Converging effects of diverse treatment modalities on frontal cortex in schizophrenia: A review of longitudinal functional magnetic resonance imaging studies

ObjectivesA variety of treatment options exist for schizophrenia, but the effects of these treatments on brain function are not clearly understood. To facilitate the development of more effective treatment strategies, it is important to identify how brain function in schizophrenia patients is affected by the diverse therapeutic approaches that are currently available. The aim of the present article is to systematically review the evidence for functional brain changes associated with different treatment modalities for schizophrenia.MethodsWe searched PubMed for longitudinal functional MRI (fMRI) studies reporting on the effects of antipsychotic medications (APM), repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), cognitive remediation therapy (CRT) and cognitive behavioral therapy for psychosis (CBTp) on brain function in schizophrenia.ResultsThirty six studies fulfilled the inclusion criteria. Functional alterations were observed in diverse brain regions. Across intervention modalities, changes in fMRI parameters were reported most commonly in frontal brain regions including prefrontal cortex, anterior cingulate and inferior frontal cortex.ConclusionsWe conclude that current treatments for schizophrenia commonly induce functional brain alterations in frontal brain regions. However, interpretability is limited by inconsistency in task and region of interest selection, and failures to replicate. Further task independent fMRI studies examining treatment effects with whole brain analysis are needed to deepen our insights.     

Non-invasive brain stimulation in Parkinson’s disease: Exploiting crossroads of cognition and mood

Cognitive impairments and depression are common non-motor manifestations in Parkinson’s disease (PD). Recent evidence suggests that both partially arise via the same frontostriatal network, opening the opportunity for concomitant treatment with non-invasive brain stimulation (NIBS) techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS).In this systematic review, we evaluate the effects of NIBS on cognition and/or mood in 19 placebo-controlled studies involving 561 PD patients. Outcomes depended on the area stimulated and the technique used. rTMS over the dorsolateral-prefrontal cortex (DLPFC) resulted in significant reductions in scores of depressive symptoms with moderate to large effect sizes along with increased performance in several tests of cognitive functions. tDCS over the DLPFC improved performance in several cognitive measures, including executive functions with large effect sizes. Additional effects of tDCS on mood were not detectable; however, only non-depressed patients were assessed. Further confirmatory research is needed to clarify the contribution that NIBS could make in the care of PD patients.     

Resting-state EEG gamma power and theta–gamma coupling enhancement following high-frequency left dorsolateral prefrontal rTMS in patients with depression

Objective

We aimed to investigate neuromodulatory effects of high-frequency left dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation (rTMS) on resting-state electroencephalography (EEG) and their clinical and cognitive correlates in patients with depression.

Predictors of response to repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder

Repetitive transcranial magnetic stimulation (rTMS), based on the principle of electromagnetic induction, consists of applying series of magnetic impulses to the cerebral cortex so as to modulate neurone activity in a target zone. This technique, still experimental, could prove promising in the field of psychiatry, in particular for the treatment of major depressive disorder. It is important for the clinician to be able to assess the response potential of a given patient to rTMS, and this among other things requires relevant predictive factors to be available. This review of the literature aims to determine and analyse reported predictive factors for therapeutic response to rTMS treatment in major depressive disorder. Different parameters are studied, in particular age, the severity of the depressive episode, psychological dimensions, genetic factors, cerebral blood flows via cerebral imagery, and neuronavigation. The factors found to be associated with better therapeutic response were young age, low level of severity of the depressive episode, motor threshold intensity over 100%, more than 1000 stimulations per session, more than 10 days treatment, L/L genotype on the 5-HTTLPR transporter gene, C/C homozygosity on the promotor regions of the 5-HT1A receptor gene, Val/Val homozygosity on the BDNF gene, cordance analyses by EEG, and finally the accurate localisation provided by neuronavigation. The authors conclude that investigations in larger patient samples are required in the future, and that the work already achieved should provide lines of approach for the coming experimental studies.     

