BOLD fMRI response to direct stimulation (transcranial magnetic stimulation) of the motor cortex shows no decline with age.

Previous studies using BOLD fMRI to examine age-related changes in cortical activation used tasks that relied on peripheral systems to activate the brain. They were unable to distinguish between alterations due to age-related changes in the periphery and actual changes in cortical physiology. Transcranial magnetic stimulation (TMS), which allows direct, noninvasive stimulation of cortical neurons, was interleaved with BOLD fMRI to study 6 young and 5 old subjects. Three different tasks were compared: direct stimulation by TMS, indirect active stimulation produced by a motor task, and indirect passive stimulation produced by hearing the TMS coil discharge. Direct neuronal stimulation by TMS produced similar fMRI signal increases in both groups, suggesting that cortical physiology itself may not necessarily decline with age.

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.

Activation of prefrontal cortex and anterior thalamus in alcoholic subjects on exposure to alcohol-specific cues.

BACKGROUND: Functional imaging studies have recently demonstrated that specific brain regions become active in cocaine addicts when they are exposed to cocaine stimuli. To test whether there are regional brain activity differences during alcohol cue exposure between alcoholic subjects and social drinkers, we designed a functional magnetic resonance imaging (fMRI) protocol involving alcohol-specific cues. METHODS: Ten non-treatment-seeking adult alcoholic subjects (2 women) (mean [SD] age, 29.9 [9.9] years) as well as 10 healthy social drinking controls of similar age (2 women) (mean [SD] age, 29.4 [8.9] years) were recruited, screened, and scanned. In the 1.5-T magnetic resonance imaging scanner, subjects were serially rated for alcohol craving before and after a sip of alcohol, and after a 9-minute randomized presentation of pictures of alcoholic beverages, control nonalcoholic beverages, and 2 different visual control tasks. During picture presentation, changes in regional brain activity were measured with the blood oxygen level-dependent technique. RESULTS: Alcoholic subjects, compared with the social drinking subjects, reported higher overall craving ratings for alcohol. After a sip of alcohol, while viewing alcohol cues compared with viewing other beverage cues, only the alcoholic subjects had increased activity in the left dorsolateral prefrontal cortex and the anterior thalamus. The social drinkers exhibited specific activation only while viewing the control beverage pictures. CONCLUSIONS: When exposed to alcohol cues, alcoholic subjects have increased brain activity in the prefrontal cortex and anterior thalamus-brain regions associated with emotion regulation, attention, and appetitive behavior.

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 Kozel's 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.

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

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.

Bupropion-SR in treatment of social phobia.

A 12-week, open label flexible dosing study was conducted to evaluate the efficacy of bupropion-SR in the treatment of generalized social phobia. The primary outcome measures include the Clinical Global Impression of Improvement (CGI-I) and the Brief Social Phobia Rating Scale (BSPS). A total of 18 subjects were enrolled. Five of the ten subjects who completed all 12 weeks were considered as responders. Response to treatment was defined as a CGI-I score of 1 or 2, ("much improved" or "very much improved," respectively) and a > 50% decrease in BSPS score. The final doses for the completers ranged between 200 and 400 mg/day (mean 366 +/- 68 mg/day). The medication was generally well tolerated. Findings from this open-label trial suggest that bupropion-SR may be useful in treating generalized social phobia.

How coil-cortex distance relates to age, motor threshold, and antidepressant response to repetitive transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) is a tool with antidepressant potential that uses a coil placed on the scalp to produce a powerful magnetic field that directly stimulates only the outermost cortex. MRI scans were obtained in 29 depressed adults involved in an rTMS antidepressant clinical treatment. These scans were analyzed to investigate the effect of distance from coil to cortex on clinical parameters. Longer motor cortex distance, but not prefrontal distance, strongly correlated with increased motor threshold (P<0.01). Clinical antidepressant response did not correlate with either distance. The rTMS antidepressant responders, however, were significantly younger (t=-2.430, P<0.05), and there appears to be a maximum threshold of age and distance to prefrontal cortex for response.

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 brain's 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).

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.

Feasibility of using fMRI to study mothers responding to infant cries.

While parenting is a universal human behavior, its neuroanatomic basis is currently unknown. