased the up- regulation of pERK and pCREB expression in the rACC. Further, the activated ERK predominantly colocalized with CREB. Conclusion Either the glycine site or the GluN2B subunit of NMDARs participates in the phosphorylation of ERK and CREB induced by bath application of NMDA in brain slices or hindpaw injection of 5% formalin in rats, and these might be fundamental molecular mechanisms underlying pain affect.

Changes in functional connectivity of ventral anterior cingulate cortex in heroin abusers

Background Previous studies with animal experiments, autopsy, structural magnetic resonance imaging （MRI） and task-related functional MRI （fMRI） have confirmed that brain functional connectivity in addicts has become impaired. The goal of this study was to investigate the alteration of resting-state functional connectivity of the ventral anterior cingulate cortex （vACC） in the heroin abusers＇ brain. Methods Fifteen heroin abusers and fifteen matched healthy volunteers were studied using vACC as the region-of interest （ROI） seed. A 3.0 T scanner with a standard head coil was the imagining apparatus. T2＊-weighted gradient-echo planar imaging （GRE-EPI） was the scanning protocol. A ROI seed based correlation analysis used a SPM5 software package as the tool for all images processing. Results This study showed a functional connection to the insula vACC in heroin abusers. Compared with controls, heroin users showed decreased functional connectivity between the nucleus accumbens （NAc） and vACC, between the parahippocampala gyrus/amgdala （PHC/amygdala） and vACC, between the thalamus and vACC, and between the posterior cingulated cortex/precuneus （PCC/pC） and vACC. Conclusion The altered resting-state functional connectivity to the vACC suggests the neural circuitry on which the addictive drug has an affect and reflects the dysfunction of the addictive brain.

Role of the Anterior Cingulate Cortex in Translational Pain Research

As the most common symptomatic reason to seek medical consultation,pain is a complex experience that has been classified into different categories and stages.In pain processing,noxious stimuli may activate the anterior cingulate cortex(ACC).But the function of ACC in the different pain conditions is not well discussed.In this review,we elaborate the commonalities and differences from accumulated evidence by a variety of pain assays for physiological pain and pathological pain including inflammatory pain,neuropathic pain,and cancer pain in the ACC,and discuss the cellular receptors and signaling molecules from animal studies.We further summarize the ACC as a new central neuromodulation target for invasive and non-invasive stimulation techniques in clinical pain management.The comprehensive understanding of pain processing in the ACC may lead to bridging the gap in translational research between basic and clinical studies and to develop new therapies.

Anterior Cingulate Cortex Mediates Hyperalgesia and Anxiety Induced by Chronic Pancreatitis in Rats

Central sensitization is essential in maintaining chronic pain induced by chronic pancreatitis(CP),but cortical modulation of painful CP remains elusive.Here,we examined the role of the anterior cingulate cortex(ACC)in the pathogenesis of abdominal hyperalgesia in a rat model of CP induced by intraductal administration of trinitrobenzene sulfonic acid(TNBS).TNBS treatment resulted in long-term abdominal hyperalgesia and anxiety in rats.Morphological data indicated that painful CP induced a significant increase in FOS-expressing neurons in the nucleus tractus solitarii(NTS)and ACC,and some FOS-expressing neurons in the NTS projected to the ACC.In addition,a larger portion of ascending fibers from the NTS innervated pyramidal neurons,the neural subpopulation primarily expressing FOS under the condition of painful CP,rather than GABAergic neurons within the ACC.CP rats showed increased expression of vesicular glutamate transporter 1,and increased membrane trafficking and phosphorylation of the N-methyl-D-aspartate receptor(NMDAR)subunit NR2B and theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor(AMPAR)subunit GluR1 within the ACC.Microinjection of NMDAR and AMPAR antagonists into the ACC to block excitatory synaptic transmission significantly attenuated abdominal hyperalgesia in CP rats,which was similar to the analgesic effect of endomorphins injected into the ACC.Specifically inhibiting the excitability of ACC pyramidal cells via chemogenetics reduced both hyperalgesia and comorbid anxiety,whereas activating these neurons via optogenetics failed to aggravate hyperalgesia and anxiety in CP rats.Taken together,these findings provide neurocircuit,biochemical,and behavioral evidence for involvement of the ACC in hyperalgesia and anxiety in CP rats,as well as novel insights into the cortical modulation of painful CP,and highlights the ACC as a potential target for neuromodulatory interventions in the treatment of painful CP.