rTMS与MECT对难治性抑郁症疗效及认知功能影响的随机对照研究

目的 比较抗抑郁药联合重复经颅磁刺激(rTMS)或无抽搐电休克(MECT)治疗难治性抑郁症的疗效,并探讨两者对抑郁症患者认知功能的影响.方法 将40例难治性抑郁症患者随机分成rTMS治疗组和MECT治疗组,分别于治疗前、治疗1周、2周应用汉密尔顿抑郁量表(HAMD)和临床记忆量表评定临床疗效及认知功能改变,采用不良反应量表(TESS)、生命体征、体格检查、心电图、脑电图评价安全性.结果 两组患者HAMD总分、认知障碍因子分在治疗1周、2周差异无统计学意义(P>0.05);治疗2周后,rTMS组总分及各因子评分均较治疗前提高(P<0.05),MECT组指向记忆、无意义图形再认、人像特点回忆评分较治疗前明显下降(P<0.05);治疗后两组间比较,MECT组患者的临床记忆量表总分、指向记忆、图像自由回忆、人像特点回忆评分均显著低于rTMS组,差异有统计学意义(P<0.05).治疗中两组恶心、呕吐、头痛发生率的差异无统计学意义(P>0.05),MECT组主诉记忆力下降者比例高于rTMS组(P<0.05).结论 rTMS与MECT治疗难治性抑郁症疗效相当,rTMS对认知功能的改善作用优于MECT.     

重复经颅磁刺激治疗脑卒中后抑郁对照研究

目的探讨重复经颅磁刺激治疗脑卒中后抑郁患者的临床疗效。方法将120例脑卒中后抑郁患者随机分为两组,每组60例,两组均接受神经内科常规治疗,研究组联合重复经颅磁刺激治疗,连续治疗1个月,观察6个月。治疗前后采用脑卒中患者临床神经功能缺损程度评分标准评定神经功能缺损状况,采用汉密顿抑郁量表评定抑郁状况。结果治疗1个月、6个月末,研究组汉密顿抑郁量表评分显著低于对照组（u=22．91、19．23,P〈0．01）,神经功能恢复效果显著优于对照组（Х^2=6．99、6．92,P〈0．05）。结论重复经颅磁刺激治疗能显著改善脑卒中后抑郁患者的抑郁情绪,有利于神经功能的恢复。     

Cerebral blood flow in the ventromedial prefrontal cortex correlates with treatment response to low-frequency right prefrontal repetitive transcranial magnetic stimulation in the treatment of depression

Aims: Low‐frequency right prefrontal repetitive transcranial magnetic stimulation (rTMS) is effective in treating depression, and its antidepressant effects have proven to correlate with decreases in cerebral blood flow (CBF) in the orbitofrontal cortex and subgenual cingulate cortex. However, a predictor of treatment response to low‐frequency right prefrontal rTMS in depression has not been identified yet. The aim of this study was to estimate regional CBF in the frontal regions and investigate the correlation with treatment response to low‐frequency right prefrontal rTMS in depression. Methods: We examined 26 depressed patients for the correlation between treatment response to rTMS and regional CBF in the frontal regions, by analyzing their brain scans with ^99mTc‐ethyl cysteinate dimer before rTMS treatment. CBF in 16 brain regions was estimated using fully automated region of interest analysis software. Two principal components were extracted from CBF in 16 brain regions by factor analysis with maximum likelihood method and Promax rotation with Kaiser normalization. Results: Sixteen brain regions were divided into two groups: dorsolateral prefrontal cortex (superior frontal, medial frontal, middle frontal, and inferior frontal regions) and ventromedial prefrontal cortex (anterior cingulate, subcallosal, orbital, and rectal regions). Treatment response to rTMS was not correlated with CBF in the dorsolateral prefrontal cortex, but it was correlated with CBF in the ventromedial prefrontal cortex. Conclusion: These findings suggest that CBF in the ventromedial prefrontal cortex may be a potential predictor of low‐frequency right prefrontal rTMS, and depressed patients with increased CBF in the ventromedial prefrontal cortex may show a better response.     

