Beyond functional MRI signals:molecular and cellular modifiers of the functional connectome and cognition

Our brain is constantly active.Even at rest,the brain carries out essential functions such as maintenance of resting potentials,subthreshold synaptic activity,and spiking activity related to information processing.This resting activity can be assessed with several in vivo tools,such as resting-state functional magnetic resonance imaging.This technique measures subtle changes in blood flow,volume,and oxygenation that occur over time.Although vascular in nature,resting-state functional magnetic resonance imaging is considered a reliable proxy of neural activity and several studies have shown that the brain is functionally divided into interacting neural networks called the“functional connectome”.

Advances in functional MRI research in bipolar disorder:from the perspective of mood states

Bipolar disorder is characterised by recurrent and alternating episodes of mania/hypomania and depression.Current breakthroughs in functional MRI techniques have uncovered the functional neuroanatomy of bipolar disorder.However,the pathophysiology underlying mood instability,mood switching and the development of extreme mood states is less well understood.This reviewpresents a comprehensive overviewof current evidence from functional MRI studies from the perspective of mood states.We first summarise the disrupted brain activation patterns and functional connectivity that have been reported in bipolar disorder,irrespective of the mood state.We next focus on research that solely included patients in a single mood state for a better understanding of the pathophysiology of bipolar disorder and research comparing patients with different mood states to dissect mood state-related effects.Finally,we briefly summarise current theoretical models and conclude this review by proposing potential avenues for future research.A comprehensive understanding of the pathophysiology with consideration of mood states could not only deepen our understanding of how acute mood episodes develop at a neurophysiological level but could also facilitate the identification of biological targets for personalised treatment and the development of new interventions for bipolar disorder.

Acupuncture at Waiguan (TE5) influences activation/deactivation of functional brain areas in ischemic stroke patients and healthy people A functional MRI study

In the present study, 10 patients with ischemic stroke in the left hemisphere and six healthy controls were subjected to acupuncture at right Waiguan （TE5）. In ischemic stroke subjects, functional MRI showed enhanced activation in Broadmann areas 5, 6, 7, 18, 19, 24, 32, the hypothalamic inferior lobe, the mamiilary body, and the ventral posterolateral nucleus of the left hemisphere, and Broadmann areas 4, 6, 7, 18, 19 and 32 of the right hemisphere, but attenuated activation of Broadmann area 13, the hypothalamic inferior lobe, the posterior lobe of the tonsil of cerebellum, and the culmen of the anterior lobe of hypophysis, in the left hemisphere and Broadmann area 13 in the right hemisphere. In ischemic stroke subjects, a number of deactivated brain areas were enhanced, including Broadmann areas 6, 11,20, 22, 37, and 47, the culmen of the anterior lobe of hypophysis, alae lingulae cerebella, and the posterior lobe of the tonsil of cerebellum of the left hemisphere, and Broadmann areas 8, 37, 45 and 47, the culmen of the anterior lobe of hypophysis, pars tuberalis adenohypophyseos, inferior border of lentiform nucleus, lateral globus pallidus, inferior temporal gyrus, and the parahippocampal gyrus of the right hemisphere. These subjects also exhibited attenuation of a number of deactivated brain areas, including Broadmann area 7. These data suggest that acupuncture at Waiguan specifically alters brain function in regions associated with sensation, vision, and motion in ischemic stroke patients. By contrast, in normal individuals, acupuncture at Waiguan generally activates brain areas associated with insomnia and other functions.

Activated and deactivated functional brain areas in the Deqi state: A functional MRI study

We compared the activities of functional regions of the brain in the Deqi versus non-Deqi state, as reported by physicians and subjects cludng acupuncture, Twelve healthy volunteers received sham and true needling at the Waiguan （TE5） acupoint. Real-time cerebral functional MRI showed that compared with non-sensation after sham needling, true needling activated Brodmann areas 3, 6, 8, 9, 10, 11, 13, 20, 21, 37, 39, 40, 43, and 47, the head of the caudate nucleus, the parahippocampal gyrus, thalamus and red nucleus. True needling also deactivated Brodmann areas 1,2, 3, 4, 5, 6, 7, 9. 10. 18.24.31.40 and 46.

