A narrative review on invasive brain stimulation for treatment-resistant depression

While most patients with depression respond to pharmacotherapy and psychotherapy, about one-third will present treatment resistance to these interventions. For patients with treatment-resistant depression (TRD), invasive neurostimulation therapies such as vagus nerve stimulation, deep brain stimulation, and epidural cortical stimulation may be considered. We performed a narrative review of the published literature to identify papers discussing clinical studies with invasive neurostimulation therapies for TRD. After a database search and title and abstract screening, relevant English-language articles were analyzed. Vagus nerve stimulation, approved by the U.S. Food and Drug Administration as a TRD treatment, may take several months to show therapeutic benefits, and the average response rate varies from 15.2-83%. Deep brain stimulation studies have shown encouraging results, including rapid response rates (> 30%), despite conflicting findings from randomized controlled trials. Several brain regions, such as the subcallosal-cingulate gyrus, nucleus accumbens, ventral capsule/ventral striatum, anterior limb of the internal capsule, medial-forebrain bundle, lateral habenula, inferior-thalamic peduncle, and the bed-nucleus of the stria terminalis have been identified as key targets for TRD management. Epidural cortical stimulation, an invasive intervention with few reported cases, showed positive results (40-60% response), although more extensive trials are needed to confirm its potential in patients with TRD.

Posterior cingulate gyri metabolic alterations in HIV-positive patients with and without memory deficits / Alterações metabólicas no giro do cíngulo posterior em pacientes HIV-positivos com e sem déficit de memória

Abstract Objective: We aimed to evaluate whether human immunodeficiency virus (HIV)-positive patients with and without clinically significant memory deficits and healthy control participants differ on in vivo hydrogen-1 magnetic resonance spectroscopy (H-MRS) in the posterior cingulate gyri. Materials and Methods: In total, 21 HIV-positive patients with memory deficit (HIV+wMD) were compared with 15 HIV-positive patients without memory deficit (HIV+wOMD) and 22 sex-, age-, and education-matched control participants. Memory impairments were classified based on the participants' performance on the Rey Auditory Verbal Learning Test. Short echo time (30 ms), single-voxel H-MRS was performed using a 1.5-T magnetic resonance scanner. Results: The HIV+wMD and HIV+wOMD groups had higher choline/creatine ratio in the posterior cingulate gyri than the control group. There were no significant metabolite ratio differences between the HIV+wMD and HIV+wOMD groups. Conclusion: HIV-positive patients with and without memory deficits had significantly higher choline/creatine ratios than controls in the posterior cingulate gyri, which may reflect cerebral inflammation, altered cell membrane metabolism, microgliosis, and/or astrocytosis.

Resumo Objetivo: Nós avaliamos se os pacientes HIV-positivos com e sem déficits de memória clinicamente significativos e controles saudáveis diferem na espectroscopia de prótons do giro do cíngulo posterior, por ressonância magnética (RM) cerebral. Materiais e Métodos: Vinte e um pacientes HIV-positivos com déficit de memória foram comparados com 15 pacientes HIV-positivos sem déficit de memória e 22 controles, pareados por sexo, idade e escolaridade. As deficiências de memória foram classificadas por meio do desempenho no Teste de Aprendizagem Auditivo-Verbal de Rey. A espectroscopia de prótons foi realizada com tempo de eco curto (30 ms), por voxel único, no giro do cíngulo posterior, utilizando aparelho de RM de 1,5 T. Resultados: Os pacientes HIV-positivos com e sem déficit de memória apresentaram aumento da relação colina/creatina no giro do cíngulo posterior, comparados aos controles. Não houve diferenças significativas nas relações metabólicas no grupo HIV-positivo com déficit de memória, em relação ao grupo de pacientes HIV-positivo sem déficit. Conclusão: Pacientes HIV-positivos com e sem déficits de memória apresentaram relações colina/creatina significativamente aumentadas em relação aos controles, no giro do cíngulo posterior, o que pode refletir inflamação cerebral, alteração do metabolismo da membrana celular, microgliose e/ou astrocitose.

