Dopamine in the prefrontal cortex plays multiple roles in the executive function of patients with Parkinson's disease

Parkinson’s disease can affect not only motor functions but also cognitive abilities,leading to cognitive impairment.One common issue in Parkinson’s disease with cognitive dysfunction is the difficulty in executive functioning.Executive functions help us plan,organize,and control our actions based on our goals.The brain area responsible for executive functions is called the prefrontal co rtex.It acts as the command center for the brain,especially when it comes to regulating executive functions.The role of the prefrontal cortex in cognitive processes is influenced by a chemical messenger called dopamine.However,little is known about how dopamine affects the cognitive functions of patients with Parkinson’s disease.In this article,the authors review the latest research on this topic.They start by looking at how the dopaminergic syste m,is alte red in Parkinson’s disease with executive dysfunction.Then,they explore how these changes in dopamine impact the synaptic structure,electrical activity,and connection components of the prefrontal cortex.The authors also summarize the relationship between Parkinson’s disease and dopamine-related cognitive issues.This information may offer valuable insights and directions for further research and improvement in the clinical treatment of cognitive impairment in Parkinson’s disease.

Atrophy of the left dorsolateral prefrontal cortex is associated with poor performance in verbal fluency in elderly poststroke women

This study aimed to investigate the association between atrophy in the prefrontal cortex with executive function and verbal fluency in elderly male and female patients poststroke. Thirty elderly female patients with non-aphasic ischemic stroke aged -〉 60 years and 30 age-matched non-aphasic male patients with ischemic stroke were recruited. Automatic magnetic resonance imaging segmentation was used to assess the volume of the whole prefrontal cortex, along with its subdivisions： anterior cingulate cortex, orbitofrontal cortex and dorsolateral prefrontal cortex. The Semantic Verbal Fluency Test was administered at 3 and 15 months poststroke. At 3 months poststroke, left dorsolateral prefrontal cortex volume was significantly correlated with Verbal Fluency Test score in female patients only （partial coefficient = 0.453, P = 0.045）, after controlling for age, education, diabetes, neurological deficit, white matter lesions volume, as well as the location and volume of infarcts. At 15 months poststroke, there remained a significant association between the left dorsolateral prefrontal cortex volume and Verbal Fluency Test （partial coefficient = 0.661, P = 0.001） and between the left prefrontal cortex volume and Verbal Fluency Test （partial coefficient = 0.573, P = 0.004） in female patients after the same adjustments. These findings indicate that atrophy of the left dorsolateral prefrontal cortex contributes to the impairment of verbal fluency in elderly female patients with stroke. Sex differences may be present in the neuropsychological mechanisms of verbal fluency impairment in patients with stroke.

Wake-promoting effects of vagus nerve stimulation after traumatic brain injury: upregulation of orexin-A and orexin receptor type 1 expression in the prefrontal cortex

Orexins, produced in the lateral hypothalamus, are important neuropeptides that participate in the sleep/wake cycle, and their expres- sion coincides with the projection area of the vagus nerve in the brain. Vagus nerve stimulation has been shown to decrease the amounts of daytime sleep and rapid eye movement in epilepsy patients with traumatic brain injury. In the present study, we investigated whether vagus nerve stimulation promotes wakefulness and affects orexin expression. A rat model of traumatic brain injury was established using the free fall drop method. In the stimulated group, rats with traumatic brain injury received vagus nerve stimulation （frequency, 30 Hz, current, 1.0 mA; pulse width, 0.5 ms; total stimulation time, 15 minutes）. In the antagonist group, rats with traumatic brain injury were intracerebroventricularly injected with the orexin receptor type 1 （OXIR） antagonist SB334867 and received vagus nerve stimulation. Changes in consciousness were observed after stimulation in each group. Enzyme-linked immunosorbent assay, western blot assay and immunohistochemistry were used to assess the levels of orexin-A and OX1R expression in the prefrontal cortex. In the stimulated group, consciousness was substantially improved, orexin-A protein expression gradually increased within 24 hours after injury and OX1R expres- sion reached a peak at 12 hours, compared with rats subjected to traumatic brain injury only. In the antagonist group, the wake-promoting effect of vagus nerve stimulation was diminished, and orexin-A and OX1R expression were decreased, compared with that of the stim- ulated group. Taken together, our findings suggest that vagus nerve stimulation promotes the recovery of consciousness in comatose rats after traumatic brain injury. The upregulation of orexin-A and OXIR expression in the prefrontal cortex might be involved in the wake-promoting effects of vagus nerve stimulation.