A central analgesic mechanism of acupuncture for migraine An ongoing functional MRI study

Shaoyang acupoints are the most frequently used in migraine treatment. However, the central anal- gesic mechanism remains poorly understood. Studies have demonstrated that single stimulus of the verum acupuncture in healthy subjects can induce significant connectivity or activity changes in pain- related central networks compared with sham acupuncture. However, these findings are not indicative of the central analgesic mechanism of acupuncture at Shaoyang acupoints. Thus, we recruited 100 migraine sufferers and randomly assigned them into five groups： Shaoyang uncommon acupoint, Shaoyang common acupoint, Yangming uncommon acupoint, non-acupoint control, and blank control groups. Subjects were subjected to evaluation of curative effects and functional MRI prior to and after 10 and 20 acupuncture treatments. All subjects were diagnosed by physicians and enrolled following clinical physical examination. Subjects were observed during 1-4 weeks after inclusion. At the fifth week, the first clinical evaluation and resting functional MRI were conducted. The Shaoyang uncom- mon acupoint, Shaoyang common acupoint, Yangming uncommon acupoint, and non-acupoint control grousp then were treated with acupuncture, five times per week, 20 times in total over 4 weeks. The second and third clinical evaluations and resting functional MRI screenings were conducted following 10 and 20 acupuncture treatments. The blank control group was observed during the 5 to 8 week pe- riod, followed by clinical evaluation and resting functional MRI. The aim of this study was to examine changes in brain functional activity and central networks in subjects with migraine undergoing acu- puncture at Shaoyang uncommon acupoints. This study provides a further explanation of the central analgesic mechanism by which acupuncture at Shaoyang acupoints treats migraine,

Functional MRI activation of primary and secondary motor areas in healthy subjects

BACKGROUND： Functional MRI （fMRI） demonstrates the localization of hand representation in the motor cortex, thereby providing feasible noninvasive mapping of functional activities in the human brain. OBJECTIVE： To observe cortical activation within different cortical motor regions during repetitive hand movements in healthy subjects through the use of fMRI. DESIGN： An observational study, with each subject acting as his own control. SETTING： Department of Radiology, the First Affiliated Hospital of Nanchang University. PARTICIPANTS： Seven healthy volunteers, 4 males and 3 females, aged 19 to 38 years, participated in the study. All subjects were right-handed, with no neurological or psychological disorders. Informed written consent was obtained from all subjects, and the study was approved by the Institutional Review Board of the First Affiliated Hospital of Nanchang University. METHODS： The study was performed at the Department of Radiology between June-August 2005. A 1.5 Tesla Siemens MRI scanner （Symphony, Germany） was used to acquire T1-weighted structural images, which were oriented parallel to the line running through the anterior and the posterior commissures. Subjects were instructed on a task and were allowed to practice briefly prior to the imaging procedure. The motor activation task consisted of the right hand performing a clenching movement. The T1-W images were acquired from six alternating epochs of rest and activation from all seven healthy subjects. Data were collected with echoplanar imaging of brain oxygen level dependent （BOLD） sequence. Each series comprised six cycles of task performance （30 seconds）, alternating with rest （30 seconds） periods, and 3-second time intervals. The differences between active and baseline fMRI imaging were calculated using the student t-test. Differential maps were overlaid on the high resolution TI-W structural image for neuroanatomical correlation of activation areas. MAIN OUTCOME MEASURES： The omega-shaped hand knobs were recognized on T1-W structural images. Active signal changes in the primary （M1） and secondary motor （M2） areas, as well as the relationship between the hand knobs and M1 area activation, were analyzed. Region of interest was selected for signal change quantitative graphic analysis. RESULTS： All 7 enrolled volunteers were included in the final analysis. In the present study, hand knob structures were recognized on T1-weighted images in all subjects and were omega-shaped in the axial plane. Significant functional activations were observed in the contralateral primary motor area of all subjects. Activation signals were distributed mainly in the central sulcus around the hand knob. The contralateral primary sensory （S1） cortex was activated in most cases, and ipsilateral M1 was activated in 3 subjects. Contralateral or bilateral supplementary motor area （SMA） was also activated in 6 cases. Premotor area, or super parietal lobe, was activated in two subjects. Three-dimensional reconstruction demonstrated that the active signal of M1 was primarily located at the middle-lateral surface of the contralateral precentral gyrus in Brodman＇s area 4, and the signal of SMA activation was located in the mesial surface of the premotor area. CONCLUSION： The knob structure of the precentral gyrus is the representative motor area for hand movement. The cerebral cortical motor network was extensively activated during voluntary hand movements in normal subjects. In alert, conscious human subjects, the activated fMRI signal safely and non-invasively localized and lateralized the motor cortical activity associated with simple voluntary repetitive hand movements. Whether higher cognitive functions, such as perception and speech, can be similarly mapped using the fMRI technique and the BOLD method remains to be determined in future well-designed human studies.

