Effects of Low-Level Light Therapy on Resting-State Connectivity Following Moderate Traumatic Brain Injury: Secondary Analyses of a Double-blinded Placebo-controlled Study.

Background Low-level light therapy (LLLT) has been shown to modulate recovery in patients with traumatic brain injury (TBI). However, the impact of LLLT on the functional connectivity of the brain when at rest has not been well studied. Purpose To use functional MRI to assess the effect of LLLT on whole-brain resting-state functional connectivity (RSFC) in patients with moderate TBI at acute (within 1 week), subacute (2-3 weeks), and late-subacute (3 months) recovery phases. Materials and Methods This is a secondary analysis of a prospective single-site double-blinded sham-controlled study conducted in patients presenting to the emergency department with moderate TBI from November 2015 to July 2019. Participants were randomized for LLLT and sham treatment. The primary outcome of the study was to assess structural connectivity, and RSFC was collected as the secondary outcome. MRI was used to measure RSFC in 82 brain regions in participants during the three recovery phases. Healthy individuals who did not receive treatment were imaged at a single time point to provide control values. The Pearson correlation coefficient was estimated to assess the connectivity strength for each brain region pair, and estimates of the differences in Fisher z-transformed correlation coefficients (hereafter, z differences) were compared between recovery phases and treatment groups using a linear mixed-effects regression model. These analyses were repeated for all brain region pairs. False discovery rate (FDR)-adjusted P values were computed to account for multiple comparisons. Quantile mixed-effects models were constructed to quantify the association between the Rivermead Postconcussion Symptoms Questionnaire (RPQ) score, recovery phase, and treatment group. Results RSFC was evaluated in 17 LLLT-treated participants (median age, 50 years [IQR, 25-67 years]; nine female), 21 sham-treated participants (median age, 50 years [IQR, 43-59 years]; 11 female), and 23 healthy control participants (median age, 42 years [IQR, 32-54 years]; 13 male). Seven brain region pairs exhibited a greater change in connectivity in LLLT-treated participants than in sham-treated participants between the acute and subacute phases (range of z differences, 0.37 [95% CI: 0.20, 0.53] to 0.45 [95% CI: 0.24, 0.67]; FDR-adjusted P value range, .010-.047). Thirteen different brain region pairs showed an increase in connectivity in sham-treated participants between the subacute and late-subacute phases (range of z differences, 0.17 [95% CI: 0.09, 0.25] to 0.26 [95% CI: 0.14, 0.39]; FDR-adjusted P value range, .020-.047). There was no evidence of a difference in clinical outcomes between LLLT-treated and sham-treated participants (range of differences in medians, -3.54 [95% CI: -12.65, 5.57] to -0.59 [95% CI: -7.31, 8.49]; P value range, .44-.99), as measured according to RPQ scores. Conclusion Despite the small sample size, the change in RSFC from the acute to subacute phases of recovery was greater in LLLT-treated than sham-treated participants, suggesting that acute-phase LLLT may have an impact on resting-state neuronal circuits in the early recovery phase of moderate TBI. ClinicalTrials.gov Identifier: NCT02233413 © RSNA, 2024 Supplemental material is available for this article.

Cerebral vasomotor reactivity in reversible cerebral vasoconstriction syndrome.

Background Altered cerebrovascular tone is implicated in reversible cerebral vasoconstriction syndrome (RCVS). We evaluated vasomotor reactivity using bedside transcranial Doppler in RCVS patients. Methods In this retrospective case-control study, middle cerebral artery (MCA) blood flow velocities were compared at rest and in response to breath-hold in RCVS ( n = 8), Migraineurs ( n = 10), and non-headache Controls ( n = 10). Hyperventilation response was measured in RCVS. Results In RCVS, Breath Holding Index (BHI) was severely reduced in seven of eight patients and 14/16 MCAs; seven of 16 MCAs showed exhausted (BHI < 0.1) or inverted (BHI < 0) vasomotor reactivity. Mean BHI in RCVS (0.23 ± 0.5) was significantly lower than Migraine (1.52 ± 0.57) and Controls (1.51 ± 0.32), p < 0.001. Triphasic velocity responses were seen in all groups. The maximum Vmean decline during the middle negative phase was -15.5 ± 9.2% in RCVS, -15.4 ± 7% in Migraine, and -10.3 ± 5% in Controls ( p = 0.04). In the late positive phase, average Vmean increase was 6.2 ± 14% in RCVS, which was significantly lower ( p < 0.001) than Migraine (30.5 ± 11%) and Controls (30.2 ± 6%). With hyperventilation, RCVS patients showed 23% decrease in Vmean. Conclusion Cerebral arterial tone is abnormal in RCVS, with proximal vasoconstriction and abnormally reduced capacity for vasodilation. Further studies are needed to determine the utility of BHI to diagnose RCVS before angiographic reversibility is established, and to estimate prognosis.