Spatial and temporal plasticity of synaptic organization in anterior cingulate cortex following peripheral inflammatory pain: multi-electrode array recordings in rats

To explore whether experiencing inflammatory pain has an impact upon intracortical synaptic organization, the planar multi-electrode array （MEA） technique and 2-dimensional current source density （2D-CSD） imaging were used in slice preparations of the anterior cingulate cortex （ACC） from rats. Synaptic activity across different layers of the ACC was evoked by deep layer stimulation through one electrode. The layer-localization of both local field potentials （LFPs） and the spread of current sink calculated by 2D-CSD analysis was characterized pharmacologically. Moreover, the induction of long-term potentiation （LTP） and changes in LTP magnitude were also evaluated. We found that under naive conditions, the current sink was initially generated in layer Ⅵ, then spread to layer Ⅴ and finally confined to layers Ⅱ-Ⅲ. This spatial pattern of current sink movement typically reflected changes in depolarized sites from deep layers （Ⅴ-Ⅵ） to superficial layers （Ⅱ-Ⅲ） where intra- and extra- cortical inputs terminate. In the ACC slices from rats in an inflamed state （for 2 h） caused by intraplantar bee-venom injection, the spatial profile of intra-ACC synaptic organization was significantly changed,showing an enlarged current sink distribution and a leftward shift of the stimulus-response curves relative to the naive and saline controls. The change was more distinct in the superficial layers （Ⅱ-Ⅲ） than in the deep site. In terms of temporal properties, the rate of LTP induction was significantly increased in layers Ⅱ-Ⅲ by inflammatory pain. However, the magnitude of LTP was not significantly enhanced by this treatment. Taken together, these results show that inflammatory pain results in distinct spatial and temporal plasticity of synaptic organization in the ACC, which may lead to altered synaptic transmission and modulation.

Infusion of methylphenidate into the basolateral nucleus of amygdala or anterior cingulate cortex enhances fear memory consolidation in rats

The psychostimulant methylphenidate (MPD; also called Ritalin) is a blocker of dopamine and norepi-nephrine transporter. It has been clinically used for treatment of Attention Deficit and Hyperactivity Disorder (ADHD). There have been inconsistent reports regarding the effects of systemically adminis-tered MPD on learning and memory, either in animals or humans. In the present study, we investigated the effect of direct infusion of MPD into the basolateral nucleus of amygdala (BLA) or the anterior cin-gulate cortex (ACC) on conditioned fear memory. Rats were trained on a one-trial step-through inhibi-tory avoidance task. MPD was infused bilaterally into the BLA or the ACC, either at ‘0’ or 6 h post-training. Saline was administered as control. Memory retention was tested 48 h post-training. In-tra-BLA or intra-ACC infusion of MPD ‘0’ h but not 6 h post-training significantly improved 48-h memory retention: the MPD-treated rats had significant longer step-through latency than controls. The present results indicate that action of MPD in the BLA or the ACC produces a beneficial effect on the consoli-dation of inhibitory avoidance memory.

Electroacupuncture Alleviates Anxiety-like Behavior in Pain Aversion Rats by Attenuating the Expression of Neuropeptide Y in Anterior Cingulate Cortex

Background:Pain is considered as a multidimensional conscious experience that includes a sensory component and a negative affective-motivational component.Electroacupuncture(EA)is widely used to treat pain and paininduced negative emotions,however,little is known about the mechanisms underlying the effect of EA.Objective:This study investigated the effect of EA on alleviating the anxiety-like behaviors in pain aversion rats and its anterior cingulate cortex(ACC)regulation mechanism.Methods:After a Freund’s complete adjuvant(CFA)-conditioned place aversion(C-CPA)model was established in rats,EA treatment(2/100 Hz,30 min,once/day,4 days totally)was applied at bilateral Zusanli(ST36)and Kunlun(BL60)acupoints.Von Frey filaments were used to measure changes of pain withdrawal threshold(PWT)at indicated time points.Elevated zero maze(EZM)was used to investigate the changes of pain-related anxiety and CPA was used to investigate the changes of pain aversion.The protein expression levels of GAD67,PV,and NPY in ACC were detected by Western blotting.Results:Compared with the control group,the staying time in the"CFA-paired compartment"was significantly reduced,and the PWT was decreased in model group.In the EZM assessment,the distance and the time in open arm,as well as the number of open arm entries of model group were significantly lower than those in the control group.In the CPA assessment,the time spent in the"CFA-paired compartment"was significantly decreased in model group compared with control group,and EA reversed the changes in pain sensation and in pain-related emotions.Western blotting showed that the NPY level,but not the levels of GAD67 and PV,was significantly increased in the ACC of the model group compared to that of the control group.The increased expression of NPY in the ACC was significantly downregulated by EA,while sham EA produced no such effect.Conclusion:EA can effectively relieve the pain and pain-related emotions,and its mechanism may be achieved by down-regulating the expression of NPY in the ACC.