Short-term environmental enrichment exposure induces proliferation and maturation of doublecortin-positive cells in the prefrontal cortex

Previous studies have demonstrated that doublecortin-positive immature neurons exist pre- dominantly in the superficial layer of the cerebral cortex of adult mammals such as guinea pigs, and these neurons exhibit very weak properties of self-proliferation during adulthood under physiological conditions. To verify whether environmental enrichment has an impact on the proliferation and maturation of these immature neurons in the prefrontal cortex of adult guinea pigs, healthy adult guinea pigs were subjected to short-term environmental enrichment. Animals were allowed to play with various cognitive and physical stimulating objects over a period of 2 weeks, twice per day, for 60 minutes each. Immunofluorescence staining results indicated that the number of doublecortin-positive cells in layer II of the prefrontal cortex was significantly increased after short-term environmental enrichment exposure. In addition, these doublecortin-positive cells co-expressed 5-bromo-2-deoxyuridine （a marker of cell prolifera- tion）, c-Fos （a marker of cell viability） and NeuN （a marker of mature neurons）. Experimental findings showed that short-term environmental enrichment can induce proliferation, activation and maturation of doublecortin-positive cells in layer II of the prefrontal cortex of adult guinea pigs.

Neurochemical metabolites in the medial prefrontal cortex in bipolar disorder A proton magnetic resonance spectroscopy study

The aim of this study was to investigate proton magnetic resonance spectroscopy metabolite values in the medial prefrontal cortex of individuals with euthymic bipolar disorder. The subjects consisted of 15 patients with euthymic bipolar disorder type I and 15 healthy controls. We performed proton magnetic resonance spectroscopy of the bilateral medial prefrontal cortex and measured levels of N-acetyl aspartate, choline and creatine. Levels of these three metabolites in the medial prefrontal cortex were found to be lower in patients with bipolar disorder compared with healthy controls. A positive correlation was found between illness duration and choline levels in the right medial prefrontal cortex. Our study suggests that during the euthymic period, there are abnormalities in cellular energy and membrane phospholipid metabolism in the medial prefrontal cortex, and that this may impair neuronal activity and integrity.

Chronic stress causes protein kinase C epsilon-aldehyde dehydrogenase 2 signaling pathway perturbation in the rat hippocampus and prefrontal cortex,but not in the myocardium

Chronic stress is strongly associated with the occurrence and development of depression and cardiovascular disease.Stress can induce altered mitochondrial function and activation of apoptosis in the cardio-cerebral system.However,it is unknown whether the protein kinase C ε（PKCε）-aldehyde dehydrogenase 2（ALDH2） pathway is altered under chronic stress,and this study sought to address this question.A rat model of depression was established using a chronic unpredictable mild stress（CUMS） protocol.After experiencing CUMS for 4 weeks,the sucrose preference test and the forced swim test verified depressive-like behaviors.Enzyme linked immunosorbent assays showed that ALDH2 activity was decreased in the rat hippocampus and prefrontal cortex,but was not altered in the myocardium.Western blot assays demonstrated reduced levels of ALDH2 and PKCε,but increased levels of 4-hydroxy-2-nonenal（4 HNE） adducts.Caspase-3 expression did not obviously alter,but active forms of caspase-3 were increased in the hippocampus and prefrontal cortex.In the myocardium,expression of ALDH2,PKCε and 4 HNE adducts did not remarkably alter;while caspase-3 expression was reduced and the active forms of caspase-3 were upregulated.Pearson＇s correlation test demonstrated that expression of 4 HNE adducts was positively correlated with levels of the active forms of caspase-3 in the hippocampus and prefrontal cortex,but not in the myocardium.In conclusion,chronic stress can damage the PKCε-ALDH2 signaling pathway in the hippocampus and prefrontal cortex,but not in the myocardium.Moreover,4 HNE is associated with active forms of caspase-3 in the hippocampus and prefrontal cortex.