A case study of magnetic resonance imaging of cerebrovascular reactivity: a powerful imaging marker for mild traumatic brain injury.

PRIMARY OBJECTIVE: To use breath-hold functional magnetic resonance imaging (fMRI) to localize the brain regions with impaired cerebrovascular reactivity (CVR) in a female patient diagnosed with mild traumatic brain injury (mTBI). The extent of impaired CVR was evaluated 2 months after concussion. Follow-up scan was performed 1 year post-mTBI using the same breath-hold fMRI technique. RESEARCH DESIGN: Case report. METHODS AND PROCEDURES: fMRI blood oxygenation dependent level (BOLD) signals were measured under breath-hold challenge in a female mTBI patient 2 months after concussion followed by a second fMRI with breath-hold challenge 1 year later. CVR was expressed as the percentage change of BOLD signals per unit time of breath-hold. MAIN OUTCOMES: In comparison with CVR measurement of normal control subjects, statistical maps of CVR revealed substantial neurovascular deficits and hemispheric asymmetry within grey and white matter in the initial breath-hold fMRI scan. Follow-up breath-hold fMRI performed 1 year post-mTBI demonstrated normalization of CVR accompanied with symptomatic recovery. CONCLUSIONS: CVR may serve as an imaging biomarker to detect subtle deficits in both grey and white matter for individual diagnosis of mTBI. The findings encourage further investigation of hypercapnic fMRI as a diagnostic tool for mTBI.

Analysis of maternal and fetal cardiovascular systems during hyperglycemic pregnancy in the nonobese diabetic mouse.

Preconception or gestationally induced diabetes increases morbidities and elevates long-term cardiovascular disease risks in women and their children. Spontaneously hyperglycemic (d)-NOD/ShiLtJ female mice, a type 1 diabetes model, develop bradycardia and hypotension after midpregnancy compared with normoglycemic, age- and gestational day (GD)-matched control (c-NOD) females. We hypothesized that onset of the placental circulation at GD 9-10 and rapid fetal growth from GD 14 correlate with aberrant hemodynamic outcomes in d-NOD females. To develop further gestational time-course correlations between maternal cardiac and renal parameters, high-frequency ultrasonography was applied to d- and c-NOD mice (virgin and at GD 8-16). Cardiac output and left ventricular (LV) mass increased in c-NOD but not in d-NOD mice. Ultrasound and postmortem histopathology showed overall greater LV dilation in d-NOD than in c-NOD mice at mid to late gestation. These changes suggest blunted remodeling and altered functional adaptation of d-NOD hearts. Umbilical cord ultrasounds revealed lower fetal heart rates from GD 12 and lower umbilical flow velocities at GD 14 and GD 16 in d-NOD versus c-NOD pregnancies. From GD 14 to GD 16, d-NOD fetal losses exceeded c-NOD fetal losses. Similar aberrant responses in pregnancies of women with diabetes may elevate postpartum maternal and child cardiovascular risk, particularly if mothers lack adequate prenatal care or have poor glycemic control during gestation.

Success Rate of Transcranial Doppler Scanning of Cerebral Arteries at Different Transtemporal Windows in Healthy Elderly Individuals.