Comparison of the effect between electroacupuncture and NSAIDs on pain memory based on cAMP/PKA/CREB pathway in anterior cingulate gyrus / 中国针灸

OBJECTIVE@#To observe the direct intervention effects of electroacupuncture (EA) and non-steroid anti-inflammatory drugs (NSAIDs) on pain memory, and to explore their effects on cAMP/PKA/cAMP pathway in anterior cingulate gyrus (ACC).@*METHODS@#Fifty clean healthy male SD rats were randomly divided into a control group, a model group, an indomethacin group, an EA group and a sham EA group, 10 rats in each group. Except the control group, the pain memory model was established in the remaining four groups by twice injection of carrageenan at foot; 0.1 mL of 2%λ-carrageenan was subcutaneously injected at the left foot of rats; 14 days later, when the pain threshold of rats of each group returned to the basic level, the second injection was performed with the same procedure. The rats in the EA group were treated with EA at bilateral "Zusanli" (ST 36) for 30 min; the rats in the indomethacin group was treated with indomethacin intragastric administration with the dose of 3 mg/kg; the rats in the sham EA group was treated with EA without electricity at the point 0.3 mm forward "Zusanli" (ST 36) with the depth of 2 mm for 30 min; the rats in the control group was not given any invention. All the above interventions were performed 5 h, 1 d, 2 d and 3 d after the second injection of 2% λ-carrageenan. The left-side paw withdrawal thresholds (PWT) were observed before the first injection, 4 h, 3 d, 5 d after the first injection, before the second injection and 4 h, 1 d, 2 d, 3 d after the second injection. Three days after the second injection, the number of positive cells of cAMP, p-PKA, p-CREB and the number of positive cells of protein co-expression in the right ACC brain area were detected by immunofluorescence, and the relative protein expression of p-PKA and p-CREB were detected by Western blot.@*RESULTS@#Compared with the control group, the PWTs in the model group decreased significantly 4 h, 3 d and 5 d after the first injection and 1 d, 2 d and 3 d after the second injection (<0.05); compared with the control group, the positive expression of cAMP, p-PKA and p-CREB in the right ACC brain area in the model group increased significantly (<0.05), and the number of positive cells of the co-expression of cAMP/p-PKA and p-PKA/p-CREB also increased significantly (<0.05). Compared with the model group, indomethacin group and sham EA group, the PWTs in the EA group were increased significantly 1 d, 2 d and 3 d after the second injection (<0.05); compared with the model group, indomethacin group and sham EA group, the positive expression of p-PKA and p-CREB in the right ACC brain area in the EA group decreased significantly (<0.05), and the number of positive cells of co-expression of cAMP/p-PKA and p-PKA/p-CREB was decreased significantly (<0.05). Compared with the model group and sham EA group, the positive expression of cAMP in the right ACC brain area was decreased in the EA group (<0.05).@*CONCLUSION@#EA have a direct intervention effect on pain memory, which have significant advantage over NSAIDs in the treatment of chronic pain. The advantage effect of EA on pain memory may be related to the inhibition of cAMP/PKA/CREB pathway in ACC area.

Primary research of multi-voxel proton-magnetic resonance spectroscopy in Alzheimer's disease / 实用放射学杂志

Objective To explore the spatial distribution of abnormal brain areas and metabolic changes in Alzheimer's disease (AD),and provide a reference for early clinical diagnosis of AD.Methods Sixteen cases of AD patients and 1 6 healthy controls (HC)underwent multi-voxel 1H-MRS examination with semi-LASER sequence.The posterior cingulate gyrus section was localized as the volume of interest(VOI)level.The VOI consisted of bilateral posterior cingulate gyrus,occipital lobe cortex,lateral ventricle paratrigonal white matter and dorsal thalamus.N-acetylaspartate (NAA),creatine (Cr),choline (Cho),myo-inositol (MI)and glutamate-glutamine (Glx)concentration were measured.Differences in metabolite were compared between AD and HC groups.Relationships between metabolite and clinical mini-mental state examination(MMSE)score were analyzed.Results For metabolite index in VOI of right hemisphere:the AD group displayed significantly lower NAA,NAA/Cr,NAA/MI and higher MI,MI/Cr levels in posterior cingulate gyrus,lower NAA,Glx levels in occipital lobe cortex,lower NAA and higher Cho levels in dorsal thalamus.For metabolite index in VOI of left hemisphere:the AD group displayed significantly lower NAA,NAA/Cr,NAA/MI,Glx/Cr and higher MI/Cr levels in posterior cingulate gyrus,lower NAA and higher Cho/Cr levels in occipital lobe cortex,lower NAA and higher cho levels in lateral ventricle paratrigonal white matter,lower Glx and higher Cho levels in dorsal thalamus.NAA/Cr was positively correlated with Glx/Cr in left posterior cingulate gyrus in AD group.Conclusion NAA is decreased while MI is increased in posterior cingulate gyrus in AD patients.Cho is increased in both grey and white matter.Glx is decreased mainly within grey matter,involving both cortex and sub cortex structures.