High frequency heart rate variability evoked by repetitive transcranial magnetic stimulation over the medial prefrontal cortex: A preliminary investigation on brain processing of acute stressor-evoked cardiovascular reactivity

Introduction: Transcranial Magnetic Stimulation (TMS) is a non-invasive technique for brain stimulation. Repetitive TMS (rTMS) over the medial Prefrontal Cortex (mPFC), Broadman Area 10 (BA10) may stimulate transynaptically perigenual Anterior Cingulate Cortex (pACC, BA 33), insula, amigdala, hypothalamus and connected branches of the Autonomic Nervous System (ANS) involved in stressorevoked cardiovascular reactivity. Stressors are associated with an increase in sympathetic cardiac control, a decrease in parasympathetic control, or both, and, consequently, an increase in systolic/stroke volume, total vascular impedance/resistance and heart rate, a decrease of baroreflex sensitivity, i.e., an increase in blood pressure/arterial tension. Objectives and Aims: The present work aims, using TMS and accordingly to Gianaros modeling, based on functional neuroimaging studies and previous neuroanatomical data from animal models, to probe the connectivity of brain systems involved in stressor-evoked cardiovascular reactivity and to explore TMS potential as a tool for detection and stratification of individual differences concerning this reactivity and hemorreological risk factors correlated with the development of Coronary Heart Disease (CHD). Methods: Both subjects, a 52 years old male and a 40 years old female with previous increased Low Frequency (LF)/High Frequency (HF) Heart Rate Variability (HRV) ratios (respectively, 4.209/3.028) without decompensated cardiorespiratory symptoms, gave informed consent, and ethico-legal issues have been observed. Electroencephalographic (EEG) monitoring has been performed for safety purposes. Immediately after administration, over the mPFC, of 15 pulses of rTMS, during 60 second, with an inductive electrical current, at the stimulating coil, of 85.9 Ampère per μsecond and 66 Ampère per μsecond, respectively, for male and female subjects (a “figure-of-eight” coil and magnetic stimulator MagLite, Dantec/Medtronic, have been used), HRV spectrum analysis (cStress software) has been performed (during 5 minutes, in supine position). Results: In both subjects, LF power, HF power and LF/HF ratio results, before and after rTMS administration, pointed towards sympathetic attenuation and parasympathetic augmentation (respectively, in male/female subject: decreased LF power—65.1 nu/69.3 nu, before rTMS;56.1 nu/41.6 nu, after rTMS;increased HF power—15.5 nu/22.9 nu, before rTMS;30.9 nu/45.5 nu, after rTMS). Conclusions: In this preliminary investigation, the existence of a link between “mind” and heart’s function has been put in evidence, through a reversible “virtual” lesion, of brain systems involved in cardiovascular control, caused by TMS. Repetitive TMS over mPFC decreased brain function involved in stressorevoked cardiovascular reactivity, suggesting the importance of TMS in the management of stress-related cardiovascular disorders.