This study measured the rates of success in applying transcranial Doppler (TCD) scanning at the middle, posterior and anterior temporal windows (MTW, PTW and ATW) in the elderly. A hand-held 1.6-MHz pulsed-wave TCD transducer was used to search for cerebral arteries at MTW, PTW and ATW locations. Physical attributes of the head, including head circumference and the distance between tragi on both sides ("tragus-to-tragus arc length"), were also measured to explore the associations with successful rates. Among 396 healthy elderly participants (aged 62.6 ± 6.0 y, 140 men), 81.1% (n = 321; 127 men) had one or more temporal windows penetrable by TCD ultrasound (n = 286 [72.2%] at MTW, n = 195 [49.2%] at PTW and n = 106 [26.8%] at ATW). Regression analysis revealed that successful scanning increased significantly in male participants at three window locations. Younger age significantly increased successful scanning at the MTW and ATW. Smaller tragus-to-tragus arc length increased successful scanning at the MTW, but unsuccessful scanning at the ATW. Our findings support using MTW as the first location when positioning the TCD transducer for the scanning of cerebral arteries in the elderly population. When performing TCD scanning on two temporal windows, we propose choosing the MTW and PTW.

Record of a single fMRI experiment in May of 1991.

The discovery of BOLD fMRI at MGH in May 1991 was 1) built on the ongoing effort to develop new MR techniques for perfusion measurement with intrinsic blood contrast, 2) supported by the critical MGH expertise and experience on magnetic susceptibility and deoxyhemoglobin research, 3) inspired by the breakthrough in brain fMRI using dynamic susceptibility contrast (DSC) of the external contrast agent Gd-DTPA, 4) facilitated by the flow-BOLD insight of a hypoxia experiment, and 5) made possible by the availability of clinical echo planar imaging (EPI). The simultaneous demonstration of flow-weighted fMRI derived its intellectual origin from work on steady state arterial spin labeling (ASL). The free-wheeling and fertile intellectual environment structured by Dr. Thomas Brady and Dr. Bruce Rosen at the MGH-NMR Center provided the indispensable support for highly risky ideas to roam and succeed. The paper offers a first person account of the steps that led to the May experiment and its aftermath.

Restoring cerebral dopamine homeostasis by electrical forepaw stimulation: an FMRI study.

Deviation of dopamine homeostasis is known to be associated with disorders like drug addiction and Parkinson's disease. As dopamine function is tightly regulated within the basal ganglia circuitry, cortical perturbation would lead to modulation of dopaminergic activity in the striatum. We proposed and tested if somatosensory activity such as forepaw stimulation could modulate dopaminergic function. Specifically, we tested in rats if electrical forepaw stimulation (EFS) could attenuate dopamine release in the brain if dopamine is excessive, and boost dopamine release if dopamine is deficient. We had previously demonstrated that EFS effectively attenuated excessive DA concentration in the striatum. We now show in this manuscript with fMRI that EFS boosted DA release on two DA deficient conditions: (1) with quinpirole challenge, and (2) partial Parkinsonism model (PD). Quinpirole alone decreased dopamine release and thus the cerebral blood volume (CBV) that was restored by EFS. EFS also succeeded in increasing CBV in the basal-ganglia circuitry of the PD rats, but not in the controls. Context-dependent connectivity analysis showed increased connectivity during the basal state in the PD rats, compared with the controls. This "enhanced" yet abnormal connectivity of PD rats was reduced post-EFS. Our results suggest that EFS resets the deficient DA system by partially increasing DA release, in the meanwhile lessening the need for recruiting extra functional network in the basal ganglia circuitry. This study shows not only the capacity of peripheral stimulation to perturb neurotransmitter function, but also the potential of peripheral stimulation to restore neurotransmitter homeostasis.

Early time points perfusion imaging: theoretical analysis of correction factors for relative cerebral blood flow estimation given local arterial input function.

If local arterial input function (AIF) could be identified, we present a theoretical approach to generate a correction factor based on local AIF for the estimation of relative cerebral blood flow (rCBF) under the framework of early time points perfusion imaging (ET). If C(t), the contrast agent bolus concentration signal time course, is used for rCBF estimation in ET, the correction factor for C(t) is the integral of its local AIF. The recipe to apply the correction factor is to divide C(t) by the integral of its local AIF to obtain the correct rCBF. By similar analysis, the correction factor for the maximum derivative (MD1) of C(t) is the maximum signal of AIF and the correction factor for the maximum second derivative (MD2) of C(t) is the maximum derivative of AIF. In the specific case of using normalized gamma-variate function as a model for AIF, the correction factor for C(t) (but not for MD1) at the time to reach the maximum derivative is relatively insensitive to the shape of the local AIF.

Early time points perfusion imaging: relative time of arrival, maximum derivatives and fractional derivatives.

