Methodologies for task-fMRI based prognostic biomarkers in response to aphasia treatment.

With the diversity in aphasia coupled with diminished gains at the chronic phase, it is imperative to deliver effective rehabilitation plans. Treatment outcomes have therefore been predicted using lesion-to-symptom mapping, but this method lacks holistic functional information about the language-network. This study, therefore, aims to develop whole-brain task-fMRI multivariate analysis to neurobiologically inspect lesion impacts on the language-network and predict behavioral outcomes in persons with aphasia (PWA) undergoing language therapy. In 14 chronic PWA, semantic fluency task-fMRI and behavioral measures were collected to develop prediction methodologies for post-treatment outcomes. Then, a recently developed imaging-based multivariate method to predict behavior (i.e., LESYMAP) was optimized to intake whole-brain task-fMRI data, and systematically tested for reliability with mass univariate methods. We also accounted for lesion size in both methods. Results showed that both mass univariate and multivariate methods identified unique biomarkers for semantic fluency improvements from baseline to 2-weeks post-treatment. Additionally, both methods demonstrated reliable spatial overlap in task-specific areas including the right middle frontal gyrus when identifying biomarkers of language discourse. Thus whole-brain task-fMRI multivariate analysis has the potential to identify functionally meaningful prognostic biomarkers even for relatively small sample sizes. In sum, our task-fMRI based multivariate approach holistically estimates post-treatment response for both word and sentence production and may serve as a complementary tool to mass univariate analysis in developing brain-behavior relationships for improved personalization of aphasia rehabilitation regimens.

The association between language-based task-functional magnetic resonance imaging hemodynamics and baseline GABA+ and glutamate-glutamine measured in pre-supplementary motor area: A pilot study in an aging model.

Aging is a natural phenomenon that elicits slow and progressive cerebrovascular and neurophysiological changes that eventually lead to cognitive decline. The objective of this pilot study is to examine the association of GABA+ and glutamate-glutamine (Glx) complex with language-based blood oxygen level dependent (BOLD) hemodynamics in an aging model. More specifically, using standard BOLD we will first attempt to validate whether previously reported findings for BOLD amplitude and resting neurochemical relationships hold in an aging model. Secondly, we will investigate how our recently established neurosensitized task-BOLD energetics relate to resting GABA+ and Glx, especially accounting for titration of task difficulty. To support the above endeavors, we optimize the baseline fitting for edited magnetic resonance spectroscopy (MRS) difference spectra to sensitize GABA+ and Glx concentrations to aging-related differences. We identify a spline-knot spacing of 0.6ppm to yield the optimal aging-related differences in GABA+ and Glx. The optimized MRS values were then graduated to relate to task-BOLD hemodynamics. Our results did not replicate previous findings that relate task-BOLD amplitude and resting GABA+ and Glx. However, we did identify neurochemistry relationships with the vascularly-driven dispersion component of the hemodynamic response function, specifically in older participants. In terms of neuro-sensitized BOLD energetics and the underlying role of GABA+ and Glx, our data suggests that the task demands are supported by both neurometabolites depending on the difficulty of the task stimuli. Another novelty is that we developed task-based functional parcellation of pre-SMA using both groups. In sum, we are the first to demonstrate that multimodal task-fMRI and MRS studies are beneficial to improve our understanding of the aging brain physiology, and to set the platform to better inform approaches for clinical care in aging-related neurovascular diseases. We also urge future studies to replicate our findings in a larger population incorporating a lifespan framework.

Relationships between frontal metabolites and Alzheimer's disease biomarkers in cognitively normal older adults.

Elevated expression of ß-amyloid (Aß1-42) and tau are considered risk-factors for Alzheimer's disease in healthy older adults. We investigated the effect of aging and cerebrospinal fluid levels of Aß1-42 and tau on 1) frontal metabolites measured with proton magnetic resonance spectroscopy (MRS) and 2) cognition in cognitively normal older adults (n = 144; age range 50-85). Levels of frontal gamma aminobutyric acid (GABA+) and myo-inositol relative to creatine (mI/tCr) were predicted by age. Levels of GABA+ predicted cognitive performance better than mI/tCr. Additionally, we found that frontal levels of n-acetylaspartate relative to creatine (tNAA/tCr) were predicted by levels of t-tau. In cognitively normal older adults, levels of frontal GABA+ and mI/tCr are predicted by aging, with levels of GABA+ decreasing with age and the opposite for mI/tCr. These results suggest that age- and biomarker-related changes in brain metabolites are not only located in the posterior cortex as suggested by previous studies and further demonstrate that MRS is a viable tool in the study of aging and biomarkers associated with pathological aging and Alzheimer's disease.