Resting motor threshold changes and clinical response to prefrontal repetitive transcranial magnetic stimulation in depressed patients

Aims: Several variables are able to influence the antidepressant effects of repetitive transcranial magnetic stimulation (rTMS), particularly the intensity of stimulation, which is generally expressed according to the resting motor threshold (RMT). The aim of our study was to investigate whether or not RMT changes during the treatment of resistant depression by rTMS and whether these fluctuations could alter treatment outcome. Methods: Seventy‐five inpatients suffering from unipolar or bipolar treatment‐resistant depression and who had been antidepressant‐free or taking a stable antidepressant drug and a daily dose of benzodiazepine for at least a month received a left prefrontal rTMS session once a day for 10 days at 10 Hz and 95% RMT. Results: For the whole group, no significant fluctuation of RMT was observed between the first and the second week of rTMS treatment. However, RMT increased, decreased or remained constant throughout treatment depending on the patient. These RMT changes influenced the outcome of the 10 sessions concerning the severity of depressive and anxiety symptoms, measured by the Beck Depression Inventory and State Trait Anxiety, respectively. Conclusions: Our results justify calculating RMT regularly, and suggest that its variations play a role in treatment outcome.     

Transcranial direct current stimulation preconditioning modulates the effect of high-frequency repetitive transcranial magnetic stimulation in the human motor cortex

Experimental studies emphasize the importance of homeostatic plasticity as a mean of stabilizing the properties of neural circuits. In the present work we combined two techniques able to produce short-term (5-Hz repetitive transcranial magnetic stimulation, rTMS) and long-term (transcranial direct current stimulation, tDCS) effects on corticospinal excitability to evaluate whether and how the effects of 5-Hz rTMS can be tuned by tDCS preconditioning. Twelve healthy subjects participated in the study. Brief trains of 5-Hz rTMS were applied to the primary motor cortex at an intensity of 120% of the resting motor threshold, with recording of the electromyograph traces evoked by each stimulus of the train from the contralateral abductor pollicis brevis muscle. This interventional protocol was preconditioned by 15 min of anodal or cathodal tDCS delivered at 1.5 mA intensity. Our results showed that motor-evoked potentials (MEPs) increased significantly in size during trains of 5-Hz rTMS in the absence of tDCS preconditioning. After facilitatory preconditioning with anodal tDCS, 5-Hz rTMS failed to produce progressive MEP facilitation. Conversely, when 5-Hz rTMS was preceded by inhibitory cathodal tDCS, MEP facilitation was not abolished. These findings may give insight into the mechanisms of homeostatic plasticity in the human cerebral cortex, suggesting also more suitable applications of tDCS in a clinical setting.     

Endogenous opioids mediate left dorsolateral prefrontal cortex rTMS-induced analgesia

The concurrent rise of undertreated pain and opiate abuse poses a unique challenge to physicians and researchers alike. A focal, noninvasive form of brain stimulation called repetitive transcranial magnetic stimulation (rTMS) has been shown to produce acute and chronic analgesic effects when applied to dorsolateral prefrontal cortex (DLPFC), but the anatomical and pharmacological mechanisms by which prefrontal rTMS induces analgesia remain unclear. Data suggest that DLPFC mediates top-down analgesia via gain modulation of the supraspinal opioidergic circuit. This potential pathway might explain how prefrontal rTMS reduces pain. The purpose of this sham-controlled, double-blind, crossover study was to determine whether left DLPFC rTMS-induced analgesia was sensitive to μ-opioid blockade. Twenty-four healthy volunteers were randomized to receive real or sham TMS after either intravenous saline or naloxone pretreatment. Acute hot and cold pain via quantitative sensory testing and hot allodynia via block testing on capsaicin-treated skin were assessed at baseline and at 0, 20, and 40 minutes after TMS treatment. When compared to sham, real rTMS reduced hot pain and hot allodynia. Naloxone pretreatment significantly reduced the analgesic effects of real rTMS. These results demonstrate that left DLPFC rTMS-induced analgesia requires opioid activity and suggest that rTMS drives endogenous opioidergic pain relief in the human brain. Further studies with chronic dosing regimens of drugs that block or augment the actions of opiates are needed to determine whether TMS can augment opiates in chronic or postoperative pain management.