The effects of laser stimulation at acupoint ST36 on anxiety-like behaviors and anterior cingulate cortex c-Fos expression in a rat post-traumatic stress disorder model.

Post-traumatic stress disorder (PTSD) is a mental disorder that is linked with the onset of multiple anxiety-like behaviors. This study was designed to assess how these behaviors and anterior cingulate cortex (ACC) c-Fos expression were impacted by 10.6-µm laser stimulation at acupoint ST36 a rat model of PTSD. A rat model of PTSD was prepared via prolonged exposure of animals to a stressor, followed by a 7-day period during which animals were allowed to rest undisturbed in their cages. Rats were randomized into four experimental groups (n = 12/group): the control, PTSD, LS, and sham LS groups. Control group animals were not subjected to SPS procedures prior to behavioral testing. LS and sham LS animals were administered LS treatment at bilateral ST36 acupoints or non-acupoints, respectively, for a 7-day period. Animals were then assessed for performance in elevated plus maze (EPM) tests and open-field tests (OFT), and their plasma corticosterone levels were measured. In addition, c-Fos-positive nuclei in the ACC were detected via immunohistochemical staining. Relative to sham LS treatment and PTSD model control rats, LS was associated with increased time spent in both open EPM test arms and in the central area in the OFT (P < 0.05). The PTSD model group exhibited a significant reduction in ACC c-Fox expression, while LS treatment significantly increased this expression (P < 0.001). In addition, a correlation was detected between anxiety-like behaviors and altered ACC neuronal activation. The results of this study indicate that LS at acupoint ST36 can have a previously unreported effect on anxiety-like behaviors in the context of PTSD, with ACC neuronal activation potentially being implicated as a driver of this effect.

Radiosurgery for Behavioral Disorders.

Psychiatric illnesses create great suffering for patients and the medical solution is sometimes limited. The experience observed after treating patients with obsessive-compulsive disorder (OCD), depression, and anorexia nervosa by Gamma Knife radiosurgery (GKRS) is presented. Ten patients with medically refractory OCD, 3 patients with depression resistant to medical treatment and electroconvulsive therapy, and 5 patients with refractory anorexia nervosa have been treated. Bilateral anterior capsulotomy has been performed to treat OCD and bilateral cingulotomy has been applied to treat severe depression and anorexia nervosa. The accumulated experience about treatment of OCD by GKRS is reviewed. In our experience, 70% of OCD patients achieved a full response. We observed a significant improvement in patients with depression and anorexia nervosa evidenced by the scales of assessment (mean reduction of 40% in the Beck Depression Inventory at 1-year follow-up and 40% average increase of body mass index at 6-month follow-up). No side effects have been observed. These procedures are effective in reducing obsession, compulsion, depression, and anxiety, improving the quality of life of the patients without side effects.

Manipulation of Subcortical and Deep Cortical Activity in the Primate Brain Using Transcranial Focused Ultrasound Stimulation.

The causal role of an area within a neural network can be determined by interfering with its activity and measuring the impact. Many current reversible manipulation techniques have limitations preventing their application, particularly in deep areas of the primate brain. Here, we demonstrate that a focused transcranial ultrasound stimulation (TUS) protocol impacts activity even in deep brain areas: a subcortical brain structure, the amygdala (experiment 1), and a deep cortical region, the anterior cingulate cortex (ACC, experiment 2), in macaques. TUS neuromodulatory effects were measured by examining relationships between activity in each area and the rest of the brain using functional magnetic resonance imaging (fMRI). In control conditions without sonication, activity in a given area is related to activity in interconnected regions, but such relationships are reduced after sonication, specifically for the targeted areas. Dissociable and focal effects on neural activity could not be explained by auditory confounds.

Exposure to blue wavelength light modulates anterior cingulate cortex activation in response to 'uncertain' versus 'certain' anticipation of positive stimuli.