The Role of Cortico-Thalamo-Cortical Circuits in Language: Recurrent Circuits Revisited.

Based on a review of recent literature, a recurrent circuit model describes how cortico-thalamo-cortical and cortico-cortical circuitry supports word retrieval, auditory-verbal comprehension, and other language functions. Supporting data include cellular and layer-specific cortico-thalamic, thalamo-cortical, and cortico-cortical neuroanatomy and electrophysiology. The model posits that during word retrieval, higher order cortico-thalamo-cortical relays maintain stable representations of semantic information in feedforward processes at the semantic-lexical interface. These stable semantic representations are compared to emerging lexical solutions to represent the semantic construct to determine how well constructs are associated with each other. The resultant error signal allows cortico-cortical sculpting of activity between the semantic and lexical mechanisms until there is a good match between these two levels, at which time the lexical solution will be passed along to the cortical processor necessary for the next stage of word retrieval. Evidence is cited that high gamma activity is the neural signature for processing in the cortico-thalamo-cortical and cortico-cortical circuitry. Methods for testing hypotheses generated from this recurrent circuit model are discussed. Mathematical modeling may be a useful tool in exploring underlying properties of these circuits.

Feasibility of Auricular Field Stimulation in Fibromyalgia: Evaluation by Functional Magnetic Resonance Imaging, Randomized Trial.

OBJECTIVE: To evaluate the feasibility of recruitment, preliminary efficacy, and acceptability of auricular percutaneous electrical nerve field stimulation (PENFS) for the treatment of fibromyalgia in veterans, using neuroimaging as an outcome measure and a biomarker of treatment response. DESIGN: Randomized, controlled, single-blind. SETTING: Government hospital. SUBJECTS: Twenty-one veterans with fibromyalgia were randomized to standard therapy (ST) control or ST with auricular PENFS treatment. METHODS: Participants received weekly visits with a pain practitioner over 4 weeks. The PENFS group received reapplication of PENFS at each weekly visit. Resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) data were collected within 2 weeks prior to initiating treatment and 2 weeks following the final treatment. Analysis of rs-fcMRI used a right posterior insula seed. Pain and function were assessed at baseline and at 2, 6, and 12 weeks post-treatment. RESULTS: At 12 weeks post-treatment, there was a nonsignificant trend toward improved pain scores and significant improvements in pain interference with sleep among the PENFS treatment group as compared with the ST controls. Neuroimaging data displayed increased connectivity to areas of the cerebellum and executive control networks in the PENFS group as compared with the ST control group following treatment. CONCLUSIONS: There was a trend toward improved pain and function among veterans with fibromyalgia in the ST + PENFS group as compared with the ST control group. Pain and functional outcomes correlated with altered rs-fcMRI network connectivity. Neuroimaging results differed between groups, suggesting an alternative underlying mechanism for PENFS analgesia.

The effect of time since stroke, gender, age, and lesion size on thalamus volume in chronic stroke: a pilot study.

Recent stroke studies have shown that the ipsi-lesional thalamus longitudinally and significantly decreases after stroke in the acute and subacute stages. However, additional considerations in the chronic stages of stroke require exploration including time since stroke, gender, intracortical volume, aging, and lesion volume to better characterize thalamic differences after cortical infarct. This cross-sectional retrospective study quantified the ipsilesional and contralesional thalamus volume from 69 chronic stroke subjects' anatomical MRI data (age 35-92) and related the thalamus volume to time since stroke, gender, intracortical volume, age, and lesion volume. The ipsi-lesional thalamus volume was significantly smaller than the contra-lesional thalamus volume (t(68) = 13.89, p < 0.0001). In the ipsilesional thalamus, significant effect for intracortical volume (t(68) = 2.76, p = 0.008), age (t(68) = 2.47, p = 0.02), lesion volume (t(68) = - 3.54, p = 0.0008), and age*time since stroke (t(68) = 2.46, p = 0.02) were identified. In the contralesional thalamus, significant effect for intracortical volume (t(68) = 3.2, p = 0.002) and age (t = - 3.17, p = 0.002) were identified. Clinical factors age and intracortical volume influence both ipsi- and contralesional thalamus volume and lesion volume influences the ipsilesional thalamus. Due to the cross-sectional nature of this study, additional research is warranted to understand differences in the neural circuitry and subsequent influence on volumetrics after stroke.

