Jeffrey P. Lorberbaum

A potential role for thalamocingulate circuitry in human maternal behavior

BACKGROUND Little is known about the regional brain basis of human maternal behavior. To understand this better, we have been examining brain activity in mothers listening to infant cries. METHODS We measured functional Magnetic Resonance Imaging brain activity in healthy, breastfeeding first-time mothers with young infants while they listened to infant cries, white noise control sounds, and a rest condition. Based on the thalamocingulate theory of maternal behavior and pilot work, we hypothesized that the cingulate, medial thalamus, medial prefrontal cortex, and right orbitofrontal cortex would display more activity with infant cries than with white noise (comparison 1) and would uniquely activate with the cries, meaning that these regions would display activity with cry minus rest but not with white noise minus rest (comparison 2). RESULTS In hypothesized regions, the group displayed more activity in the medial thalamus, medial prefrontal and right orbitofrontal cortices with both comparisons. The anterior and posterior cingulate cortex displayed more activity only with comparison 1. In non-hypothesized brain regions, several other structures thought important in rodent maternal behavior displayed activity with both comparisons including the midbrain, hypothalamus, dorsal and ventral striatum, and vicinity of the lateral septal region. CONCLUSIONS Our results partially support our hypotheses and are generally consistent with neuroanatomical studies of rodent maternal behavior.

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.

The transcranial magnetic stimulation motor threshold depends on the distance from coil to underlying cortex: a replication in healthy adults comparing two methods of assessing the distance to cortex

Using transcranial magnetic stimulation (TMS), a handheld electrified copper coil against the scalp produces a powerful and rapidly oscillating magnetic field, which in turn induces electrical currents in the brain. The amount of electrical energy needed for TMS to induce motor movement (called the motor threshold [MT]), varies widely across individuals. The intensity of TMS is dosed relative to the MT. Kozel et al observed in a depressed cohort that MT increases as a function of distance from coil to cortex. This article examines this relationship in a healthy cohort and compares the two methods of assessing distance to cortex. Seventeen healthy adults had their TMS MT determined and marked with a fiducial. Magnetic resonance images showed the fiducials marking motor cortex, allowing researchers to measure distance from scalp to motor and prefontal cortex using two methods: 1) measuring a line from scalp to the nearest cortex and 2) sampling the distance from scalp to cortex of two 18-mm-square areas. Confirming Kozels previous finding, we observe that motor threshold increases as distance to motor cortex increased for both methods of measuring distance and that no significant correlation exists between MT and prefontal cortex distance. Distance from TMS coil to motor cortex is an important determinant of MT in healthy and depressed adults. Distance to prefontal cortex is not correlated with MT, raising questions about the common practice of dosing prefontal stimulation using MT determined over motor cortex.

A review of functional neuroimaging studies of vagus nerve stimulation (VNS).

Vagus nerve stimulation (VNS) is a new method for preventing and treating seizures, and shows promise as a potential new antidepressant. The mechanisms of action of VNS are still unknown, although the afferent direct and secondary connections of the vagus nerve are well established and are the most likely route of VNS brain effects. Over the past several years, many groups have used functional brain imaging to better understand VNS effects on the brain. Since these studies differ somewhat in their methodologies, findings and conclusions, at first glance, this literature may appear inconsistent. Although disagreement exists regarding the specific locations and the direction of brain activation, the differences across studies are largely due to different methods, and the results are not entirely inconsistent. We provide an overview of these functional imaging studies of VNS. PET (positron emission tomography) and SPECT (single photon emission computed tomography) studies have implicated several brain areas affected by VNS, without being able to define the key structures consistently and immediately activated by VNS. BOLD (blood oxygen level dependent) fMRI (functional magnetic resonance imaging), with its relatively high spatio-temporal resolution, performed during VNS, can reveal the location and level of the brains immediate response to VNS. As a whole, these studies demonstrate that VNS causes immediate and longer-term changes in brain regions with vagus innervations and which have been implicated in neuropsychiatric disorders. These include the thalamus, cerebellum, orbitofrontal cortex, limbic system, hypothalamus, and medulla. Functional neuroimaging studies have the potential to provide greater insight into the brain circuitry behind the activity of VNS.

Quetiapine treatment in patients with posttraumatic stress disorder: An open trial of adjunctive therapy

In this 6-week, open-label trial, combat veterans meeting DSM-IV criteria for posttraumatic stress disorder (PTSD) were treated with the atypical antipsychotic quetiapine. The starting dose was 25 mg at bedtime with subsequent titration based on tolerability and clinical response. Primary outcome was measured using the Clinician Administered PTSD Scale (CAPS). Secondary assessments of efficacy included the Positive and Negative Symptom Scale (PANSS), the Hamilton Rating Scale for Depression, and the Clinical Global Impression Scale. Safety and tolerability evaluations included neurologic ratings, vital signs, and assessment of treatment-emergent side effects. Eighteen of 20 patients enrolled in the study completed 6 weeks of open-label treatment. The dose range of quetiapine was 25 to 300 mg daily, with an average of 100±70 mg/d. There was significant improvement in CAPS scores, from 89.8±15.7 to 67.5±21.0 (t=4.863, df=18, P <0.005), and composite PANSS ratings from baseline to endpoint. General psychopathology (PANSS) and depressive symptoms (HRSD) were also reduced at the 6-week end point. There were no serious adverse events and no clinically significant changes in vital signs or neurologic ratings. This preliminary open trial suggests that quetiapine is well tolerated and may have efficacy in reducing PTSD symptoms in patients who have not had an adequate response other medications. Studies utilizing a randomized, controlled trial design and larger sample sizes are needed to better define the potential role of quetiapine and other atypical antipsychotics in the treatment of PTSD.