Time of arrival (TOA) of a bolus of contrast agent to the tissue voxel is a reference time point critical for the Early Time Points Perfusion Imaging Method (ET) to make relative cerebral blood flow (rCBF) maps. Due to the low contrast to noise (CNR) condition at TOA, other useful reference time points known as relative time of arrival data points (rTOA) are investigated. Candidate rTOA's include the time to reach the maximum derivative, the maximum second derivative, and the maximum fractional derivative. Each rTOA retains the same relative time distance from TOA for all tissue flow levels provided that ET's basic assumption is met, namely, no contrast agent has a chance to leave the tissue before the time of rTOA. The ET's framework insures that rCBF estimates by different orders of the derivative are theoretically equivalent to each other and monkey perfusion imaging results supported the theory. In rCBF estimation, maximum values of higher order fractional derivatives may be used to replace the maximum derivative which runs a higher risk of violating ET's assumption. Using the maximum values of the derivative of orders ranging from 1 to 1.5 to 2, estimated rCBF results were found to demonstrate a gray-white matter ratio of approximately 3, a number consistent with flow ratio reported in the literature.

Early time points perfusion imaging.

The aim was to investigate the feasibility of making relative cerebral blood flow (rCBF) maps from MR images acquired with short TR by measuring the initial arrival amount of Gd-DTPA evaluated within a time window before any contrast agent has a chance to leave the tissue. We named this rCBF measurement technique utilizing the early data points of the Gd-DTPA bolus the "early time points" method (ET), based on the hypothesis that early time point signals were proportional to rCBF. Simulation data were used successfully to examine the ideal behavior of ET while monkey's MRI results offered encouraging support to the utility of ET for rCBF calculation. A better brain coverage for ET could be obtained by applying the Simultaneous Echo Refocusing (SER) EPI technique. A recipe to run ET was presented, with attention paid to the noise problem around the time of arrival (TOA) of the contrast agent.

Impaired Cerebrovascular Reactivity in Huntington's Disease.

There is increasing evidence that impairments of cerebrovascular function and/or abnormalities of the cerebral vasculature might contribute to early neuronal cell loss in Huntington's disease (HD). Studies in both healthy individuals as well as in patients with other neurodegenerative disorders have used an exogenous carbon dioxide (CO2) challenge in conjunction with functional magnetic resonance imaging (fMRI) to assess regional cerebrovascular reactivity (CVR). In this study, we explored potential impairments of CVR in HD. Twelve gene expanded HD individuals, including both pre-symptomatic and early symptomatic HD and eleven healthy controls were administered a gas mixture targeting a 4-8 mmHg increase in CO2 relative to the end-tidal partial pressure of CO2 (P ET CO2) at rest. A Hilbert Transform analysis was used to compute the cross-correlation between the time series of regional BOLD signal changes (ΔBOLD) and increased P ET CO2, and to estimate the response delay of ΔBOLD relative to P ET CO2. After correcting for age, we found that the cross-correlation between the time series for regional ΔBOLD and for P ET CO2 was weaker in HD subjects than in controls in several subcortical white matter regions, including the corpus callosum, subcortical white matter adjacent to rostral and caudal anterior cingulate, rostral and caudal middle frontal, insular, middle temporal, and posterior cingulate areas. In addition, greater volume of dilated perivascular space (PVS) was observed to overlap, primarily along the periphery, with the areas that showed greater ΔBOLD response delay. Our preliminary findings support that alterations in cerebrovascular function occur in HD and may be an important, not as yet considered, contributor to early neuropathology in HD.

Cerebrovascular Responses to O2-CO2 Exchange Ratio under Brief Breath-Hold Challenge in Patients with Chronic Mild Traumatic Brain Injury.