Strength of resting state functional connectivity and local GABA concentrations predict oral reading of real and pseudo-words.

Reading is a learned activity that engages multiple cognitive systems. In a cohort of typical and struggling adult readers we show evidence that successful oral reading of real words is related to gamma-amino-butyric acid (GABA) concentration in the higher-order language system, whereas reading of unfamiliar pseudo-words is not related to GABA in this system. We also demonstrate the capability of resting state functional connectivity (rsFC) combined with GABA measures to predict single real word compared to pseudo-word reading performance. Results show that the strength of rsFC between left fusiform gyrus (L-FG) and higher-order language systems predicts oral reading behavior of real words, irrespective of the local concentration of GABA. On the other hand, pseudo-words, which require grapheme-to-phoneme conversion, are not predicted by the connection between L-FG and higher-order language system. This suggests that L-FG may have a multi-functional role: lexical processing of real words and grapheme-to-phoneme processing of pseudo-words. Additionally, rsFC between L-FG, pre-motor, and putamen areas are positively related to the oral reading of both real and pseudo-words, suggesting that text may be converted into a phoneme sequence for speech initiation and production regardless of whether the stimulus is a real word or pseudo-word. In summary, from a systems neuroscience perspective, we show that: (i) strong rsFC between higher order visual, language, and pre-motor areas can predict and differentiate efficient oral reading of real and pseudo-words. (ii) GABA measures, along with rsFC, help to further differentiate the neural pathways for previously learned real words versus unfamiliar pseudo-words.

Neuroimaging of the component white matter connections and structures within the cerebellar-frontal pathway in posterior fossa tumor survivors.

INTRODUCTION: In posterior fossa tumor survivors, lower white matter integrity (WMI) in the right cerebellar-left frontal pathway has been well documented and appears to be related to proximity to the cerebellum, radiation treatment, as well as time since treatment in both cranial radiation and surgery-only treatment groups. The current study investigated theories of transneural degeneration following cerebellar tumor resection that may underlie or relate to reductions in WMI and regional brain volumes using correlations. We hypothesized a positive relationship between the volume of the right cerebellum and known white matter output pathways, as well as with the volume of structures that receive cerebellar projections along the pathway. METHODS: Adult survivors of childhood brain tumors were recruited (n = 29; age, M = 22 years, SD = 5; 45% female). Age- and gender-matched controls were also included (n = 29). Participants completed 3 T diffusion-weighted and T1 MPRAGE MRI scans. Brain structure volume relative to intracranial vault served as regional volumetric measures. Fractional anisotropy (FA) and radial diffusivity (RD) served as WMI measures. In the survivor group, partial correlations between WMI and regional volume included controlling for disease severity. RESULTS: In posterior fossa tumor survivors, the volumes of the cerebellum, thalamus, and frontal lobe were correlated with WMI of the thalamic-frontal segment of the cerebellar-frontal pathway (r = 0.41-0.49, p < .05). Cerebellar atrophy was correlated with reduced WMI in the cerebellar-rubral segment (FA, r = -0.32 p > .05; RD, r = 0.53, p < .01). In the no-radiation survivor group, the regional volume of each structure along the pathway was associated with WMI in the cerebellar-rubral segment. In the radiation survivor group, significant correlations were found between the regional brain volume of each structure and the thalamic-frontal segment of the pathway. DISCUSSION: The results of this multimodal neuroimaging study provide correlational evidence that the mechanism of injury subsequent to brain tumor treatment may be different depending on type of treatment(s). Without radiation, the primary mechanism of injury is cerebellar tumor growth, resection, and hydrocephalus. Therefore, the most proximal connection to that injury (cerebellar-rubral pathway) was correlated with reductions in volume along the pathway. In contrast, the survivor group treated with radiation may have had possible radiation-induced demyelination of the thalamic-frontal portion of the pathway, based on a strong correlation with volume loss in the cerebellum, red nucleus, thalamus, and frontal lobe.

Functional Magnetic Resonance Imaging Evaluation of Auricular Percutaneous Electrical Neural Field Stimulation for Fibromyalgia: Protocol for a Feasibility Study.

