Charlotte C. Teneback

A combined TMS/fMRI study of intensity-dependent TMS over motor cortex.

BACKGROUND Transcranial magnetic stimulation (TMS) allows noninvasive stimulation of neurons using time-varying magnetic fields. Researchers have begun combining TMS with functional imaging to simultaneously stimulate and image brain activity. Recently, the feasibility of interleaving TMS with functional magnetic resonance imaging (fMRI) was demonstrated. This study tests this new method to determine if TMS at different intensities shows different local and remote activation. METHODS Within a 1.5 Tesla (T) MRI scanner, seven adults were stimulated with a figure-eight TMS coil over the left motor cortex for thumb, while continuously acquiring blood oxygen level dependent (BOLD) echoplanar images. TMS was applied at 1 Hz in 18-second long trains delivered alternately at 110% and 80% of motor threshold separated by rest periods. RESULTS Though the TMS coil caused some artifacts and reduced the signal to noise ratio (SNR), higher intensity TMS caused greater activation than lower, both locally and remotely. The magnitude (approximately 3% increase) and temporal onset (2 to 5 sec) of TMS induced blood flow changes appear similar to those induced using other motor and cognitive tasks. CONCLUSIONS Though work remains in refining this potentially powerful method, combined TMS/fMRI is both technically feasible and produces measurable dose-dependent changes in brain activity.

Unilateral left prefrontal transcranial magnetic stimulation (TMS) produces intensity-dependent bilateral effects as measured by interleaved BOLD fMRI

Transcranial magnetic stimulation (TMS) administered over the prefrontal cortex has been shown to subtly influence neuropsychological tasks, and has antidepressant effects when applied daily for several weeks. Prefrontal TMS does not, however, produce an immediate easily observable effect, making it hard to determine if one has stimulated the cortex. Most prefrontal TMS studies have stimulated using intensity relative to the more easily determined motor threshold (MT) over motor cortex. Five healthy adults were studied in a 1.5 T MRI scanner during short trains of 1 Hz TMS delivered with a figure eight MR compatible TMS coil followed by rest epochs. In a randomized manner, left prefrontal TMS was delivered at 80%, 100% and 120% of MT interleaved with BOLD fMRI acquisition. Compared to rest, all TMS epochs activated auditory cortex, with 80% MT having no other areas of significant activation. 100% MT showed contralateral activation and 120% MT showed bilateral prefrontal activation. Higher intensity TMS, compared to lower, in general produced more activity both under the coil and contralaterally. Higher prefrontal TMS stimulation intensity produces greater local and contralateral activation. Importantly, unilateral prefrontal TMS produces bilateral effects, and TMS at 80% MT produces only minimal prefrontal cortex activation.

Serial Vagus Nerve Stimulation Functional MRI in Treatment-Resistant Depression

Vagus nerve stimulation (VNS) therapy has shown antidepressant effects in open acute and long-term studies of treatment-resistant major depression. Mechanisms of action are not fully understood, although clinical data suggest slower onset therapeutic benefit than conventional psychotropic interventions. We set out to map brain systems activated by VNS and to identify serial brain functional correlates of antidepressant treatment and symptomatic response. Nine adults, satisfying DSM-IV criteria for unipolar or bipolar disorder, severe depressed type, were implanted with adjunctive VNS therapy (MRI-compatible technique) and enrolled in a 3-month, double-blind, placebo-controlled, serial-interleaved VNS/functional MRI (fMRI) study and open 20-month follow-up. A multiple regression mixed model with blood oxygenation level dependent (BOLD) signal as the dependent variable revealed that over time, VNS therapy was associated with ventro-medial prefrontal cortex deactivation. Controlling for other variables, acute VNS produced greater right insula activation among the participants with a greater degree of depression. These results suggest that similar to other antidepressant treatments, BOLD deactivation in the ventro-medial prefrontal cortex correlates with the antidepressant response to VNS therapy. The increased acute VNS insula effects among actively depressed participants may also account for the lower dosing observed in VNS clinical trials of depression compared with epilepsy. Future interleaved VNS/fMRI studies to confirm these findings and further clarify the regional neurobiological effects of VNS.

Prefrontal repetitive transcranial magnetic stimulation (rTMS) changes relative perfusion locally and remotely

Although transcranial magnetic stimulation has been used as a stand‐alone brain mapping tool, relatively few studies have attempted to couple TMS with functional brain imaging to understand the neurobiological effects of TMS. Technical problems of placing a TMS coil in a PET or MRI scanner have hampered previous efforts at imaging the immediate effects of TMS. Perfusion SPECT offers the advantage of tracer injection away from the camera, with later image development. We wondered if perfusion SPECT could be used to visualize brain changes during rTMS over the left prefrontal cortex—a region where rTMS has been shown to cause changes in mood or working memory. Eight healthy adult subjects were scanned with brain SPECT scintigraphy using 30 mCi (1110 MBq) Neurolite® (DuPont Pharma) on a triple‐headed Picker camera. Each subject had three scans: (1) baseline, (2) bolus tracer injection during seconds 10–20 of a train of 2 min of left prefrontal rTMS (10 Hz; 60% motor threshold (MT); 10 s on/off, 600 stimuli) (2MIN), and (3) exactly as in the 2MIN, but immediately after subjects had received 18 min of high frequency stimulation (20 Hz; 80% MT; 2 s on/28 s off, 1440+600=2040 total stimuli) (20MIN). Scans were linearly transformed into Talairach space using SPM96b and compared across conditions (p<0·05 for display). Contrary to our prestudy hypothesis, there was no relative increase at the coil site during the 2 min or the 20 min scan compared to baseline. In fact, at the 20 min comparison perfusion was relatively decreased in the right prefrontal cortex, bilateral anterior cingulate, and anterior temporal cortex. Also, relative perfusion was significantly increased in the orbitofrontal cortex (L>R) and hypothalamus at 20 min and at 2 min, with thalamic increases occurring at the 20 min scan compared to baseline. There was an apparent TMS dose effect with twice as many decreases at 20 min than 2 min. Directly comparing the 20 min to the 2 min scans demonstrated opposite hemisphere decreases and relative increases in the ipsilateral (left) hemisphere as a function of more TMS stimuli. Full interpretation of these results is hampered by incomplete knowledge of the effect of the relative amount of stimulation to rest during tracer uptake, pharmacokinetics of tracer uptake, and depth and intensity of the magnetic field. Nevertheless, coupling rTMS with split‐dose perfusion SPECT appears to be a promising method for understanding the brain changes associated with rTMS, and for directly visualizing neural circuits. We have demonstrated that prefrontal rTMS at high frequencies has both local and remote effects. These imaging results may help explain the cognitive and behavioural effects demonstrated in other prefrontal rTMS studies involving mood and working memory. Copyright