Distinct neuronal excitability alterations of medial prefrontal cortex in early-life neglect model of rats

Object:Early-life neglect has irreversible emotional effects on the central nervous system.In this work,we aimed to elucidate distinct functional neural changes in me-dial prefrontal cortex(mPFC)of model rats.Methods:Maternal separation with early weaning was used as a rat model of early-life neglect.The excitation of glutamatergic and GABAergic neurons in rat mPFC was recorded and analyzed by whole-cell patch clamp.Results:Glutamatergic and GABAergic neurons of mPFC were distinguished by typi-cal electrophysiological properties.The excitation of mPFC glutamatergic neurons was significantly increased in male groups,while the excitation of mPFC GABAergic neurons was significant in both female and male groups,but mainly in terms of rest membrane potential and amplitude,respectively.Conclusions:Glutamatergic and GABAergic neurons in medial prefrontal cortex showed different excitability changes in a rat model of early-life neglect,which can contribute to distinct mechanisms for emotional and cognitive manifestations.

Effects of nitric oxide on the prefrontal cortex in stressed rats

BACKGROUND： Nitric oxide （NO） exhibits both protective and detrimental effects in the central nervous system. OBJECTIVE： To investigate the effect of NO on the prefrontal cortex in neonatal stressed rats. DESIGN, TIME AND SETTING： A randomized, controlled, animal study was performed at the Anatomical Department of Iran University of Medical Sciences from May 2007 to August 2008. MATERIALS; Forty-eight male, Wistar rats were obtained from Pasteur＇s Institute, Tehran, Iran. METHODS： Rat stress models were established by immobilization and randomly received intraperitoneal injection of 2 mL physiological saline, L-arginine （200 mg/kg） as a NO precursor, N（G）-nitro-L-arginine methyl ester （20 mg/kg）, or subcutaneous injection of 7-nitroindazole （25 mg/kg） as a NO synthase inhibitor. MAIN OUTCOME MEASURES： After the rats were treated for 4 weeks, the frontal cortex was harvested for histological observation and NO detection. RESULTS： Subcutaneous administration of N（G）-nitro-L-arginine methyl ester or 7-nitroindazole resulted in significantly lower prefrontal cortex thickness and NO production compared with subcutaneous administration of L-arginine （P 〈 0.05）. Prefrontal cortex thickness significantly increased in rats following L-arginine treatment, compared with physiological saline intervention （P 〈 0.05）. CONCLUSION： NO exhibited protective effects on the prefrontal cortex of stressed rats.

Altered functional connectivity of prefrontal cortex in chronic heroin abusers

In this study, we investigated alterations in the resting-state functional connectivity of the prefrontal cortex in chronic heroin abusers using functional magnetic resonance imaging. We found that, compared with normal controls, in heroin abusers the left prefrontal cortex showed decreased functional connectivity with the left hippocampus, right anterior cingulate, left middle frontal gyrus, right middle frontal gyrus and right precuneus. However, the right prefrontal cortex showed decreased functional connectivity with the left orbital frontal cortex and the left middle frontal gyrus in chronic heroin abusers. These alterations of resting-state functional connectivity in the prefrontal cortices of heroin abusers suggest that their frontal executive neural network may be impaired, and that this may contribute to their continued heroin abuse and relapse after withdrawal.