BACKGROUND: Fibromyalgia is a chronic pain state that includes widespread musculoskeletal pain, fatigue, psychiatric symptoms, cognitive and sleep disturbances, and multiple somatic symptoms. Current therapies are often insufficient or come with significant risks, and while there is an increasing demand for non-pharmacologic and especially non-opioid pain management such as that offered through complementary and alternative medicine therapies, there is currently insufficient evidence to recommend these therapies. Percutaneous electrical neural stimulation (PENS) is an evidence-based treatment option for pain conditions that involves electrical current stimulation through needles inserted into the skin. Percutaneous electrical neural field stimulation (PENFS) of the auricle is similar to PENS, but instead of targeting a single neurovascular bundle, PENFS stimulates the entire ear, covering all auricular branches of the cranial nerves, including the vagus nerve. The neural mechanisms of PENFS for fibromyalgia symptom relief are unknown. OBJECTIVE: We hypothesize that PENFS treatment will decrease functional brain connectivity between the default mode network (DMN) and right posterior insula in fibromyalgia patients. We expect that the decrease in functional connectivity between the DMN and insula will correlate with patient-reported analgesic improvements as indicated by the Defense and Veterans Pain Rating Scale (DVPRS) and will be anti-correlated with patient-reported analgesic medication consumption. Exploratory analyses will be performed for further hypothesis generation. METHODS: A total of 20 adults from the Atlanta Veterans Affairs Medical Center diagnosed with fibromyalgia will be randomized into 2 groups: 10 subjects to a control (standard therapy) group and 10 subjects to a PENFS treatment group. The pragmatic, standard therapy group will include pharmacologic treatments such as anticonvulsants, non-steroidal anti-inflammatory drugs, topical agents and physical therapy individualized to patient comorbidities and preferences, prescribed by a pain management practitioner. The PENFS group will include the above therapies in addition to the PENFS treatments. The PENFS subject group will have the Neuro-Stim System placed on the ear for 5 days then removed and replaced once per week for 4 weeks. The primary outcome will be resting functional magnetic resonance imaging connectivity between DMN and insula, which will also be correlated with pain relief and functional improvements. This connectivity will be analyzed utilizing functional connectivity magnetic resonance imaging (fcMRI) and will be compared with patient-reported analgesic improvements as indicated by the DVPRS and patient-reported analgesic medication consumption. Pain and function will be further evaluated using Patient-Reported Outcomes Measurement Information System measures and measures describing a person's functional status from Activity and Participation section of the International Classification of Functioning Disability and Health. RESULTS: This trial has been funded by the Veterans Health Administration Program Office. This study attained approval by the Emory University/Veterans Affairs (VA) institutional review board and VA Research & Development committee. Institutional review board expedited approval was granted on 2/7/17 (IRB00092224). The study start date is 6/1/17 and estimated completion date is 5/31/20. The recruitment started in June 2017. CONCLUSIONS: This is a feasibility study that is meant to demonstrate the practicality of using fcMRI to study the neural correlates of PENFS outcomes and provide information regarding power calculations in order to design and execute a larger randomized controlled clinical trial to determine the efficacy of PENFS for improving pain and function. TRIAL REGISTRATION: ClinicalTrials.gov NCT03008837; https://clinicaltrials.gov/ct2/show/NCT03008837 (Archived by WebCite at http://www.webcitation.org/6wrY3NmaQ).

Context-Dependent Neural Activation: Internally and Externally Guided Rhythmic Lower Limb Movement in Individuals With and Without Neurodegenerative Disease.

Parkinson's disease is a neurodegenerative disorder that has received considerable attention in allopathic medicine over the past decades. However, it is clear that, to date, pharmacological and surgical interventions do not fully address symptoms of PD and patients' quality of life. As both an alternative therapy and as an adjuvant to conventional approaches, several types of rhythmic movement (e.g., movement strategies, dance, tandem biking, and Tai Chi) have shown improvements to motor symptoms, lower limb control, and postural stability in people with PD (1-6). However, while these programs are increasing in number, still little is known about the neural mechanisms underlying motor improvements attained with such interventions. Studying limb motor control under task-specific contexts can help determine the mechanisms of rehabilitation effectiveness. Both internally guided (IG) and externally guided (EG) movement strategies have evidence to support their use in rehabilitative programs. However, there appears to be a degree of differentiation in the neural substrates involved in IG vs. EG designs. Because of the potential task-specific benefits of rhythmic training within a rehabilitative context, this report will consider the use of IG and EG movement strategies, and observations produced by functional magnetic resonance imaging and other imaging techniques. This review will present findings from lower limb imaging studies, under IG and EG conditions for populations with and without movement disorders. We will discuss how these studies might inform movement disorders rehabilitation (in the form of rhythmic, music-based movement training) and highlight research gaps. We believe better understanding of lower limb neural activity with respect to PD impairment during rhythmic IG and EG movement will facilitate the development of novel and effective therapeutic approaches to mobility limitations and postural instability.