Effective doctor-patient communication skills training optimizes functional organization of intrinsic brain architecture:a restingstate functional MRI study

We studied the influence of doctor-patient communication skills training on brain functional architecture using resting-state functional MRI（rs-fMRI） with a regional homogeneity（ReHo） method. Ten medical students participated in the study. A 1-year long doctor-patient communication skills training program was conducted. RsfMRI data were collected at baseline, one month and one year after training. There was a significant increase in the communication skills test average scores between baseline and 1-month duration of training（P〈0.001）. After one month of communication skills training, medical students had decreased ReHo in the right superior temporal gyrus compared with the baseline. After one year of communication skills training, students had increased ReHo in multiple regions and decreased ReHo in several regions（P 〈0.05, Alphasim corrected）. The change of ReHo values in the superior temporal gyrus negatively correlated with the change of communication skills scale score between one month after communication skills training and baseline（r=-0.734, P= 0.036）. The training program we used can be an effective approach of improving doctor-patient communication skills, and the training resulted in functional plasticity of the brain’s architecture toward optimizing locally functional organization.

The brain activation pattern of the medial temporal lobe during chewing gum: a functional MRI study

The human brain is known to be influenced by environmental stimuli（Feeney et al.,1982;Kaplan,1988）.Therefore,research on the brain activation pattern by external stimuli has been an important topic in neuroscience（Kaplan,1988）.Chewing gum has been known to have a positive effect on cognition,including alertness,attention,cognitive processing speed,

Evaluating rehabilitation interventionsin Parkinson's disease with functional MRI:a promising neuroprotective strategy

Parkinson＇s disease （PD） is a progressive neurodegenerative disorder affecting approximately 10 million people world- wide （Planetta et al., 2014; Zigmond and Smeyne, 2014）. The principal clinical features of PD are bradykinesia, rigidity, tremor at rest and postural instability （Planetta et al., 2014）. It is known that both PD itself and the use of anti-parkinson drugs are associated with several non-motor symptoms such as cognitive impairment, neuropsychiatric disturbances and sleep, autonomic, and sensory disorders （Park and Stacy, 2009; Foster et al., 2014）. The histopathological hallmark of PD is the reduction of dopaminergic cells in the substantia nigra pars compacta, causing dopamine deficiency in spe- cific nuclei of the basal ganglia such as the dorsal striatum （Fearnley and Lees, 1991; Planetta et al., 2014）. The disrup- tion of the dopaminergic system has long been regarded as the major cause of PD; however, it has been shown that a widespread involvement of several non-dopaminergic path- ways also contribute to the clinical manifestations of PD （Park et al., 2014）.

Global Functional Network Connectivity Disturbances in Parkinson’s Disease with Mild Cognitive Impairment by Resting-State Functional MRI

Examining the spontaneous BOLD activity to understand the neural mechanism of Parkinson’s disease(PD)with mild cognitive impairment(MCI)is a focus in resting-state functional MRI(rs-fMRI)studies.This study aimed to investigate the alteration of brain functional connectivity in PD with MCI in a systematical way at two levels:functional connectivity analysis within resting state networks(RSNs)and functional network connectivity(FNC)analysis.Using group independent component analysis(ICA)on rs-fMRI data acquired from 30 participants(14 healthy controls and 16 PD patients with MCI),16 RSNs were identified,and functional connectivity analysis within the RSNs and FNC analysis were carried out between groups.Compared to controls,patients with PD showed decreased functional connectivity within putamen network,thalamus network,cerebellar network,attention network,and self-referential network,and increased functional connectivity within execution network.Globally disturbed,mostly increased functional connectivity of FNC was observed in PD group,and insular network and execution network were the dominant network with extensively increased functional connectivity with other RSNs.Cerebellar network showed decreased functional connectivity with caudate network,insular network,and self-referential network.In general,decreased functional connectivity within RSNs and globally disturbed,mostly increased functional connectivity of FNC may be characteristics of PD.Increased functional connectivity within execution network may be an early marker of PD.The multi-perspective study based on RSNs may be a valuable means to assess functional changes corresponding to specific RSN,contributing to the understanding of the neural mechanism of PD.

