Norman W. Kettner

Effects of Electroacupuncture versus Manual Acupuncture on the Human Brain as Measured by fMRI

The goal of this functional magnetic resonance imaging (fMRI) study was to compare the central effects of electroacupuncture at different frequencies with traditional Chinese manual acupuncture. Although not as time‐tested as manual acupuncture, electroacupuncture does have the advantage of setting stimulation frequency and intensity objectively and quantifiably. Manual acupuncture, electroacupuncture at 2 Hz and 100 Hz, and tactile control stimulation were carried out at acupoint ST‐36. Overall, electroacupuncture (particularly at low frequency) produced more widespread fMRI signal increase than manual acupuncture did, and all acupuncture stimulations produced more widespread responses than did our placebo‐like tactile control stimulation. Acupuncture produced hemodynamic signal increase in the anterior insula, and decrease in limbic and paralimbic structures including the amygdala, anterior hippocampus, and the cortices of the subgenual and retrosplenial cingulate, ventromedial prefrontal cortex, frontal, and temporal poles, results not seen for tactile control stimulation. Only electroacupuncture produced significant signal increase in the anterior middle cingulate cortex, whereas 2‐Hz electroacupuncture produced signal increase in the pontine raphe area. All forms of stimulation (acupuncture and control) produced signal increase in SII. These findings support a hypothesis that the limbic system is central to acupuncture effect regardless of specific acupuncture modality, although some differences do exist in the underlying neurobiologic mechanisms for these modalities, and may aid in optimizing their future usage in clinical applications. Hum. Brain Mapping 24:193–205, 2005.

Acupuncture modulates resting state connectivity in default and sensorimotor brain networks.

&NA; Previous studies have defined low‐frequency, spatially consistent networks in resting fMRI data which may reflect functional connectivity. We sought to explore how a complex somatosensory stimulation, acupuncture, influences intrinsic connectivity in two of these networks: the default mode network (DMN) and sensorimotor network (SMN). We analyzed resting fMRI data taken before and after verum and sham acupuncture. Electrocardiography data were used to infer autonomic modulation through measures of heart rate variability (HRV). Probabilistic independent component analysis was used to separate resting fMRI data into DMN and SMN components. Following verum, but not sham, acupuncture there was increased DMN connectivity with pain (anterior cingulate cortex (ACC), periaqueductal gray), affective (amygdala, ACC), and memory (hippocampal formation, middle temporal gyrus) related brain regions. Furthermore, increased DMN connectivity with the hippocampal formation, a region known to support memory and interconnected with autonomic brain regions, was negatively correlated with acupuncture‐induced increase in a sympathetic related HRV metric (LFu), and positively correlated with a parasympathetic related metric (HFu). Following verum, but not sham, acupuncture there was also increased SMN connectivity with pain‐related brain regions (ACC, cerebellum). We attribute differences between verum and sham acupuncture to more varied and stronger sensations evoked by verum acupuncture. Our results demonstrate for the first time that acupuncture can enhance the post‐stimulation spatial extent of resting brain networks to include anti‐nociceptive, memory, and affective brain regions. This modulation and sympathovagal response may relate to acupuncture analgesia and other potential therapeutic effects.

Hypothalamus and amygdala response to acupuncture stimuli in Carpal Tunnel Syndrome.

Abstract Brain processing of acupuncture stimuli in chronic neuropathic pain patients may underlie its beneficial effects. We used fMRI to evaluate verum and sham acupuncture stimulation at acupoint LI‐4 in Carpal Tunnel Syndrome (CTS) patients and healthy controls (HC). CTS patients were retested after 5 weeks of acupuncture therapy. Thus, we investigated both the short‐term brain response to acupuncture stimulation, as well as the influence of longer‐term acupuncture therapy effects on this short‐term response. CTS patients responded to verum acupuncture with greater activation in the hypothalamus and deactivation in the amygdala as compared to HC, controlling for the non‐specific effects of sham acupuncture. A similar difference was found between CTS patients at baseline and after acupuncture therapy. For baseline CTS patients responding to verum acupuncture, functional connectivity was found between the hypothalamus and amygdala – the less deactivation in the amygdala, the greater the activation in the hypothalamus, and vice versa. Furthermore, hypothalamic response correlated positively with the degree of maladaptive cortical plasticity in CTS patients (inter‐digit separation distance). This is the first evidence suggesting that chronic pain patients respond to acupuncture differently than HC, through a coordinated limbic network including the hypothalamus and amygdala.

Somatosensory cortical plasticity in carpal tunnel syndrome treated by acupuncture.