Brain Activation in the Prefrontal Cortex during Motor and Cognitive Tasks in Adults

The prefrontal cortex (PFC) plays an important role in cognitive function, involved in Executive Functions (EFs) such as planning, working memory, and inhibition. Activation in the PFC also occurs during some motor activities. One commonly used tool to assess EF is the Tower of Hanoi, demonstrating sensitivity to PFC dysfunction. However, limited neuroimaging evidence is available to support the contribution of the PFC in the Tower of Hanoi task. In the current study, we use functional near infrared (fNIR) spectroscopy to examine hemodynamic responses associated with neural activity in the PFC in adults as they participate in the Tower of Hanoi task. We compared changes in cerebral oxygenation during resting, a motor task (tapping), and the Tower of Hanoi in 16 neurotypical adults, with measures of relative changes in concentration of oxygenated hemoglobin (Δoxy-Hb) and deoxygenated hemoglobin (Δdeoxy-Hb) taken throughout tasks, as well as total hemoglobin (ΔHbT) and oxygenation (Δoxy). Performance on the Tower of Hanoi was measured by the number of moves used to complete each level and the highest level of successful performance (3, 4, or 5 disks). We found a significant higher value of Δoxy-Hb and Δoxy in dorsolateral PFC (DLPFC) during the Tower of Hanoi as compared to tapping and resting. Significant changes in Δdeoxy-Hb and ΔHbT during the Tower of Hanoi were found in the right DLPFC only. These results support the notion that the Tower of Hanoi task requires higher levels of PFC activity than a similar motor task with low executive function demands.

Olanzapine Induces Inflammation and Immune Response via Activating ER Stress in the Rat Prefrontal Cortex

Objective Antipsychotics,in particular olanzapine,are first-line medications for schizophrenia.The prefrontal cortex(PFC)is an important region for antipsychotics’therapeutic effects.The PFC inflammatory and immune pathways are associated with schizophrenia pathogenesis.However,the effect of antipsychotics on the inflammatory and immune pathways in the PFC remains unclear.We aimed to examined the time-dependent effect of olanzapine on inflammatory and immune markers in the PFC of rats.Since the inflammatory and immune pathways are related to endoplasmic reticulum(ER)stress,we further investigated whether or not olanzapine-induced inflammation and immune responses were related to ER stress.Methods Expression of pro-inflammatory markers including IkappaB kinaseβ(IKKβ),nuclear factor kappa B(NFκB),tumor necrosis factorα(TNF-α),interleukin-6(IL-6)and IL-1β,and immune-related proteins including inducible nitric oxide synthase(iNOS),toll-like receptor 2(TLR2)and cluster of differentiation 14(CD14)were examined by Western blotting.Results Olanzapine treatments for 1,8 and 36 days significantly activated the inflammatory IKKβ/NFκB signaling,and increased the expression of TNF-α,IL-6,IL-1βand immune-related proteins such as iNOS,TLR4 and CD14.Olanzapine treatment for 1 day,8 and 36 days also induced ER stress in the PFC.Co-treatment with an ER stress inhibitor,4-phenylbutyrate,inhibited olanzapine-induced inflammation and the immune response in the PFC.Conclusion These results suggested olanzapine exposure could be a factor that induces central inflammation and immunological abnormities in schizophrenia subjects.Olanzapine induces PFC inflammation and immune response,possibly via activating ER stress signaling.

Altered proteomic expression in the prefrontal cortex of morphine-addicted rats

The prefrontal cortex is involved in the regulation and control of substance addiction-related cognitive, behavioral, and emotional changes. The present study identified prefrontal cortex protein profiles in morphine-addicted rats; these were subsequently compared with normal rats. Results showed 87 protein spots with differentially expressed levels in the morphine addiction group, with the majority located in meta acid zones at pH 4.2-6.8 and having a molecular weight of 30-110 kDa In addition, 2 protein spots were identified as being associated with neurotoxicity （Snap25 isoform β-Snap25 of synaptosomal-associated protein 25 and βactin）.