Breath-by-breath oxygen-carbon dioxide (O2-CO2) exchange ratio (bER) is a respiratory gas exchange (RGE) metric, which is the ratio of the changes in the partial pressure of O2 (ΔPO2) to CO2 (ΔPCO2) between end-inspiration and end-expiration, has been demonstrated to characterize the cerebrovascular responses to breath-hold challenge in healthy individuals. We aimed to explore whether bER could characterize cerebrovascular responses in patients with chronic mild traumatic brain injury (mTBI) under breath-hold challenge. We also investigated the correlation between bER and the severity of post-concussion symptoms. Blood-oxygenation-level-dependent (BOLD) images were acquired using functional magnetic resonance imaging (fMRI) on 10 patients with chronic mTBI and 10 controls without brain injury history when performing a breath-hold task. Time series of RGE metrics of ΔPO2, ΔPCO2, and bER were computed, and their cross-correlation with regional change in BOLD (ΔBOLD) was calculated. Symptom burden was assessed using the Rivermead Post Concussion Questionnaire (RPQ), and its correlation with RGE changes was also measured. Compared with controls, a diffuse decrease in the correlation between regional ΔBOLD and bER was found in the brain of patients with mTBI (pfdr < 0.05). No significant difference was found between patients and controls for the correlation of regional ΔBOLD with ΔPO2 and ΔPCO2. Symptom severity indicated by RPQ scores increased with a decrease in the averaged changes of bER (ρ = 0.79, p = 0.01) and ΔPO2 (ρ = 0.70, p = 0.03) in breath-hold epochs. Our imaging and symptom severity findings suggest that bER can be used to characterize cerebrovascular responses to breath hold in patients with mTBI. The RGE may contribute to the post-concussive symptom severity.

Persistent CO2 reactivity deficits are associated with neurological dysfunction up to one year after repetitive mild closed head injury in adolescent mice.

Cerebrovascular reactivity (CVR) deficits in adolescents with concussion may persist after resolution of neurological symptoms. Whether or not CVR deficits predict long term neurological function is unknown. We used adolescent mice closed head injury (CHI) models (54 g, 107 cm or 117 cm drop height), followed by blood oxygenation level dependent (BOLD)-functional MRI with CO2 challenge to assess CVR and brain connectivity. At one week, 3HD 107 cm mice showed delayed BOLD responses (p = 0.0074), normal striatal connectivity, and an impaired respiratory rate response to CO2 challenge (p = 0.0061 in ΔRmax). The 107 cm group developed rotarod deficits at 6 months (p = 0.02) and altered post-CO2 brain connectivity (3-fold increase in striatum to motor cortex correlation coefficient) by one year, but resolved their CVR and respiratory rate impairments, and did not develop cognitive or circadian activity deficits. In contrast, the 117 cm group had persistent CVR (delay time: p = 0.016; washout time: p = 0.039) and circadian activity deficits (free-running period: 23.7 hr in sham vs 23.9 hr in 3HD; amplitude: 0.15 in sham vs 0.2 in 3HD; peak activity: 18 in sham vs 21 in 3HD) at one year. Persistent CVR deficits after concussion may portend long-term neurological dysfunction. Further studies are warranted to determine the utility of CVR to predict chronic neurological outcome after mild traumatic brain injury.

Dynamic brain-body coupling of breath-by-breath O2-CO2 exchange ratio with resting state cerebral hemodynamic fluctuations.

BACKGROUND: The origin of low frequency cerebral hemodynamic fluctuations (CHF) in the resting state remains unknown. Breath-by breath O2-CO2 exchange ratio (bER) has been reported to correlate with the cerebrovascular response to brief breath hold challenge at the frequency range of 0.008-0.03Hz in healthy adults. bER is defined as the ratio of the change in the partial pressure of oxygen (ΔPO2) to that of carbon dioxide (ΔPCO2) between end inspiration and end expiration. In this study, we aimed to investigate the contribution of respiratory gas exchange (RGE) metrics (bER, ΔPO2 and ΔPCO2) to low frequency CHF during spontaneous breathing. METHODS: Twenty-two healthy adults were included. We used transcranial Doppler sonography to evaluate CHF by measuring the changes in cerebral blood flow velocity (ΔCBFv) in bilateral middle cerebral arteries. The regional CHF were mapped with blood oxygenation level dependent (ΔBOLD) signal changes using functional magnetic resonance imaging. Temporal features and frequency characteristics of RGE metrics during spontaneous breathing were examined, and the simultaneous measurements of RGE metrics and CHF (ΔCBFv and ΔBOLD) were studied for their correlation. RESULTS: We found that the time courses of ΔPO2 and ΔPCO2 were interdependent but not redundant. The oscillations of RGE metrics were coherent with resting state CHF at the frequency range of 0.008-0.03Hz. Both bER and ΔPO2 were superior to ΔPCO2 in association with CHF while CHF could correlate more strongly with bER than with ΔPO2 in some brain regions. Brain regions with the strongest coupling between bER and ΔBOLD overlapped with many areas of default mode network including precuneus and posterior cingulate. CONCLUSION: Although the physiological mechanisms underlying the strong correlation between bER and CHF are unclear, our findings suggest the contribution of bER to low frequency resting state CHF, providing a novel insight of brain-body interaction via CHF and oscillations of RGE metrics.