Blue wavelength light has been used as an effective treatment for some types of mood disorders and circadian rhythm related sleep problems. We hypothesized that acute exposure to blue wavelength light would directly affect the functioning of neurocircuity implicated in emotion regulation (i.e., ventromedial prefrontal cortex, amygdala, insula, and anterior cingulate cortex [ACC]) during 'certain' and 'uncertain' anticipation of negative and positive stimuli. Thirty-five healthy adults were randomized to receive a thirty-minute exposure to either blue (active) or amber (placebo) light, immediately followed by an emotional anticipation task during functional magnetic resonance imaging (fMRI). In contrast to placebo, participants in the blue light group showed significantly reduced activation within the rostral ACC during 'uncertain' anticipation (i.e., uncertainty regarding whether a positive or negative stimulus would be shown) in comparison to 'certain' anticipation of a positive stimulus. These findings may be explicable in terms of interactions between blue light exposure and the influence of specific neuromodulators on ACC-mediated decision-making mechanisms.

Regional variation in brain white matter diffusion index changes following chemoradiotherapy: a prospective study using tract-based spatial statistics.

PURPOSE: There is little known about how brain white matter structures differ in their response to radiation, which may have implications for radiation-induced neurocognitive impairment. We used diffusion tensor imaging (DTI) to examine regional variation in white matter changes following chemoradiotherapy. METHODS: Fourteen patients receiving two or three weeks of whole-brain radiation therapy (RT) ± chemotherapy underwent DTI pre-RT, at end-RT, and one month post-RT. Three diffusion indices were measured: fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). We determined significant individual voxel changes of diffusion indices using tract-based spatial statistics, and mean changes of the indices within fourteen white matter structures of interest. RESULTS: Voxels of significant FA decreases and RD increases were seen in all structures (p<0.05), with the largest changes (20-50%) in the fornix, cingula, and corpus callosum. There were highly significant between-structure differences in pre-RT to end-RT mean FA changes (p<0.001). The inferior cingula had a mean FA decrease from pre-RT to end-RT significantly greater than 11 of the 13 other structures (p<0.00385). CONCLUSIONS: Brain white matter structures varied greatly in their response to chemoradiotherapy as measured by DTI changes. Changes in FA and RD related to white matter demyelination were prominent in the cingula and fornix, structures relevant to radiation-induced neurocognitive impairment. Future research should evaluate DTI as a predictive biomarker of brain chemoradiotherapy adverse effects.

Controlled ultrasound-induced blood-brain barrier disruption using passive acoustic emissions monitoring.

The ability of ultrasonically-induced oscillations of circulating microbubbles to permeabilize vascular barriers such as the blood-brain barrier (BBB) holds great promise for noninvasive targeted drug delivery. A major issue has been a lack of control over the procedure to ensure both safe and effective treatment. Here, we evaluated the use of passively-recorded acoustic emissions as a means to achieve this control. An acoustic emissions monitoring system was constructed and integrated into a clinical transcranial MRI-guided focused ultrasound system. Recordings were analyzed using a spectroscopic method that isolates the acoustic emissions caused by the microbubbles during sonication. This analysis characterized and quantified harmonic oscillations that occur when the BBB is disrupted, and broadband emissions that occur when tissue damage occurs. After validating the system's performance in pilot studies that explored a wide range of exposure levels, the measurements were used to control the ultrasound exposure level during transcranial sonications at 104 volumes over 22 weekly sessions in four macaques. We found that increasing the exposure level until a large harmonic emissions signal was observed was an effective means to ensure BBB disruption without broadband emissions. We had a success rate of 96% in inducing BBB disruption as measured by in contrast-enhanced MRI, and we detected broadband emissions in less than 0.2% of the applied bursts. The magnitude of the harmonic emissions signals was significantly (P<0.001) larger for sonications where BBB disruption was detected, and it correlated with BBB permeabilization as indicated by the magnitude of the MRI signal enhancement after MRI contrast administration (R(2) = 0.78). Overall, the results indicate that harmonic emissions can be a used to control focused ultrasound-induced BBB disruption. These results are promising for clinical translation of this technology.

Cellular circadian clocks in mood disorders.