Carpal tunnel syndrome (CTS) is a common entrapment neuropathy of the median nerve characterized by paresthesias and pain in the first through fourth digits. We hypothesize that aberrant afferent input from CTS will lead to maladaptive cortical plasticity, which may be corrected by appropriate therapy. Functional MRI (fMRI) scanning and clinical testing was performed on CTS patients at baseline and after 5 weeks of acupuncture treatment. As a control, healthy adults were also tested 5 weeks apart. During fMRI, sensory stimulation was performed for median nerve innervated digit 2 (D2) and digit 3 (D3), and ulnar nerve innervated digit 5 (D5). Surface‐based and region of interest (ROI)‐based analyses demonstrated that while the extent of fMRI activity in contralateral Brodmann Area 1 (BA 1) and BA 4 was increased in CTS compared to healthy adults, after acupuncture there was a significant decrease in contralateral BA 1 (P < 0.005) and BA 4 (P < 0.05) activity during D3 sensory stimulation. Healthy adults demonstrated no significant test–retest differences for any digit tested. While D3/D2 separation was contracted or blurred in CTS patients compared to healthy adults, the D2 SI representation shifted laterally after acupuncture treatment, leading to increased D3/D2 separation. Increasing D3/D2 separation correlated with decreasing paresthesias in CTS patients (P < 0.05). As CTS‐induced paresthesias constitute diffuse, synchronized, multidigit symptomatology, our results for maladaptive change and correction are consistent with Hebbian plasticity mechanisms. Acupuncture, a somatosensory conditioning stimulus, shows promise in inducing beneficial cortical plasticity manifested by more focused digital representations. Hum Brain Mapp, 2007.

Somatosensory cortical plasticity in carpal tunnel syndrome—a cross-sectional fMRI evaluation

Carpal tunnel syndrome (CTS) is a common entrapment neuropathy of the median nerve characterized by paresthesias and pain in the first, second, and third digits. We hypothesize that aberrant afferent input in CTS will lead to cortical plasticity. Functional MRI (fMRI) and neurophysiological testing were performed on CTS patients and healthy adults. Median nerve innervated digit 2 (D2), and digit 3 (D3) and ulnar nerve innervated digit 5 (D5) were stimulated during fMRI. Surface-based and ROI-based analyses consistently demonstrated more extensive and stronger contralateral sensorimotor cortical representations of D2 and D3 for CTS patients as compared to healthy adults (P < 0.05). Differences were less profound for D5. Moreover, D3 fMRI activation in both the contralateral SI and motor cortex correlated positively with the D3 sensory conduction latency. Analysis of somatotopy suggested that contralateral SI representations for D2 and D3 were less separated for CTS patients (3.8 +/- 1.0 mm) than for healthy adults (7.5 +/- 1.2 mm). Furthermore, the D3/D2 separation distance correlated negatively with D2 sensory conduction latency-the greater the latency, the closer the D2/D3 cortical representations (r = -0.79, P < 0.05). Coupled with a greater extent of SI representation for these CTS affected digits, the closer cortical representations can be interpreted as a blurred somatotopic arrangement for CTS affected digits. These findings provide further evidence that CTS is not manifest in the periphery alone. Our results are consistent with Hebbian plasticity mechanisms, as our cohort of CTS patients had predominant paresthesias, which produce more temporally coherent afferent signaling from affected digits.

Brain encoding of acupuncture sensation - coupling on-line rating with fMRI

Acupuncture-induced sensations have historically been associated with clinical efficacy. These sensations are atypical, arising from sub-dermal receptors, and their neural encoding is not well known. In this fMRI study, subjects were stimulated at acupoint PC-6, while rating sensation with a custom-built, MR-compatible potentiometer. Separate runs included real (ACUP) and sham (SHAM) acupuncture, the latter characterized by non-insertive, cutaneous stimulation. FMRI data analysis was guided by the on-line rating timeseries, thereby localizing brain correlates of acupuncture sensation. Sensation ratings correlated with stimulation more (p<0.001) for SHAM (r=0.63) than for ACUP (r=0.32). ACUP induced stronger and more varied sensations with significant persistence into no-stimulation blocks, leading to more run-time spent rating low and moderate sensations compared to SHAM. ACUP sensation correlated with activation in regions associated with sensorimotor (SII, insula) and cognitive (dorsomedial prefrontal cortex (dmPFC)) processing, and deactivation in default-mode network (DMN) regions (posterior cingulate, precuneus). Compared to SHAM, ACUP yielded greater activity in both anterior and posterior dmPFC and dlPFC. In contrast, SHAM produced greater activation in sensorimotor (SI, SII, insula) and greater deactivation in DMN regions. Thus, brain encoding of ACUP sensation (more persistent and varied, leading to increased cognitive load) demonstrated greater activity in both cognitive/evaluative (posterior dmPFC) and emotional/interoceptive (anterior dmPFC) cortical regions. Increased cognitive load and dmPFC activity may be a salient component of acupuncture analgesia--sensations focus attention and accentuate bodily awareness, contributing to enhanced top-down modulation of any nociceptive afference and central pain networks. Hence, acupuncture may function as a somatosensory-guided mind-body therapy.