Broca's area - thalamic connectivity.

Broca's area is crucially involved in language processing. The sub-regions of Broca's area (pars triangularis, pars opercularis) presumably are connected via corticocortical pathways. However, growing evidence suggests that the thalamus may also be involved in language and share some of the linguistic functions supported by Broca's area. Functional connectivity is thought to be achieved via corticothalamic/thalamocortical white matter pathways. Our study investigates structural connectivity between Broca's area and the thalamus, specifically ventral anterior nucleus and pulvinar. We demonstrate that Broca's area shares direct connections with these thalamic nuclei and suggest a local Broca's area-thalamus network potentially involved in linguistic processing. Thalamic connectivity with Broca's area may serve to selectively recruit cortical regions storing multimodal features of lexical items and to bind them together during lexical-semantic processing. In addition, Broca's area-thalamic circuitry may enable cortico-thalamo-cortical information transfer and modulation between BA 44 and 45 during language comprehension and production.

Lesion symptom mapping of manipulable object naming in nonfluent aphasia: can a brain be both embodied and disembodied?

Embodied cognition offers an approach to word meaning firmly grounded in action and perception. A strong prediction of embodied cognition is that sensorimotor simulation is a necessary component of lexical-semantic representation. One semantic distinction where motor imagery is likely to play a key role involves the representation of manufactured artefacts. Many questions remain with respect to the scope of embodied cognition. One dominant unresolved issue is the extent to which motor enactment is necessary for representing and generating words with high motor salience. We investigated lesion correlates of manipulable relative to nonmanipulable name generation (e.g., name a school supply; name a mountain range) in patients with nonfluent aphasia (N = 14). Lesion volumes within motor (BA4, where BA = Brodmann area) and premotor (BA6) cortices were not predictive of category discrepancies. Lesion symptom mapping linked impairment for manipulable objects to polymodal convergence zones and to projections of the left, primary visual cortex specialized for motion perception (MT/V5+). Lesions to motor and premotor cortex were not predictive of manipulability impairment. This lesion correlation is incompatible with an embodied perspective premised on necessity of motor cortex for the enactment and subsequent production of motor-related words. These findings instead support a graded or "soft" approach to embodied cognition premised on an ancillary role of modality-specific cortical regions in enriching modality-neutral representations. We discuss a dynamic, hybrid approach to the neurobiology of semantic memory integrating both embodied and disembodied components.

Thalamic mechanisms in language: a reconsideration based on recent findings and concepts.

Recent literature on thalamic aphasia and thalamic activity during neuroimaging is selectively reviewed followed by a consideration of recent anatomic and physiological findings regarding thalamic structure and functions. It is concluded that four related corticothalamic and/or thalamocortical mechanisms impact language processing: (1) selective engagement of task-relevant cortical areas in a heightened state of responsiveness in part through the nucleus reticularis (NR), (2) passing information from one cortical area to another through corticothalamo-cortical mechanisms, (3) sharpening the focus on task-relevant information through corticothalamo-cortical feedback mechanisms, and (4) selection of one language unit over another in the expression of a concept, accomplished in concert with basal ganglia loops. The relationship and interaction of these mechanisms is discussed and integrated with thalamic aphasia and neuroimaging data into a theory of thalamic functions in language.

Delineation of motor and somatosensory thalamic subregions utilizing probabilistic diffusion tractography and electrophysiology.

PURPOSE: To employ and compare probabilistic diffusion tractography (PDT) for the explicit localization of connections from the thalamus to somatosensory cortex (S1) and primary motor cortex (M1) / supplementary motor area (SMA) with microelectrode electrophysiology in patients undergoing deep brain stimulation (DBS) surgery. MATERIALS AND METHODS: These tractography-derived connections were used to categorize voxels in the thalamus as corresponding to sensory or motor physiology. A novel model (referred to in this work as the "mixture" model) to delineate PDT-based thalamic functional subregions by thresholding fiber intensities, ie, connectivity-defined regions (CDR), was devised. Regions created using this classification method were compared with the most commonly used model (referred to in this work as the "separation" or "winner takes all" model) for defining CDRs. RESULTS: Electrophysiology data corresponded better for S1 CDRs created using the mixture model for both sensory and motor cells. Separation model CDRs showed poor correspondence against electrophysiology, with few sensory cells corresponding to the S1 separation model CDR. CONCLUSION: Mixture model-based CDRs may offer a significant improvement in delineation of functional subregions of subcortical structures.