1H-MRS detection of metabolites in posterior cingulate gyrus of Parkinson disease with cognitive impairment patients / 中国医学影像技术

Objective To investigate the value of 1H-MRS technology combined with linear combination model (LCmodel) software in diagnosis of Parkinson disease (PD) cognitive impairment.Methods Thirty-five PD patients (PD group) and 22 matched healthy subjects (control group) were collected.Patients in PD group were divided into PDN and PDMCI subgroups according to whether having cognitive impairment or not.The concentration of metabolites of posterior cingulate gyrus (PCG)was applied with 1H-MRS technology combined with LCmodel software.The differences of metabolites were compared between the two groups,and the correlations between metabolites level and cognitive status were analyzed.Results The absolute concentrations of metabolites in PDN subgroup were not significantly different from those in control group (all P＞0.05).The absolute concentrations of total creatine (tCr),N-acetyl aspartate (NAA),myo-inositol (mI) and glycerophosphocholine+ phosphocholine (tCho) in PDMCI subgroup were lower than those in control group (all P＜0.05).The absolute concentration of tCr in PDMCI subgroup was lower than that in PDN subgroup (P＜0.05).There was positive correlation among the absolute concentration of tCr (r=0.444,P=0.01),glutathione (GSH;r=0.393,P=0.024) and MMSE scores,as well as among the absolute concentration of tCr (r=0.367,P=0.035),GSH (r=0.376,P=0.031),tCho (r=0.375,P=0.031) and MoCA scores.Conclusion 1 H-MRS technology combined with LCmodel software can quantitatively analyze the changes of metabolites in PCG,therefore being helpful to evaluating PD cognitive impairment.

Basal Forebrain Cholinergic Deficits Reduce Glucose Metabolism and Function of Cholinergic and GABAergic Systems in the Cingulate Cortex

PURPOSE: Reduced brain glucose metabolism and basal forebrain cholinergic neuron degeneration are common features of Alzheimer's disease and have been correlated with memory function. Although regions representing glucose hypometabolism in patients with Alzheimer's disease are targets of cholinergic basal forebrain neurons, the interaction between cholinergic denervation and glucose hypometabolism is still unclear. The aim of the present study was to evaluate glucose metabolism changes caused by cholinergic deficits. MATERIALS AND METHODS: We lesioned basal forebrain cholinergic neurons in rats using 192 immunoglobulin G-saporin. After 3 weeks, lesioned animals underwent water maze testing or were analyzed by 18F-2-fluoro-2-deoxyglucose positron emission tomography. RESULTS: During water maze probe testing, performance of the lesioned group decreased with respect to time spent in the target quadrant and platform zone. Cingulate cortex glucose metabolism in the lesioned group decreased, compared with the normal group. Additionally, acetylcholinesterase activity and glutamate decarboxylase 65/67 expression declined in the cingulate cortex. CONCLUSION: Our results reveal that spatial memory impairment in animals with selective basal forebrain cholinergic neuron damage is associated with a functional decline in the GABAergic and cholinergic system associated with cingulate cortex glucose hypometabolism.

Stress effect on neurons of cingulate gyrus in postweaned albino mice - A histological study.