Electroacupuncture at Tianshu (ST 25) for diarrhea-predominant irritable bowel syndrome using positron emission tomography Changes in visceral sensation center

Previous studies have demonstrated that electroacupuncture therapy is effective in the treatment of irritable bowel syndrome. However, the precise mechanism of this therapy is unknown. The present study served to investigate the effects of electroacupuncture therapy on treatment of patients with diarrhea-predominant irritable bowel syndrome （IBS）. We compared brain activation maps based on the changes of cerebral glucose metabolism obtained by 18-fluorodeoxyglucose positron emission tomography scanning under three conditions： resting, rectal balloon distension and rectal balloon distension plus electroacupuncture. Under the resting condition, compared with healthy controls, IBS patients displayed an increasing regional cerebral metabolic rate of glucose over a wide range： bilateral superior temporal gyrus, right middle occipital gyrus, superior frontal gyrus and bilateral middle frontal gyrus. However, there was no significant activity in the visceral pain center. Compared with the resting condition, under the rectal balloon distension condition, patients with IBS had a greater regional cerebral metabolic rate of glucose in the prefrontal cortex, left anterior cingulate cortex, postcentral gyrus, precentral gyrus and temporal gyrus. Under the rectal balloon distension plus electroacupuncture condition, stimulation by electroacupuncture at Tianshu （ST 25） manifested a decreased regional cerebral metabolic rate of glucose in the left cingulate gyrus, right insula, right caudate nucleus, fusiform gyrus and hippocampal gyrus. Electroacupuncture therapy relieved abdominal pain, distension or discomfort by decreasing glucose metabolism in the brain.

Assessment of Stress Cognitive Control and Executive Function with Stress Control Rating Scale (ECOSTRESS) and Low Resolution Brain Electromagnetic Tomography (LORETA) (In Portuguese People in Situations of Unemployment and Economic Insufficiency)

This article reviews the constructs of stress, appraisal, coping, according to a transactional perspective, and executive function, and presents a stress control rating scale (ECOSTRESS), which design is founded in these constructs. This psychometric tool is useful in the assessment of cognitive control of stress, correlated with the function of dorsolateral prefrontal cortex. It has been validated for its use in the assessment of Portuguese people in situations of stress related to unemployment and economic insufficiency. Also, within the context of the cognitive control of stress, it is highlighted the usefulness of low resolution brain electromagnetic tomography (LORETA).

Music in depression: Neural correlates of emotional experience in remitted depression

AIM: To investigate neural and behavioral correlates of emotional experiences as potential vulnerability markers in remitted depression. METHODS: Fourteen remitted participants with a history of major depression and fourteen closely matched healthy control participants took part in the study. We used two psychiatric interviews(Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale) and one self-report scale(Beck Depression Inventory) to assess remission. Healthy control participants were interviewed by an experienced psychiatrist to exclude those who showed any current or lifetime psychiatric or neurological disorders. To explore psychosocialand cognitive-interpersonal underpinnings of potential vulnerability markers of depression, early life stress, coping styles and alexithymia were also assessed. We induced pleasant and unpleasant emotional states using congruent combinations of music and human emotional faces to investigate neural and behavioral correlates of emotional experiences; neutral stimuli were used as a control condition. Brain responses were recorded using functional magnetic resonance imaging. Behavioral responses of pleasantness, arousal, joy and fear were measured via button-press inside the resonance imaging scanner. RESULTS: The mean age of the sample was 54.9(± 11.3) years. There were no differences between remitted depressed(RD)(n = 14; 9 females and 5 males) and healthy participants(n = 14; 8 females and 6 males) regarding age, current degree of depression, early life stress, coping styles and alexithymia. On a neural level, RD participants showed reduced activations in the pregenual anterior cingulate cortex(pg ACC) in response to pleasant [parameter estimates:-0.78 vs 0.32; t(26) =-3.41, P < 0.05] and unpleasant [parameter estimates:-0.88 vs 0.56; t(26)=-4.02, P < 0.05] emotional stimuli. Linear regression analysis revealed that pg ACC activity was modulated by early life stress [β =-0.48; R2 = 0.23, F(1,27) = 7.83, P < 0.01] and taskoriented coping style [β = 0.63; R2 = 0.37, F(1,27) = 16.91, P < 0.001]. Trait anxiety modulated hippocampal responses to unpleasant stimuli [β = 0.62; R2= 0.38, F(1,27) = 15.95, P < 0.001]. Interestingly, in their reported experiences of pleasantness, arousal, happiness and fear in response to pleasant, unpleasant and neutral stimuli, RD participants did not differ significantly from healthy control participants. Adding trait anxiety or alexithymia as a covariate did not change the results.CONCLUSION: The present study indicates that, in euthymic individuals, depression history alters neural correlates, but not the subjective dimension of pleasant and unpleasant emotional experiences.