Cerebrovascular reactivity assessment with O2-CO2 exchange ratio under brief breath hold challenge.

BACKGROUND: Hypercapnia during breath holding is believed to be the dominant driver behind the modulation of cerebral blood flow (CBF). However, increasing evidence show that mild hypoxia and mild hypercapnia in breath hold (BH) could work synergistically to enhance CBF response. We hypothesized that breath-by-breath O2-CO2 exchange ratio (bER), defined as the ratio of the change in partial pressure of oxygen (ΔPO2) to that of carbon dioxide (ΔPCO2) between end inspiration and end expiration, would be able to better correlate with the global and regional cerebral hemodynamic responses (CHR) to BH challenge. We aimed to investigate whether bER is a more useful index than end-tidal PCO2 to characterize cerebrovascular reactivity (CVR) under BH challenge. METHODS: We used transcranial Doppler ultrasound (TCD) to evaluate CHR under BH challenge by measuring cerebral blood flow velocity (CBFv) in the middle cerebral arteries. Regional changes in CHR to BH and exogenous CO2 challenges were mapped with blood oxygenation level dependent (BOLD) signal changes using functional magnetic resonance imaging (fMRI). We correlated respiratory gas exchange (RGE) metrics (bER, ΔPO2, ΔPCO2, end-tidal PCO2 and PO2, and time of breaths) with CHR (CBFv and BOLD) to BH challenge. Temporal features and frequency characteristics of RGE metrics and their coherence with CHR were examined. RESULTS: CHR to brief BH epochs and free breathing were coupled with both ΔPO2 and ΔPCO2. We found that bER was superior to either ΔPO2 or ΔPCO2 alone in coupling with the changes of CBFv and BOLD signals under breath hold challenge. The regional CVR results derived by regressing BOLD signal changes on bER under BH challenge resembled those derived by regressing BOLD signal changes on end-tidal PCO2 under exogenous CO2 challenge. CONCLUSION: Our findings provide a novel insight on the potential of using bER to better quantify CVR changes under BH challenge.

Hierarchical coding of characters in the ventral and dorsal visual streams of Chinese language processing.

Functional and spatial hierarchical organization of increasingly language-like word forms has been proposed for alphabetic languages at the occipitotemporal cortex for visual word recognition. In the logographic Chinese language system, similar functional and spatial hierarchical presentations of brain responses to sublexical orthographic structure are beginning to be explored. In this study, we used whole-brain fMRI to show that a hierarchical coding of increasingly language-like character type is present in multiple Chinese language processing areas. Fluent Chinese readers were presented with Chinese synonyms/non-synonym pairs, identical/non-identical non-pronounceable pseudo-character pairs constructed with Chinese radicals, and identical/non-identical Korean character pairs. We observed the presence of a spatial gradient for increasing language-like character types in the ventral and dorsal visual streams of the cortex. At the left occipitotemporal cortex of the ventral visual stream, we observed a posterior-to-anterior gradient of character type selectivity with the anterior fusiform region being more selective for real Chinese characters and the posterior fusiform region being more selective for Korean characters. At the left and right intraparietal sulci of the dorsal visual stream, a medial-to-lateral gradient of character type selectivity was observed, with the lateral edge being more selective for real Chinese characters, the medial edge being more selective for pseudo-characters, and with less activation attributable to Korean characters. Spatial gradients of selecting character type were also identified in prefrontal cortex, dorsal striatum and lateral temporal cortex. The results suggest that the left occipitotemporal cortex and both left and right intraparietal sulci are tuned with a functional and spatial hierarchical sensitivity to the presence of semantic elements as well as different orthographic structures.

Time-variant fMRI activity in the brainstem and higher structures in response to acupuncture.