Stress is a common experience of daily life and all organisms have evolved mechanisms and strategies to deal with crucial alterations in their internal and external environment. Events early in post- weaning life influence brain development and subsequent adult behaviour. This study was conducted to observe neurodegeneration in normal and stressed condition in Postweaning age group of miceExperiments were conducted to investigate the effect of restraint stress and foot shock stress applied for 5 days (short duration) and 21 days (long duration). BALB/ C strain of Albino mice were used. In restraint stress, animals were restrained for 6 hours daily in a restraining device. In foot shock group, animals were given intermittent electric foot shock for 3 hours daily in an electric foot shock apparatus. Animal were sacrificed at the end of stress exposure period along with their age matched control mice and the brains were processed for histological examination both in control and experimental groups. Numbers of v Rao MK, Sushma RK. Stress effect on neurons of cingulate gyrus in study. IAIM, 2015; 2(7): 30-35. - A histological , B2*, Antony Sylvan , SD4, Mohandas Rao K5, Sushma RK Anatomy, Kasturba Medical College, Ma Associate Anatomy, Kasturba Medical College, Manipal University, Anatomy, Kasturba Medical College, Ma Associate Physiology, Kasturba Medical College, Manipal University, Medical College, Manipal University, Manipal, Kasturba Medical College, Manipal University, Manipal, Integrated Medicine, Vol. 2, Issue 7, July Copy right © 2015, IAIM, All Rights Reserved. Available online at http://iaimjournal.com/ ISSN: 2394-0026 (P) ISSN: 2394-0034 (O) 16-06-2015 Accepted on: 24 Nil Conflict of interest: Events early in post adult behaviour. This study was conducted t hours daily in an electric foot shock viable neurons in the cingulate gyrus regions were counted. The data were analysed between the groups. Results of the study revealed neurodegenerative changes in the stressed group compared to control in both the experimental groups. Severe neurodegenerative changes were observed on prolonged exposure to stress.

Brain structure and neural network of the reward/loss process in decision making / 中华行为医学与脑科学杂志

Objective Based on the literatures published between 2005 and 2014,review the correlation between reward/loss of brain structure and neural network,and its relationship with physical and mental ailments,aim to reveal the neural structure and network of behavioral decision mechanism.Methods By retrieving literatures on PubMed,ScienceDirect,CNKI and Wanfang database in September 2014,we used decision making,reward,loss aversion and so on as the key words.Results Totally 40 papers were enrolled,the result reviewed the clinic meaning and the brain structure and neural network of the reward/loss process in decision making.Conclusion Most studies found the reward/loss decision making mechanism of the brain structure and the physical and mental ailments caused by the two systems imbalance,but related to the precise decision making neural mechanism has yet to be studied further.

A Comparative Study of Membrane Electrical Properties of Visceral and Somatic Nociceptive Neurons of Anterior Cingulate Gyrus in Cats / 中国医科大学学报

Objective To perform a comparative study on membrane electrical properties of visceral and somatic nociceptive neurons of anterior cin?gulate gyrus(ACG)in cats,so as to provide the experimental basis for elucidating the mechanism of differences in perceptual qualities between vis?ceral pain and somatic pain from the membrane electrical aspects. Methods A total of 77 adult cats,female or male,weighting 2.0 to 3.5 kg were selected for the study. According to the properties of the greater splanchnic nerve(GSN)or saphenous nerve(SN)evoked responses of neurons in ACG and effect of morphine on the evoked responses,visceral nociceptive neurons(VNNs)having the long latency(≥50 ms)GSN evoked re?sponses or somatic nociceptive neurons(SNNs)having the long latency(≥50 ms)SN evoked responses were detected. With a glass microelectrode in vivo,a series of polarizing current of different intensity from-5 nA to+5 nA with a 50 ms duration were injected to these neurons in ACG,and the membrane electrical responses of these neurons were recorded. Finally,the membrane electrical parameters of these neurons were calculated. Re?sults Totally 254 VNNs and 172 SNNs were recorded in ACG. GSN evoked response threshold of VNNs were higher than SN evoked response threshold of SNNs. Compared with SNNs,the membrane resistance,the membrane capacity and the time constant of VNNs were larger. Conclusion Our data proved that there are some differences in the membrane electrical properties between VNNs and SNNs in ACG,which might be the mem?brane electrical basis for differences in perceptual qualities between visceral pain and somatic pain.

Effect of GR82334 on the Electric Stimulation-induced Increase of Dopamine Content in Anterior Cingulate Gyrus in Rats / 中国医科大学学报