A review of functional MRI application for brain research of Chinese language processing

As one of the most widely used languages in the world,Chinese language is distinct from most western languages in many properties,thus providing a unique opportunity for understanding the brain basis of human language and cognition.In recent years,non-invasive neuroimaging techniques such as magnetic resonance imaging(MRI)blaze a new trail to comprehensively study specific neural correlates of Chinese language processing and Chinese speakers.We reviewed the application of functional MRI(fMRI)in such studies and some essential findings on brain systems in processing Chinese.Specifically,for example,the application of task fMRI and resting-state fMRI in observing the process of reading and writing the logographic characters and producing or listening to the tonal speech.Elementary cognitive neuroscience and several potential research directions around brain and Chinese language were discussed,which may be informative for future research.

Acupoints combination correlates with activation of cerebral areas A functional MRI study

Acupoint combination is a method used for acupoint treatment of patients. Traditionally, acupoints are matched along the meridian distribution, which is a common rule in clinical practice, but the underlying mechanism remains unclear. Cerebral scans with functional magnetic resonance imaging （fMRI） have been used in the study of acupuncture and acupoint specifically. In this study, fMRI was used to detect the activation of the brain areas under different acupoints, matched along different meridians, to elucidate the acupoint combination via a modern medical approach. Forty healthy volunteers were randomly divided into the following groups： Waiguan point （SJ 5）, Waiguan （SJ 5） ＋ Zhigou （SJ 6） （2 acupoints come from the same meridian）, Waiguan （SJ 5） ＋ Neiguan （PC 6） （2 acupoints come from 2 meridians with the relationship of interior-exterior）, Waiguan （SJ 5） ＋ Yanglingquan （GB 34） （2 acupoints come from 2 meridians with the same name-Shaoyang Meridian）, and sham point groups （needling in different points on the right hand）. A real-time cerebral fMRI scan was simultaneously performed. The cerebral activation rate, and the number and strength of different regions of interest were compared among the groups. The fMRI cerebral imaging confirmed that there were some differences in the activation of cerebral areas by the needlings in SJ 5, and in combination with other acupoints. Needling at SJ 5 alone greatly activated the right cerebellum, while needling at both SJ 5 and different co-needling points activated different cerebral functional areas.

Processing Chinese hand-radicals activates the medial frontal gyrus A functional MRI investigation

Embodied semantics theory asserts that the meaning of action-related words is neurally represented through networks that overlap with or are identical to networks involved in sensory-motor processing. While some studies supporting this theory have focused on Chinese characters, less attention has been paid to their semantic radicals. Indeed, there is still disagreement about whether these radicals are processed independently. The present study investigated whether radicals are processed separately and, if so, whether this processing occurs in sensory-motor regions. Materials consisted of 72 high-frequency Chinese characters, with 18 in each of four categories： hand-action verbs with and without hand-radicals, and verbs not related to hand actions, with and without hand-radicals. Twenty-eight participants underwent functional MRI scans while reading the characters. Compared to characters without hand-radicals, reading characters with hand-radicals activated the right medial frontal gyrus. Verbs involving hand-action activated the left inferior parietal lobule, possibly reflecting integration of information in the radical with the semantic meaning of the verb. The findings may be consistent with embodied semantics theory and suggest that neural representation of radicals is indispensable in processing Chinese characters.