Interleaved transcranial magnetic stimulation/functional MRI confirms that lamotrigine inhibits cortical excitability in healthy young men.

Little is known about how lamotrigine (LTG) works within brain circuits to achieve its clinical effects. We wished to determine whether the new technique of interleaved transcranial magnetic stimulation (TMS)/functional magnetic resonance imaging (fMRI) could be used to assess the effects of LTG on activated motor or prefrontal/limbic circuits. We carried out a randomized, double-blind, crossover trial involving two visits 1 week apart with TMS measures of cortical excitability and blood oxygen level-dependent TMS/fMRI. Subjects received either a single oral dose of 325 mg of LTG or placebo on each visit. In all, 10 subjects provided a complete data set that included interleaved TMS/fMRI measures and resting motor threshold (rMT) determinations under both placebo and LTG conditions. A further two subjects provided only rMT data under the two drug conditions. LTG caused a 14.9±9.6% (mean±SD) increase in rMT 3 h after the drug, compared with a 0.6±10.9% increase 3 h after placebo (t=3.41, df =11, p<0.01). fMRI scans showed that LTG diffusely inhibited cortical activation induced by TMS applied over the motor cortex. In contrast, when TMS was applied over the prefrontal cortex, LTG increased the TMS-induced activation of limbic regions, notably the orbitofrontal cortex and hippocampus. These results suggest that LTG, at clinically relevant serum concentrations, has a general inhibitory effect on cortical neuronal excitability, but may have a more complex effect on limbic circuits. Furthermore, the interleaved TMS/fMRI technique may be a useful tool for investigating regional brain effects of psychoactive compounds.

Low frequency daily left prefrontal rTMS improves mood in bipolar depression: a placebo-controlled case report

Preliminary studies in unipolar depression indicate that daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) reduces symptoms of depression. rTMS treatment of depression occurring in the setting of bipolar disorder has been less well studied. To assess the efficacy and toxicity of rTMS in the depressed phase of bipolar disorder, we treated a man with bipolar disorder who was known to develop hypomania and mania with conventional antidepressants. A 47 year old man with Bipolar Disorder type 1, depressed phase, was entered into a double‐blind parallel treatment trial of left prefrontal rTMS. He was randomized to receive left prefrontal rTMS at low frequency (5 Hz) for 2 weeks, which was then followed by an open phase. The patients Hamilton Depression scores decreased 44 per cent across the first 2 weeks. In an open extension, his mood further improved over another 2 weeks and he was gradually tapered from rTMS treatments. He had no side effects. Importantly, he did not develop mania, as had occurred with all prior antidepressant trials. After several months he experienced a recurrence of depressive symptoms, was retreated, and re‐responded. Further studies are warranted to investigate the optimum dose, duration, location and frequency of rTMS treatments for the depressed phase of bipolar disorder.

80. Functional MRI of mothers responding to infant cries

We reportpilot fMRIdata on brainactivityin humanmotherslistening to a cryingbaby. Since animal data suggestthat maternalbehavioris impairedby cingolateablations,we hypothesizedthat motherswould have cingulateactivation,especiallyanteriorly,with this provocation. Fourbiologicalmothershavinga youngestchildless thanage fourwere studiedwith fMIU while they listenedto reeordedbaby cries (active condition)alternatingwith white noises whose temporalfeatures and averageintensitymatchedthoseof thecries(controIcondition).Weused a pairedt-test (P<O.001)to compareactiveminuscontrolscanswithin each subject. Preselected regions were then observed for at least moderateactivity.Two subjectshad antenor, 1 had middle,and 1 had posteriorcingolateactivation.Curiously,the subjectwith the youngest child (3 weeks) was the only one without any cingulate activation. Instead,she had activationof the rightorbitofrontalcortex(ROFC)and left thalamus.ROFCactivationwas,in fact,presentin 2 othersubjectsas well. In additionto the more prevalent activity in the cingulateand ROFC,seleetedregionsdemonstratingactivi~ in 1subjecteachincluded the rightinsularcortex,bilateralmedialtemporallobes,left caudate,letl thalarnus,and brainstem. These pilot results tentatively support our hypothesisthat the cingulateis involvedin maternalresponseto infant crying. Also, the ROFCmay be espccirdlyinvolvedin this response, consistentwith some data suggestingthat orbitofiontalcortex lesions cause a syndromeof child neglectand socialindifferencein monkeys.