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.

Bone Marrow Edema: Pathophysiology, Differential Diagnosis, and Imaging

Bone marrow edema (BME) has been a topic of increasing interest in the literature in recent years. BME is associated with numerous pathologies and is becoming recognized not only as a considerable pain generator, but also as an entity which is, in some cases, significantly linked to the worsening of patient prognosis. To date, no thorough imaging review of BME has been published. An electronic literature search was conducted through PubMed with a time parameter of January 1975 through December 2007. The primary search parameter was “bone marrow edema.” Over 800 papers were listed as written in English and involving humans. Other refining parameters included “AND syndrome,” “AND transient,” “AND arthritis,” “AND infection,” “AND tumor,” “AND neoplasm,” “AND iatrogenic,” “AND radiation therapy,” and “AND inflammation.” More current articles were favored over dated articles on the same topic. A total of 106 journal articles were collected concerning BME and multiple pathologic processes. The data contained therein was compiled and organized into a comprehensive format. BME can be caused by, and found concurrent with, a broad spectrum of pathologies which exhibit a variety of imaging findings. BME is also associated with the deterioration of certain pathologies. This presentation is a comprehensive discussion of different pathological conditions inducing or associated with BME. Differential diagnosis through appropriate imaging is vital to case management and could contribute to the prevention or decreased progression of certain pathologies. Continued investigation into the imaging of BME and its associated diseases, as well as the effect of BME on prognosis, is warranted.

Brain correlates of phasic autonomic response to acupuncture stimulation: An event‐related fMRI study

Autonomic nervous system (ANS) response to acupuncture has been investigated by multiple studies; however, the brain circuitry underlying this response is not well understood. We applied event‐related fMRI (er‐fMRI) in conjunction with ANS recording (heart rate, HR; skin conductance response, SCR). Brief manual acupuncture stimuli were delivered at acupoints ST36 and SP9, while sham stimuli were delivered at control location, SH1. Acupuncture produced activation in S2, insula, and mid‐cingulate cortex, and deactivation in default mode network (DMN) areas. On average, HR deceleration (HR−) and SCR were noted following both real and sham acupuncture, though magnitude of response was greater following real acupuncture and inter‐subject magnitude of response correlated with evoked sensation intensity. Acupuncture events with strong SCR also produced greater anterior insula activation than without SCR. Moreover, acupuncture at SP9, which produced greater SCR, also produced stronger sharp pain sensation, and greater anterior insula activation. Conversely, acupuncture‐induced HR− was associated with greater DMN deactivation. Between‐event correlation demonstrated that this association was strongest for ST36, which also produced more robust HR−. In fact, DMN deactivation was significantly more pronounced across acupuncture stimuli producing HR−, versus those events characterized by acceleration (HR+). Thus, differential brain response underlying acupuncture stimuli may be related to differential autonomic outflows and may result from heterogeneity in evoked sensations. Our er‐fMRI approach suggests that ANS response to acupuncture, consistent with previously characterized orienting and startle/defense responses, arises from activity within distinct subregions of the more general brain circuitry responding to acupuncture stimuli. Hum Brain Mapp 34:2592–2606, 2013.

Normative cross-sectional area of the C5-C8 nerve roots using ultrasonography.

This study will define a normal range of values for the cross-sectional area (CSA) of the C5-C8 ventral rami in normal subjects and will assess the interexaminer reliability of the CSA measurements. We also describe the normal sonoanatomy of the C5-C8 ventral rami. Thirty-three normal subjects (20 female) were scanned bilaterally. The mean CSA and reference ranges for the C5, C6, C7 and C8 ventral rami were 7.1 +/- 4.1 mm(2), 10.6 +/- 4.3 mm(2), 12.1 +/- 4.1 mm(2) and 10.7 +/- 4.8 mm(2), respectively. The intraclass correlation coefficient (ICC) demonstrated good reliability with a coefficient of 0.76 overall, with individual level coefficients at C5, C6, C7 and C8 of 0.69, 0.71, 0.76 and 0.72, respectively. This is the first study to obtain normative CSA measurements of the C5-C8 ventral rami.