Acupuncture modulation of activity in the human brainstem is not well known. This structure is plagued by physiological artifact in neuroimaging experiments. In addition, most studies have used short (<15 min) block designs, which miss delayed responses following longer duration stimulation. We used brainstem-focused cardiac-gated fMRI and evaluated time-variant brain response to longer duration (>30 min) stimulation with verum (VA, electro-stimulation at acupoint ST-36) or sham point (SPA, non-acupoint electro-stimulation) acupuncture. Our results provide evidence that acupuncture modulates brainstem nuclei important to endogenous monoaminergic and opioidergic systems. Specifically, VA modulated activity in the substantia nigra (SN), nucleus raphe magnus, locus ceruleus, nucleus cuneiformis, and periaqueductal gray (PAG). Activation in the ventrolateral PAG was greater for VA compared to SPA. Linearly decreasing time-variant activation, suggesting classical habituation, was found in response to both VA and SPA in sensorimotor (SII, posterior insula, premotor cortex) brain regions. However, VA also produced linearly time-variant activity in limbic regions (amygdala, hippocampus, and SN), which was bimodal and not likely habituation--consisting of activation in early blocks, and deactivation by the end of the run. Thus, acupuncture induces different brain response early, compared to 20-30 min after stimulation. We attribute the fMRI differences between VA and SPA to more varied and stronger psychophysical response induced by VA. Our study demonstrates that acupuncture modulation of brainstem structures can be studied non-invasively in humans, allowing for comparison to animal studies. Our protocol also demonstrates a fMRI approach to study habituation and other time-variant phenomena over longer time durations.

Electrical stimulation modulates the amphetamine-induced hemodynamic changes: an fMRI study to compare the effect of stimulating locations and frequencies on rats.

UNLABELLED: Our previous fMRI and microdialysis measurements showed that electroacupuncture (EA) at LI4 was effective in alleviating excessive cerebral dopamine release induced by d-amphetamine (AMPH) in rats. We now compare the effect of EA in adjusting excess dopamine release at two stimulating frequencies (2 Hz versus 100 Hz at LI4) and at two acupoints (forepaw (LI4) versus hindpaw (ST36), at 2 Hz). fMRI measurements of relative cerebral blood volume (rCBV) were used to monitor the brain activity of "rest", followed by AMPH challenge, 10 min "rest", and then 20 min of EA. RESULTS: EA at LI4 and ST36 significantly attenuated the AMPH-induced rCBV increases in the striatum, S1 cortex, and thalamus. Frequency: EA at 100 Hz induced greater attenuation of rCBV than EA at 2 Hz in the S1, insula, anterior cingulate cortices, dorsolateral striatum, and thalamus. Acupoints: EA at LI4 modulated a broader area in the medial anterior striatum while EA at ST36 modulated a more site-specific area in the dorsolateral striatum. In the thalamus, EA at LI4 showed greater attenuating effect than EA at ST36 did. However, in the insular cortex, EA at ST36 showed stronger attenuation. CONCLUSION: EA at both LI4 and ST36 was effective in restoring dopamine homeostasis from an excess state, with the most effective response at LI4 with 100 Hz, while the responses to 2Hz EA at LI4 and ST36 showed slightly different spatial distribution of MR signal. This therefore provided insight into the neurophysiological basis of electroacupuncture effects in cortical and subcortical circuits.

Inhibition of stimulated dopamine release and hemodynamic response in the brain through electrical stimulation of rat forepaw.

The subcortical response to peripheral somatosensory stimulation is not well studied. Prior literature suggests that somatosensory stimulation can affect dopaminergic tone. We studied the effects of electrical stimulation near the median nerve on the response to an amphetamine-induced increase in synaptic dopamine. We applied the electrical stimulation close to the median nerve 20 min after administration of 3mg/kg amphetamine. We used fMRI and microdialysis to measure markers of dopamine (DA) release, together with the release of associated neurotransmitters of striatal glutamate (Glu) and gamma-aminobutyric acid (GABA). Changes in cerebral blood volume (CBV), a marker used in fMRI, indicate that electrical stimulation significantly attenuated increased DA release (due to AMPH) in the striatum, thalamus, medial prefrontal and cingulate cortices. Microdialysis showed that electrical stimulation increased Glu and GABA release and attenuated the AMPH-enhanced DA release. The striatal DA dynamics correlated with the CBV response. These results demonstrate that electrical stimulation near the median nerve activates Glu/GABA release, which subsequently attenuate excess striatal DA release. These data provide evidence for physiologic modulation caused by electroacupuncture at points near the median nerve.