Objective To investigate the effects of GR82334 caudal veins injection(iv)or intrathecal injection(ith)on the increase of dopamine (DA)content in rats anterior cingulate gyrus(ACG)induced by heavy current stimulation of saphenous nerve(SN). Methods Totally 42 male Wi-star rats were randomly divided into six groups,including control group,sham stimulation group,SN stimulation group,GR82334(ith)group,NS (ith)group,GR82334(iv)group,and NS(iv)group. At the end of the study,rats of different groups were sacrificed,then the right side ACG were collected and weighted. ACG samples were then homogenized with 0.1 mol/L perchloric acid solution. After spinning at 10 000 r/min(4℃)for 20 min,20μL of the supernatant were harvest from each sample. High performance liquid chromatography electrochemical detection was used to mea-sure DA content. Results Heavy current stimulation of SN caused obvious increase of the DA content in ACG. GR82334(iv or ith)antagonized the significant increase of DA content in ACG induced by the stimulating SN. However,GR82334(ith)did not completely antagonized the increase of DA content in ACG induced by electric stimulating SN. Conclusion The results indicated that there is connection between SN and the dopami-nergic nervous system in ACG,and SN afferent nociceptive signals can activate ACG dopaminergic neurons to release DA. Peripheral and central NK-1 receptors are involved in the process of significant increase of DA content in ACG induced by SN afferent signals. However,there are other central paths of SN information input to ACG to induce obvious increases of DA content,in which other neurotransmitters and receptors may be involved.

The fronto-cingulate executive function in recurrent depression revealed by the magnetic source imaging / 中华行为医学与脑科学杂志

ObjectiveTo investigate the variation of executive function of fronto-cingulate cortex in spatio-temporal sequence in recurrent depressed patients.MethodsEighteen recurrent depressed patients and twenty-one age-,gender- and education- matched healthy controls were involved in the Stroop word-color interference test to detect the executive function of anterior cingulate and prefrontal regions by magnetoencephaloraphy scanning.Results 1.Compared to healthy controls,the increased activation of brain regions in depressed patients during different time periods were separately shown as follows( t represents activation strength):( 1 ) 100 ～ 200 ms:the right anterior cingulate gyrus ( t =1.81,T value means activation strength),the bilateral medial frontal gyrus ( t =1.91,t =1.86),the left superior frontal gyms( t =1.79 ),the right middle frontal gyrus( t =1.82 ),the right inferior frontal gyrus ( t =1.82 ).( 2 ) 200 ～ 300 ms:the left anterior cingulate gyrus ( t =1.82 ).( 3 ) 250 ～ 350 ms:the left anterior cingulate gyrus ( t =2.67 ),the left medial frontal gyrus ( t =2.43 ),the left inferior frontal gyrus ( t=1.91 ).(4)300 ～400ms:the left anterior frontal gyrus(t=2.26),the bilateral inferior gyrus( t=1.97,t=2.66),the left medial frontal gyrus(t=2.35).(5)350 ～450ms:the left anterior cingulate gyrus(t=2.02),the left medial frontal gyrus ( t =2.00),the bilateral inferior frontal gyrus ( t =1.74,t =1.78 ).( 6 ) 400 ～ 500 ms:the left anterior cingulate gyrus( t=2.01 ),the left medial frontal gyrus( t =1.97).2.Compared to healthy controls,patients showed decreased activation in the left middle frontal gyms ( t =1.79) and the left superior gyrus(t =1.76) in 200 ～ 300 ms.ConclusionExecutive dysfunction is reflected in depressed patients with the activation inefficiency in anterior cingulate and prefrontal regions in spatio-temporal sequence.

Neural Substrates of Posttraumatic Stress Disorder: Functional Magnetic Resonance Imaging Study Using Negative Priming Task

OBJECTIVES: Posttraumatic stress disorder(PTSD) has been primarily associated with emotional problems. Recently, however, the impact of PTSD on cognitive processes has interested a growing number of researchers. The current study is aimed at investigating the cognitive aspects of PTSD at both behavioral and neurological levels. METHODS: We recruited individuals with PTSD who survived the Daegu subway explosion in 2003 as well as non-PTSD individuals as a control group. To evaluate the inhibitory processes and the neural mechanisms, we had these individuals perform the negative priming task simultaneously with functional MRI scanning. RESULTS: Behaviorally, the negative priming effect was intact in the control group but was not evident in the PTSD group. In the imaging results, only the PTSD group showed the negative priming effect (i.e., increased activation of the negative priming condition as opposed to the neutral condition) in the dorsolateral prefrontal cortex, anterior cingulate cortex, and inferior temporal gyrus. The PTSD group also showed increased activity for the positive priming condition as opposed to the neutral condition in the claustrum. These results confirm and extend the previous findings that the integrity of the ACC is compromised in the trauma survivors due to disrupted white matter tract. CONCLUSIONS: The current results suggest that deteriorated performance of the PTSD group may be due to the functional problem as well as the structural abnormalities.