An fMRI study of the differences in brain activity during active ankle dorsiflexion and plantarflexion.

Little is known regarding the differences in active cortical and subcortical systems during opposing movements of an agonist-antagonist muscle group. The objective of this study was to characterize the differences in cortical activation during active ankle dorsiflexion and plantarflexion using functional MRI (fMRI). Eight right-handed healthy adults performed auditorily cued right ankle dorsiflexions and plantarflexions during fMRI. Differences in activity patterns between dorsiflexion and plantarflexion during fMRI were assessed using between- and within-subject voxel-wise t-tests. Results indicated that ankle dorsiflexion recruited significantly more regions in left M1, the supplementary motor area (SMA) bilaterally, and right cerebellum. Both movements activated similar left hemisphere regions in the putamen and thalamus. Dorsiflexion activated additional areas in the right putamen. Results suggest that ankle dorsiflexion and plantarflexion may be controlled by both shared and independent neural circuitry. This has important implications for functional investigations of gait pathology and how rehabilitation may differentially affect each movement.

Neural signatures of semantic and phonemic fluency in young and old adults.

As we age, our ability to select and to produce words changes, yet we know little about the underlying neural substrate of word-finding difficulties in old adults. This study was designed to elucidate changes in specific frontally mediated retrieval processes involved in word-finding difficulties associated with advanced age. We implemented two overt verbal (semantic and phonemic) fluency tasks during fMRI and compared brain activity patterns of old and young adults. Performance during the phonemic task was comparable for both age groups and mirrored by strongly left-lateralized (frontal) activity patterns. On the other hand, a significant drop of performance during the semantic task in the older group was accompanied by additional right (inferior and middle) frontal activity, which was negatively correlated with performance. Moreover, the younger group recruited different subportions of the left inferior frontal gyrus for both fluency tasks, whereas the older participants failed to show this distinction. Thus, functional integrity and efficient recruitment of left frontal language areas seems to be critical for successful word retrieval in old age.

Functional magnetic resonance imaging before and after aphasia therapy: shifts in hemodynamic time to peak during an overt language task.

BACKGROUND AND PURPOSE: Comparing the temporal characteristics of hemodynamic responses in activated cortical regions of aphasic patients before and after therapy would provide insight into the relationship between improved task performance and changes in blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signal. This study investigated differences in the time to peak (TTP) of hemodynamic responses in activated regions of interest (ROIs), before and after therapy, and related them to changes in task performance. METHODS: Three aphasic patients and 3 controls overtly generated a single exemplar in response to a category. For the patients, TTP of hemodynamic responses in selected ROIs was compared before and after language therapy. The timing differences between auditory cues and verbal responses were compared with TTP differences between auditory and motor cortices. RESULTS: The selected ROIs were significantly activated in both aphasic patients and controls during overt word generation. In the aphasic patients, both the timing difference from auditory cues to verbal responses and the TTP difference between auditory and motor cortices decreased after rehabilitation, becoming similar to the values found in controls. CONCLUSIONS: Findings indicate that (1) rehabilitation increased the speed of word-finding processes; (2) TTP analysis was sensitive to this functional change and can be used to represent improvement in behavior; and (3) it is important to monitor the behavioral performance that might correlate with the temporal pattern of the hemodynamic response.

Semantic monitoring of words with emotional connotation during fMRI: contribution of anterior left frontal cortex.

Previous studies showed that cortex in the anterior portions of the left frontal and temporal lobes participates in generating words with emotional connotations and processing pictures with emotional content. If these cortices process the semantic attribute of emotional connotation, they should be active whenever processing emotional connotation, without respect to modality of input or mode of output. Thus, we hypothesized that they would activate during monitoring of words with emotional connotations. Sixteen normal subjects performed semantic monitoring of words with emotional connotations, animal names, and implement names during fMRI. Cortex in the anterior left frontal lobe demonstrated significant activity for monitoring words with emotional connotations compared to monitoring tone sequences, animal names, or implement names. Together, the current and previous results implicate cortex in the anterior left frontal lobe in semantic processing of emotional connotation, consistent with connections of this cortex to paralimbic association areas. Current findings also indicate that neural substrates for processing emotional connotation are independent of substrates for processing the categories of living and nonliving things.