BOLD-f MRI response to single-pulse transcranial magnetic stimulation (TMS).

Five healthy volunteers were studied using interleaved transcranial magnetic stimulation/functional magnetic resonance imaging (TMS/fMRI) and an averaged single trial (AST) protocol. Blood oxygenation level‐dependent (BOLD)‐fMRI response to single TMS pulses over the motor cortex was detectable in both the ipsilateral motor cortex under the TMS coil and the contralateral motor cortex, as well as bilaterally in the auditory cortex. The associated BOLD signal increase showed the typical fMRI hemodynamic response time course. The brains response to a single TMS pulse over the motor cortex at 120% of the level required to induce thumb movement (1.0%–1.5% signal increase) was comparable in both level and duration to the auditory cortex response to the sound accompanying the TMS pulse (1.5% –2.0% signal increase). J. Magn. Reson. Imaging 2000;11:569–574.

Motor cortex brain activity induced by 1-Hz transcranial magnetic stimulation is similar in location and level to that for volitional movement.

Bohning DE, Shastri A, McGavin L, et al. Motor cortex brain activity induced by 1-Hz transcranial magnetic stimulation is similar in location and level to that for volitional movement. Invest Radiol 2000;35:676–683. RATIONALE AND OBJECTIVES.The relatively high temporal and spatial resolution of functional MR imaging was used to compare the blood oxygenation level dependent (BOLD) response associated with movement induced by transcranial magnetic stimulation (TMS) with that for a similar movement executed volitionally (VOL). METHODS.Seven healthy adults were studied in a 1.5-T MR scanner. One hertz TMS at 110% of motor threshold was applied over the motor cortex for the thumb in 21-pulse trains in alternation with VOL every 63 seconds and interleaved with functional MR imaging. RESULTS.BOLD increases in motor cortex associated with TMS and VOL movement were similar (2%–3%). Mean separation of their centers of activity was 3.7 ± 1.9 mm (mean displacement: left/right = 0.3 ± 4.1 mm; superior/inferior = 0.7 ± 1.9 mm). There was no indication of supraphysiological brain activity. CONCLUSIONS.Motor cortex BOLD response associated with thumb movement induced by 1-Hz TMS at 110% motor threshold is similar in both location and level to that caused by a similar movement executed volitionally.

Lack of significant changes on magnetic resonance scans before and after 2 weeks of daily left prefrontal repetitive transcranial magnetic stimulation for depression.

Repetitive transcranial magnetic stimulation (rTMS) is a new technology for exploring brain function. With this method, a small electromagnet is placed on the scalp; by activating and deactivating it, nerve cells in the underlying superficial cortex are depolarized. Several studies have found that prefrontal rTMS has potential efficacy in treating depression, and this technology, in addition to being a research tool, may soon play a role in psychiatric practice. Thus, establishing the safety of this technology is important and has been studied insufficiently. The authors performed T1-weighted three-dimensional volumetric magnetic resonance (MR) imaging on 22 depressed adults (15 active, 7 control) before and after they participated in a 2-week double-blinded, placebo-controlled trial of daily left prefrontal rTMS for the treatment of depression (a total of 16,000 stimuli). Seventeen patients also had paired T2-weighted scans. In a blinded manner, MR scans were qualitatively and quantitatively assessed for structural changes. No qualitative structural differences were observed before and after treatment. In addition, volumetric analysis of the prefrontal lobe showed no changes in the 2 weeks of the study. In conclusion, 10 days of daily prefrontal rTMS at these intensities and frequencies does not cause observable structural changes on MR scans in depressed adults.

Augmenting Atypical Antipsychotics with a Cognitive Enhancer (Donepezil) Improves Regional Brain Activity in Schizophrenia Patients: A Pilot Double-blind Placebo Controlled BOLD fMRI Study

Cognitive impairments are cardinal features of schizophrenia and predictors of poor vocational and social outcome. Imaging studies with verbal fluency tasks (VFT) lead some to suggest that in schizophrenia, the combination of a failure to deactivate the left temporal lobe and a hypoactive frontal lobe reflects a functional disconnectivity between the left prefrontal cortex and temporal lobe. Others have theorized that an abnormal cingulate gyrus modulates such fronto-temporal connectivity. Thus addition of a cognitive enhancing medication to current antipsychotic therapy might improve functionality of networks necessary in working memory and internal concept generation. To test this hypothesis, we serially measured brain activity in 6 subjects on stable atypical antipsychotics performing a VFT, using BOLD fMRI. Measurements were made at baseline and again after groups were randomized to receive 12 weeks of donepezil (an acetylcholinesterase inhibitor) and placebo in a blind cross-over design. Donepezil addition provided a functional normalization with an increase in left frontal lobe and cingulate activity when compared to placebo and from baseline scans. This pilot study supports the cingulate’s role in modulating cognition and neuronal connectivity in schizophrenia.