Effects of task orientation on subsequent source memory as revealed by functional MRI

Episodic memories are composed of various interrelated elements, including those specific to items of central interest and those pertaining to related features, such as the color, shape, size, spatial location, temporal order, and media or modalities of presentation. Memory about a core item （such as a word, object, or picture） is called item memory while memory about the context or related fea- tures of a core item is defined as source memory. What determines which sources within an episode are successfully remembered is of particular interest to researchers. Behavioral evidence suggests that the orientation of a memory task influences whether the related source of the item will be re- membered later. This study explored changes in the hippocampus and prefrontal cortex while par- ticipants completed two tasks： an item-oriented task and a source-oriented task. We used functional MRI to investigate the neural mechanisms by which task orientation influences source encoding. We found that subsequent source memory effects in the right prefrontal cortex and hippocampus were modulated by task orientation, whereas task orientation modulated item memory effects in the prefrontal cortex. These findings highlight the possibility that the hippocampus contributes to the intentional encoding of item-source associations, whereas the prefrontal cortex is biased toward processing information to which attention is directed.

Effects of visual information regarding tactile stimulation on the somatosensory cortical activation：a functional MRI study

Many studies have investigated the evidence for tactile and visual interactive responses to activation of various brain regions.However,few studies have reported on the effects of visuo-tactile multisensory integration on the amount of brain activation on the somatosensory cortical regions.The aim of this study was to examine whether coincidental information obtained by tactile stimulation can affect the somatosensory cortical activation using functional MRI.Ten right-handed healthy subjects were recruited for this study.Two tasks（tactile stimulation and visuotactile stimulation）were performed using a block paradigm during f MRI scanning.In the tactile stimulation task,in subjects with eyes closed,tactile stimulation was applied on the dorsum of the right hand,corresponding to the proximal to distal directions,using a rubber brush.In the visuotactile stimulation task,tactile stimulation was applied to observe the attached mirror in the MRI chamber reflecting their hands being touched with the brush.In the result of SPM group analysis,we found brain activation on the somatosensory cortical area.Tactile stimulation task induced brain activations in the left primary sensory-motor cortex（SM1）and secondary somatosensory cortex（S2）.In the visuo-tactile stimulation task,brain activations were observed in the both SM1,both S2,and right posterior parietal cortex.In all tasks,the peak activation was detected in the contralateral SM1.We examined the effects of visuo-tactile multisensory integration on the SM1 and found that visual information during tactile stimulation could enhance activations on SM1 compared to the tactile unisensory stimulation.

Peri-infarct reorganization at the centrum semiovale and corona radiata A diffusion tensor tractography and functional MRI study

Peri-infarct reorganization has been reported in stroke patients with a lesion at the cerebral cortex, corona radiata, or pons, separately. However, there have been no reports describing the patients with peri-infarct reorganization at multiple levels. The present study reported a patient with a middle cerebral artery infarct who showed complete paralysis of the right extremities at stroke onset. Results showed that at 3 years after stroke onset, patient＇s motor function of the affected hand appeared to have been recovered by the motor tract, which reorganized into the anterior areas of the infarcted centrum semiovale and corona radiata, as demonstrated by diffusion tensor tractography study analyzed using functional MRI activation results. This result indicates that the human brain can show extensive brain plasticity and that saving the adjacent area or penumbra around the infarct even though the lesion from multiple levels is important for functional recovery after stroke.

Onsite-effects of dual-hemisphere versus conventional single-hemisphere transcranial direct current stimulation A functional MRI study

We performed functional MRI examinations in six right-handed healthy subjects.During functional MRI scanning,transcranial direct current stimulation was delivered with the anode over the right primary sensorimotor cortex and the cathode over the left primary sensorimotor cortex using dual-hemispheric transcranial direct current stimulation.This was compared to a cathode over the left supraorbital area using conventional single-hemispheric transcranial direct current stimulation. Voxel counts and blood oxygenation level-dependent signal intensities in the right primary sensorimotor cortex regions were estimated and compared between the two transcranial direct current stimulation conditions.Our results showed that dual-hemispheric transcranial direct current stimulation induced greater cortical activities than single-hemispheric transcranial direct current stimulation.These findings suggest that dual-hemispheric transcranial direct current stimulation may provide more effective cortical stimulation than single-hemispheric transcranial direct current stimulation.