Bipolar disorder (BD) and major depressive disorder (MDD) are heritable neuropsychiatric disorders associated with disrupted circadian rhythms. The hypothesis that circadian clock dysfunction plays a causal role in these disorders has endured for decades but has been difficult to test and remains controversial. In the meantime, the discovery of clock genes and cellular clocks has revolutionized our understanding of circadian timing. Cellular circadian clocks are located in the suprachiasmatic nucleus (SCN), the brain's primary circadian pacemaker, but also throughout the brain and peripheral tissues. In BD and MDD patients, defects have been found in SCN-dependent rhythms of body temperature and melatonin release. However, these are imperfect and indirect indicators of SCN function. Moreover, the SCN may not be particularly relevant to mood regulation, whereas the lateral habenula, ventral tegmentum, and hippocampus, which also contain cellular clocks, have established roles in this regard. Dysfunction in these non-SCN clocks could contribute directly to the pathophysiology of BD/MDD. We hypothesize that circadian clock dysfunction in non-SCN clocks is a trait marker of mood disorders, encoded by pathological genetic variants. Because network features of the SCN render it uniquely resistant to perturbation, previous studies of SCN outputs in mood disorders patients may have failed to detect genetic defects affecting non-SCN clocks, which include not only mood-regulating neurons in the brain but also peripheral cells accessible in human subjects. Therefore, reporters of rhythmic clock gene expression in cells from patients or mouse models could provide a direct assay of the molecular gears of the clock, in cellular clocks that are likely to be more representative than the SCN of mood-regulating neurons in patients. This approach, informed by the new insights and tools of modern chronobiology, will allow a more definitive test of the role of cellular circadian clocks in mood disorders.

Damage to the right dorsal anterior cingulate cortex induces panic disorder.

Brain imaging studies suggest that panic disorder (PD) is mediated by several brain regions, including the anterior cingulate cortex (ACC). In the present report we describe a patient who experienced a panic attack during awake surgery (case 1) and another patient who developed PD after surgery and radiotherapy (case 2). In case 1, the patient experienced repeated panic attacks when the tumor at the upper border of right dorsal ACC was removed during awake surgery. In case 2, the patient developed PD at six months after surgery and Cyberknife radiotherapy. MRI examination revealed that the dorsal ACC size was reduced at six months after surgery and that the dorsal ACC was absent at two years after surgery, possibly due to radiotherapy-induced damage by radiotherapy. Profile of mood states (POMS) testing characterized the presence of tension-anxiety as the common abnormal symptom in cases 1 and 2. In conclusion, these results suggest that damage to the right dorsal ACC can induce PD and that this structure likely plays a pathophysiologic role in PD.

Testing for causality with transcranial direct current stimulation: pitch memory and the left supramarginal gyrus.

Neuroimaging studies have implicated the left supramarginal gyrus in short-term auditory memory processing, including memory for pitch. The present study investigated the causal role of the left supramarginal gyrus in short-term pitch memory by comparing the effects of cathodal transcranial direct current stimulation when applied over the left or right supramarginal gyrus with sham transcranial direct current stimulation. Only cathodal transcranial direct current stimulation over the left supramarginal gyrus had a detrimental effect on short-term pitch-memory performance in 11 adult participants. These results provide support for the important role of the left supramarginal gyrus in short-term memory for pitch information, and they further demonstrate the potential of transcranial direct current stimulation to modulate the functional contribution of a brain area to a particular cognitive process.

Comparison of anterior cingulate and primary somatosensory neuronal responses to noxious laser-heat stimuli in conscious, behaving rats.

In this study, we investigated single-unit responses of the primary sensorimotor cortex (SmI) and anterior cingulate cortex (ACC) to noxious stimulation of the tail of the rat. The influences of morphine on these nociceptive responses were also compared. Multiple single-unit activities were recorded from two eight-channel microwire arrays chronically implanted in the tail region of the SmI and ACC, respectively. CO2 laser-heat irradiation of the middle part of the tail at an intensity slightly higher than that causing a maximal tail flick response was used as a specific noxious stimulus. Examined individually, ACC neurons were less responsive than SmI neurons to laser-heat stimulus, in that only 51% of the ACC units (n = 125) responded compared with 88% of the SmI units (n = 74). Among these responsive ACC units, many had a very long latency and long-lasting excitatory type of response that was seldom found in the SmI. When ensemble activities were examined, laser heat evoked both short- (60 approximately 150 ms) and long-latency (151 approximately 600 ms) responses in the SmI and ACC. Latencies of both responses were longer in the ACC. Furthermore, a single dose of 2.5-10 mg/kg morphine intraperitoneally suppressed only the long latency response in the SmI, but significantly attenuated both responses in the ACC. These effects of morphine were completely blocked by prior treatment with the opiate receptor blocker, naloxone. These results provide further evidence suggesting that the SmI and ACC may play different roles in processing noxious information.