ANAGRAM PROBLEM-SOLVING AND LEARNING IN ANTERIOR PREFRONTAL CORTEX

We utilized Near-Infrared(NIR)spectroscopy to closely investigate the activation change in anterior prefrontal cortex(aPFC)during verbal anagram problem-solving and learning.We used a parametric design of anagram-solving with three difficulty levels and evaluated anagram skill with two sets of subjects and protocols.The first protocol was a one-time evaluation of untrained subjects(n=10)and the second protocol evaluated subjects over 6 weeks of training(n=6).The untrained subjects in the first protocol demonstrated blood oxygenation corresponding to neuronal activation in the aPFC in response to medium and hard difficulty levels of the stimuli,while the easy anagram task deoxygenated the aPFC bilaterally,corresponding to deactivation.Higher performers have more aPFC activation than lower performers in the medium difficulty level anagram-solving task.Six weeks of training in the second protocol showed that training reduced oxygenation in aPFC.In particular,subjects with lower baseline skill in anagram production showed a larger reduction in oxygenation where true performance gains occurred(medium difficulty)and smaller reduction where the performance gains were limited(hard anagrams).Association of the aPFC activation with the difficulty of the complex task suggests that aPFC is a part of a circuit for execution of task performance.In addition,more use of aPFC by untrained high performers suggests that the role of the aPFC is to increase efficiency of a problem-solving task.Thus,the NIR spectroscopy showed that the aPFC is a key structure in the circuit implementing the development of anagram skill.

Neuronal degeneration in the hippocampus and dorsolateral prefrontal cortex in depressive disorder Correlation between ~1H-MRS and Minnesota Multiphasic Personality Inventory

Previous studies using magnetic resonance imaging（MRI）and functional MRI to study depression have primarily focused on proton magnetic resonance spectroscopy（1H-MRS）appearance in various areas of the brain and volume measurements in the limbic system.However,results have not been consistent.To the best of our knowledge,very little is known about the relationship between 1H-MRS appearance and depression inventory.In the present study,the relationship between 1H-MRS appearance in depressive patients and Minnesota Multiphasic Personality Inventory-2 scale was analyzed.MRI and 1H-MRS exhibited widened sulci and cisterns,as well as an absence of abnormal signals in depressive patients.In addition,N-acetyl aspartate/total creatine ratios in bilateral hippocampi and dorsolateral prefrontal cortex were significantly less in depressive patients than in control subjects（P 〈 0.01）.In contrast,choline-containing compounds/total creatine ratios in the dorsolateral prefrontal cortex were significantly greater in depressive patients than in control subjects（P 〈 0.01）.These ratios significantly and positively correlated with patient total depression scores as assessed using the Minnesota Multiphasic Personality Inventory-2 scale（r=0.934 7,0.878 7,P 〈 0.01）.These results suggested that 1H-MRS could be used to reveal a reduced number of neurons in the hippocampus and dorsolateral prefrontal cortex,as well as altered membrane phospholipid metabolism in the dorsolateral prefrontal cortex,in patients with depressive disorder.Abnormal mechanisms partially reflected severity of depressive disorder.

Ritalin Dose Response Effect on Medial Prefrontal Cortex and on Animal Behavior

The prefrontal cortex (PFC) is involved in complex planning, learning, memory, attention and integrates sensory information. It was reported that the PFC was dysfunctional in attention deficit hyperactivity disorder (ADHD). Methylphenidate (MPD), a drug often prescribed for the treatment of ADHD, has potential for abuse and misuse. Most MPD studies were completed in adult subjects;however, most users were adolescents. The objective of this study was to investigate the acute and chronic dose response characteristics of MPD on PFC neuronal activity recorded in freely behaving adolescent rats. Four groups of animals were used: saline (control), 0.6, 2.5, and 10 mg/kg MPD. Acute MPD elicited a dose response increase in animals’ locomotor activity. Rechallenge with MPD at experimental day (ED10) when compared to the effect of MPD at ED1 showed no significant differences. When the animals were divided into two groups based on their individual responses to chronic MPD exposure, some animals expressed behavioral tolerance and some expressed behavioral sensitization. Electrophysiologically, a dose response characteristic for acute and chronic MPD exposure was observed. With increasing MPD doses, more PFC units responded by changing their firing rate. Moreover, the neuronal responses to chronic MPD recorded from animals expressing behavioral tolerance were significantly different compared to the neuronal population responses recorded from animals expressing behavioral sensitization. The majority of the PFC units recorded from animals expressing behavioral tolerance responded to MPD predominately by decreasing their firing rates, whereas PFC units recorded from behaviorally sensitized animals mainly showed an increase in their firing rates.