Stress prevention by modulation of autonomic nervous system (heart rate variability): A preliminary study using transcranial direct current stimulation

Introduction: Transcranial Direct Current Stimulation (tDCS) is a non-invasive, technique for brain stimulation. Anodal stimulation causes neuronal depolarisation and long-term potentiation, while cathodal stimulation causes hyperpolarisation and long-term depression. Stressors are associated with an increase in sympathetic cardiac control, a decrease in parasympathetic control, or both. Associated with these reactions is a frequently reported increase in Low Frequency (LF) Heart Rate Variability (HRV), a decrease in High Frequency (HF) power, and/or an increase in the LF/HF ratio. Objectives and aims: The present work aims to explore the tDCS potential in the modulation of the Autonomic Nervous System (ANS), through indirect stimulation of Anterior Cingulate Cortex (ACC). Methods: Two subjects, a 39 year old female and a 49 year old male, gave informed consent. Saline soaked synthetic sponges involving two, thick, metalic (stainless steel) rectangles, with an area of 25 cm2 each have been used as electrodes, connected to Iomed Phoresor II Auto device. It has been delivered a 2 mA current, for 20 minutes, over the left Dorsolateral Prefrontal Cortex (DLPFC) (Anode). Spectrum analysis (cStress software) of HRV has been performed before and after tDCS administration. Results: The female/male subject results of LF power, HF power and LF/HF ratio, before tDCS administration, were, respectively: 50.1 nu/60 nu, 46.1 nu/21.7 nu and 1.087/2.771;and, after tDCS administration, respectively: 33.5 nu/52.7 nu, 47.6 nu/ 22.8 nu and 0.704/2.312. Conclusions: tDCS over the left DLPFC (left ACC) increased parasympathetic activity and decreased sympathetic activity, suggesting the importance of tDCS in the management of stress-related disorders.

Effect of Level of Processing Prior to Response on Cognitive Control:Evidence from ERP

Based on the idea that intentions have different penetrability to perception and thought, four Stroop-like tasks, AA, AW, WA, and WW are used. Event-related brain potentials are recorded as participants completed these tasks, and standardized low resolution brain electromagnetic tomography （sLORETA） is used to localize the sources at specific time points. These results show that there is an interference effect in the AA and WA tasks, but not in the AW or WW tasks. The activated brain areas related to the interference effect in the AA task are the PFC （prefrontal cortex） and ACC （anterior cingulated cortex）, and PFC aetivation takes place prior to ACC activation, but only in WA task. Combined with previous results, a new neural mechanism of cognitive control is proposed.

Abnormal functional connectivity with mood regulating circuit in unmedicated individual with major depression： a resting-state functional magnetic resonance study

Background Reports on mood regulating circuit （MRC） indicated different activities between depressed patients and healthy controls. The functional networks based on MRC have not been described in major depression disorder （MDD）. Both the anterior cingulate cortex （ACC） and thalamus are all the key regions of MRC. This study was to investigate the two functional networks related to ACC and thalamus in MDD. Methods Sixteen patients with MDD on first episode which never got any medication and sixteen matched health controls were scanned by 3.0 T functional magnetic resonance imaging （fMRI） during resting-state. The pregenual anterior cingulate cortex （pgACC） was used as seed region to construct the functional network by cortex section. The thalamus was used as seed region to construct the functional network by limbic section. Paired-t tests between-groups were performed for the seed-target correlations based on the individual fisher z-transformed correlation maps by SPM2. Results Depressed subjects exhibited significantly great functional connectivity （FC） between pgACC and the parahippocampus gyrus in one cluster （size 923） including left parahippocampus gyrus （-21, -49,7）, left parietal lobe （-3, -46, 52） and left frontal lobe （-27, -46, 28）. The one cluster （size 962） of increased FC on thalamus network overlapped the precuneus near to right parietal lobe （9, -52,46） and right cingulate gyrus （15, -43, 43） in health controls. Conclusions Abnormal functional networks exist in earlier manifestation of MDD related to MRC by both cortex and limbic sections. The increased functional connectivity of pgACC and decreased functional connectivity of thalamus is mainly involved in bias mood processing and cognition.