Roles of NMDA receptor NR2A and NR2B subtypes for long-term depression in the anterior cingulate cortex.

The anterior cingulate cortex (ACC) is thought to be important for the establishment, consolidation and retrieval of permanent memory. In many brain regions, including the hippocampus, it is suggested that long-term potentiation (LTP) and long-term depression (LTD), the cellular mechanisms for learning and memory, require the activation of glutamate N-methyl-D-aspartate receptors (NMDARs). In the hippocampus, the NR2A subunit is believed to be involved in the induction of LTP, whereas the NR2B subunit contributes to the formation of LTD. However, LTD has been less well studied in the ACC as compared with the hippocampus and little is known about the role of NMDA subtype receptors in cingulate LTD. Here we show that LTD can be induced by the combination of presynaptic stimulation with postsynaptic depolarization ('pairing training') in adult mouse ACC neurons. This form of LTD is an NMDAR- and voltage-dependent mechanism and a postsynaptic Ca2+ increase is required for the induction of LTD. Furthermore, our studies provide direct physiological evidence that both NR2A and NR2B subunits are involved in the induction of LTD in the ACC.

A parametric assessment of GABA antagonist effects on paired-pulse facilitation in the rat anterior cingulate cortex.

Paired-pulse facilitation (PPF) is a form of short-term plasticity that can be used qualitatively to characterize the synaptic effects of neuroactive compounds. As we have shown previously, CNQX has a marked effect on PPF which can be measured quantitatively. The aim of the present study was to examine quantitatively possible differences in the effects of the post- and pre-synaptic GABA antagonists on PPF in vitro. Experiments were performed on slices taken from the coronal anterior cingulate cortex (ACC) of Sprague-Dawley rats. The stimuli consisted of a pair of biphasic pulses with an inter-pulse interval of 40ms. Evoked extracellular field potentials in layers 2/3 of the ACC were recorded. Quantitative assessment of PPF was achieved by calculating two parameters, the PPFmax (theoretical maximal PPF) and the Stmax (stimulus intensity that produces the PPFmax). Picrotoxin treatment produced increases in both the PPFmax and Stmax, by increasing the stimulus producing the half-maximal effect. In contrast, CGP-55845 treatment produced an increase in only the PPFmax, which was due to an alteration in the asymptotic values of the response amplitudes. Our findings show that the effect of different GABA receptor antagonists on short-term synaptic facilitation in the ACC may be assessed and specified quantitatively.

Kainate receptor-mediated synaptic transmission in the adult anterior cingulate cortex.

Kainate (KA) receptors are expressed widely in the CNS. However, little is known about their functional characterization, molecular identity, and role in synaptic transmission in the forebrain of adult mice. Patch-clamp recordings in genetically modified mice show that postsynaptic KA receptors contribute to fast synaptic transmission in pyramidal neurons in the anterior cingulate cortex (ACC), a forebrain region critical for higher-order cognitive brain functions such as memory and mental disorders. Single-shock stimulation could induce small KA receptor-mediated excitatory postsynaptic currents (KA EPSCs) in the presence of picrotoxin, D-2-amino-5-phosphono-pentanoic acid, and a selective AMPA receptor antagonist, GYKI 53655. KA EPSCs had a significantly slower rise time course and decay time constant compared with AMPA receptor-mediated EPSCs. High-frequency repetitive stimulation significantly facilitated the KA EPSCs. Genetic deletion of the GluR6 or GluR5 subunit significantly reduced, and GluR5 and 6 double knockout completely abolished, KA EPSCs and KA-activated currents in ACC pyramidal neurons. Our results show that KA receptors contribute to synaptic transmission in adult ACC pyramidal neurons and provide a synaptic basis for the physiology and pathology of KA receptors in ACC-related functions.