The Distribution and Morphological Diversity of GABA-containing Neurons in The Prefrontal Cortex of Human Newborn Baby Infant

The prefrontal cortex of a human full termnewborn infant just after accidental death was studies by mcans of immunocytochemical technique with antibody directedagainst GABA(Immunonuclear Corp.)and ABC kit(Vector)。GABA-containing neurons were found over all layers and all were nonpyramidal cells.The laminar distribution of GABA-containing ne-urons was not even between different layers,density in laye Ⅱ was prominently higher than any other layers,density in layer Ⅲ and layer Ⅳ was higher than that in layer V and Ⅵ.

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.

Dopamine D2 receptors in the dorsomedial prefrontal cortex modulate social hierarchy in male mice

Social hierarchy greatly influences behavior and health.Both human and animal studies have signaled the medial prefrontal cortex(mPFC)as specifically related to social hierarchy.Dopamine D1 receptors(D1Rs)and D2 receptors(D2Rs)are abundantly expressed in the mPFC,modulat-ing its functions.However,it is unclear how DR-expressing neurons in the mPFC regulate social hierarchy.Here,using a confrontation tube test,we found that most adult C57BL/6J male mice could establish a linear social rank after 1 week of cohabitation.Lower rank individuals showed social anxiety together with decreased serum testosterone levels.D2R expression was significantly downregulated in the dorsal part of mPFC(dmPFC)in lower rank individuals,whereas D1R expression showed no significant difference among the rank groups in the whole mPFC.Virus knockdown of D2Rs in the dmPFC led to mice being particularly prone to lose the contests in the confrontation tube test.Finally,simultaneous D2R activation in the subordinates and D2R inhibition in the dominants in a pair switched their dominant-subordinate relationship.The above results indicate that D2Rs in the dmPFC play an important role in social dominance.Our findings provide novel insights into the divergent func-tions of prefrontal D1Rs and D2Rs in social dominance,which may contribute to ameliorating social dysfunctions along with abnormal social hierarchy.

Dorsolateral prefrontal cortex, working memory and episodic memory processes: insight through transcranial magnetic stimulation techniques

The ability to recall and recognize facts we experienced in the past is based on a complex mechanism in which several cerebral regions are implicated. Neuroimaging and lesion studies agree in identifying the frontal lobe as a crucial structure for memory processes, and in particular for working memory and episodic memory and their relationships. Furthermore, with the introduction of transcranial magnetic stimulation （TMS） a new way was proposed to investigate the relationships between brain correlates, memory functions and behavior. The aim of this review is to present the main findings that have emerged from experiments which used the TMS technique for memory analysis. They mainly focused on the role of the dorsolateral prefrontal cortex in memory process. Furthermore, we present state-of-the-art evidence supporting a possible use of TMS in the clinic. Specifically we focus on the treatment of memory deficits in depression and anxiety disorders.

Prefrontal cortex and the dysconnectivity hypothesis of schizophrenia

Schizophrenia is hypothesized to arise from disrupted brain connectivity. This ＂dysconnectivity hypothesis＂ has generated interest in discovering whether there is anatomical and functional dysconnectivity between the prefrontal cortex （PFC） and other brain regions, and how this dysconnectivity is linked to the impaired cognitive functions and aberrant behaviors of schizophrenia. Critical advances in neuroimaging technologies, including diffusion tensor imaging （DTI） and functional magnetic resonance imaging （fMRI）, make it possible to explore these issues. DTI affords the possibility to explore anatomical connectivity in the human brain in vivo and fMRI can be used to make inferences about functional connections between brain regions. In this review, we present major advances in the understanding of PFC anatomical and functional dysconnectivity and their implications in schizophrenia. We then briefly discuss future prospects that need to be explored in order to move beyond simple mapping of connectivity changes to elucidate the neuronal mechanisms underlying schizophrenia.