Preoperative functional MRI localization of language areas in Chinese patients with brain tumors Validation with intraoperative electrocortical mapping

Ten Chinese patients with brain tumors involving language regions were selected. Preoperative functional MRI was performed to locate Broca＇s or Wernicke＇s area, and the cortex that was essential for language function was determined by electrocortical mapping. A site-by-site comparison between functional MRI and electrocortical mapping was performed with the aid of a neuronavigation device. Results showed that the sensitivity and specificity of preoperative functional MRI were 80.0% and 85.0% in Broca＇s area and 66.6% and 85.2% in Wemicke＇s area, respectively. These experimental findings indicate that functional MRI is an accurate, reliable technique with which to identify the location of Wernicke＇s area or Broca＇s area in patients with brain tumors.

Changes in brain activation patterns according to cross-training effect in serial reaction time task An functional MRI study

Cross-training is a phenomenon related to motor learning, where motor performance of the untrained limb shows improvement in strength and skill execution following unilateral training of the homologous contralateral limb. We used functional MRI to investigate whether motor performance of the untrained limb could be improved using a serial reaction time task according to motor sequential learning of the trained limb, and whether these skill acquisitions led to changes in brain activation patterns. We recruited 20 right-handed healthy subjects, who were randomly allocated into training and control groups. The training group was trained in performance of a serial reaction time task using their non-dominant left hand, 40 minutes per day, for 10 days, over a period of 2 weeks. The control group did not receive training. Measurements of response time and percentile of response accuracy were performed twice during pre- and post-training, while brain functional MRI was scanned during performance of the serial reaction time task using the untrained right hand. In the training group, prominent changes in response time and percentile of response accuracy were observed in both the untrained right hand and the trained left hand between pre- and post-training. The control group showed no significant changes in the untrained hand between pre- and post-training. In the training group, the activated volume of the cortical areas related to motor function （i.e., primary motor cortex, premotor area, posterior parietal cortex） showed a gradual decrease, and enhanced cerebellar activation of the vermis and the newly activated ipsilateral dentate nucleus were observed during performance of the serial reaction time task using the untrained right hand, accompanied by the cross-motor learning effect. However, no significant changes were observed in the control group. Our findings indicate that motor skills learned over the 2-week training using the trained limb were transferred to the opposite homologous limb, and motor skill acquisition of the untrained limb led to changes in brain activation patterns in the cerebral cortex and cerebellum.

The Role of Baseline Functional MRI as a Predictor of Post-Stroke Rehabilitation Efficacy in Patients with Moderate to Severe Upper Extremity Dysfunction

Introduction: Upper extremity impairment is one of the common complications following a stroke. There are numerous rehabilitation strategies to address this problem. However, patients with moderate to severe upper limb disabilities respond differently to the same rehabilitation protocol. Apart from each patient’s unique characteristics, there are specific brain reorganizing patterns that affect the post-rehabilitation response rate. Functional magnetic resonance imaging (fMRI) determines brain activation area and connectivity patterns and has been utilized in the neurorehabilitation field. Material and Methods: Six stroke patients who suffered from moderate to severe upper extremity dysfunction were enrolled in this pilot study. Upper extremity function tests including the Fugl-Meyer assessment test for upper extremity (FMA-UE), and Wolf Motor Function Test (WMFT) were utilized before and after completing an intensive rehabilitation. The intensive rehabilitation program was conducted one hour a day for five days per week for four weeks. Moreover, fMRI was applied before initiating rehabilitation. The regions of interest were those associated with movement, including Brodmann areas (BA) BA1-BA6. Results: Six stroke patients in the sub-acute to chronic phase and ages ranging between 33 - 75 years were enrolled. All patients showed an improvement in upper limb function after four weeks of rehabilitation. Patient number one (Pt1) had the most improvement in FMA-UE, while patient number four (Pt4) recovered the most measured by WMFT. Pt1 demonstrated increased activity in all contralesional regions, whereas Pt4 had only increased activity in ipsilesional areas. Furthermore, patients with greater activation in the ipsilesional BA6 (Pt1, Pt4, Pt5, and Pt6) had better responses to the rehabilitation therapy. Conclusion: Patients with greater activation in the baseline fMRI, particularly ipsilesional BA6, had a better response to the intensive rehabilitation therapy. However, the patients with the most severe hand dysfunction showed lesser improvement despite the same brain activity as others in the initial fMRI.