Electrical stimulation of the anterior cingulate cortex reduces responses of rat dorsal horn neurons to mechanical stimuli.

The anterior cingulate cortex (ACC) is involved in the affective and motivational aspect of pain perception. Behavioral studies show a decreased avoidance behavior to noxious stimuli without change in mechanical threshold after stimulation of the ACC. However, as part of the neural circuitry of behavioral reflexes, there is no evidence showing that ACC stimulation alters dorsal horn neuronal responses. We hypothesize that ACC stimulation has two phases: a short-term phase in which stimulation elicits antinociception and a long-term phase that follows stimulation to change the affective response to noxious input. To begin testing this hypothesis, the purpose of this study was to examine the response of spinal cord dorsal horn neurons during stimulation of the ACC. Fifty-eight wide dynamic range spinal cord dorsal horn neurons from adult Sprague-Dawley rats were recorded in response to graded mechanical stimuli (brush, pressure, and pinch) at their respective receptive fields, while simultaneous stepwise electrical stimulations (300 Hz, 0.1 ms, at 10, 20, and 30 V) were applied in the ACC. The responses to brush at control, 10, 20, and 30 V, and recovery were 14.2 +/- 1.4, 12.3 +/- 1.2, 10.9 +/- 1.2, 10.3 +/- 1.1, and 14.1 +/- 1.4 spikes/s, respectively. The responses to pressure at control, 10, 20, and 30 V, and recovery were 39.8 +/- 4.7, 25.6 +/- 3.0, 25.0 +/- 3.0, 21.6 +/- 2.4, and 34.2 +/- 3.7 spikes/s, respectively. The responses to pinch at control, 10, 20, and 30 V, and recovery were 40.7 +/- 3.8, 30.6 +/- 3.1, 27.8 +/- 2.8, 27.2 +/- 3.2, and 37.4 +/- 3.9 spikes/s, respectively. We conclude that electrical stimulation of the ACC induces significant inhibition of the responses of spinal cord dorsal horn neurons to noxious mechanical stimuli. The stimulation-induced inhibition begins to recover as soon as the stimulation is terminated. These results suggest differential short-term and long-term modulatory effects of the ACC stimulation on nociceptive circuits.

Quantitative assessment of the effect of CNQX on paired-pulse facilitation in the anterior cingulate cortex.

Paired-pulse facilitation (PPF) is a form of short-term plasticity which has been used qualitatively to characterize the action of neuroactive compounds. The aims of the present study were to develop a model that allows the quantitative assessment of PPF and to evaluate the influence of CNQX, an AMPA receptor antagonist, on synaptic plasticity based on parameters derived from this model. Experiments were performed on brain slices taken from the coronal anterior cingulate cortex (ACC) of Sprague-Dawley rats. Stimulation was applied to layer 5 of the ACC. In all experiments, the stimuli comprised a pair of biphasic pulses generated by an isolated pulse stimulator under software control. An inter-pulse interval of 40 ms was employed, and the evoked extracellular field potentials in layer 2/3 of the ACC were recorded. An equation was adopted to describe the PPF at different stimulation intensities. Nonlinear fitting was used to obtain the coefficients of the equation which would allow the description of the experimental data. CNQX exerted an influence on the area under the curve for the PPF versus stimulation plot by changing the values of the parameter K (the voltage causing a half-maximal response). The model was elaborated based on features of the ligand-receptor interaction which can be reliably specified empirically, and its applicability was illustrated by characterizing the influence of CNQX on PPF in the ACC. An algorithm for the assessment of PPF using different sets of parameters is also discussed.

Functional imaging during covert auditory attention in multiple sclerosis.

Recent literature suggests that the brain in multiple sclerosis (MS) undergoes reorganization that subserves the performance of visual and motor tasks. We identified sites of cerebral activity in 16 MS patients while performing a covert attention (CA) task, presented in the auditory modality. Positron emission tomography (PET) revealed activation of rostral/dorsal anterior cingulate cortex (ACC) in normal subjects studied previously. Activity in this region was not significant in MS patients, but there was a large region of activity in superior temporal cortex. Decreased activation of frontal attentional networks and greater activity in sensory/perceptual cortical areas (auditory association cortex) suggests a reduction of transmission along white matter tracts connecting these regions. This study demonstrates cingulate hypoactivity and cerebral reorganization during auditory attention in MS.

Sensorimotor integration in the precentral gyrus: polysensory neurons and defensive movements.

The precentral gyrus of monkeys contains a polysensory zone in which the neurons respond to tactile, visual, and sometimes auditory stimuli. The tactile receptive fields of the polysensory neurons are usually on the face, arms, or upper torso, and the visual and auditory receptive fields are usually confined to the space near the tactile receptive fields, within about 30 cm of the body. Electrical stimulation of this polysensory zone, even in anesthetized animals, evokes a specific set of movements. The movements resemble those typically used to defend the body from objects that are near, approaching, or touching the skin. In the present study, to determine whether the stimulation-evoked movements represent a normal set of defensive movements, we tested whether they include a distinctive, nonsaccadic, centering movement of the eyes that occurs during defensive reactions. We report that this centering movement of the eyes is evoked by stimulation of sites in the polysensory zone. We also recorded the activity of neurons in the polysensory zone while the monkey made defensive reactions to an air puff on the face. The neurons became active during the defensive movement, and the magnitude of this activity was correlated with the magnitude of the defensive reaction. These results support the hypothesis that the polysensory zone in the precentral gyrus contributes to the control of defensive movements. More generally, the results support the view that the precentral gyrus can control movement at the level of complex sensorimotor tasks.

Metabolic changes after repetitive transcranial magnetic stimulation (rTMS) of the left prefrontal cortex: a sham-controlled proton magnetic resonance spectroscopy (1H MRS) study of healthy brain.

Rapid transcranial magnetic stimulation is being increasingly used in the treatment of psychiatric disorders, especially major depression. However, its mechanisms of action are still unclear. The aim of this study was to assess metabolic changes by proton magnetic resonance spectroscopy following high-frequency rapid transcranial magnetic stimulation (20 Hz), both immediately after a single session and 24 h after a series of five consecutive sessions. Twelve healthy volunteers were enrolled in a prospective single-blind, randomized study [sham (n = 5) vs. real (n = 7)]. Three brain regions were investigated (right, left dorsolateral prefrontal cortex, left anterior cingulate cortex). A single as well as a series of consecutive rapid transcranial magnetic stimulations affected cortical glutamate/glutamine levels. These effects were present not only close to the stimulation site (left dorsolateral prefrontal cortex), but also in remote (right dorsolateral prefrontal cortex, left cingulate cortex) brain regions. Remarkably, the observed changes in glutamate/glutamine levels were dependent on the pre-transcranial magnetic stimulation glutamate/glutamine concentration, i.e. the lower the pre-stimulation glutamate/glutamine level, the higher the glutamate/glutamine increase observed after short- or long-term stimulation (5 days). In general, the treatment was well tolerated and no serious side-effects were reported. Neither transient mood changes nor significant differences in the outcome of a series of neuropsychological test batteries after real or sham transcranial magnetic stimulation occurred in our experiment. In summary, these data indicate that rapid transcranial magnetic stimulation may act via stimulation of glutamatergic prefrontal neurons.

Felonious sex crime: the possibility of unilateral cerebral irradiation for the offenders.

Some felonious sex crimes might result from compulsions that the perpetrator finds impossible to control. Under judicial systems derived from British law, the court should be extraordinarily careful in mandating any medical procedure. However, if a rapist or child molester voluntarily asks a physician for help, then medical ethics might allow destruction of part of the patient's brain for the purpose of controlling compulsive behaviour. The part of the human brain primarily associated with volition might be near the anterior cingulate sulcus. Could unilateral irradiation of an area near the anterior cingulate sulcus partially destroy the patient's volition? By leaving intact the patient's will based on language and by partially destroying the patient's will based on intuition, could the physician diminish the patient's will to commit felonious sex crimes? Would some patients reject chemical castration but accept unilateral irradiation of an area near the anterior cingulate sulcus?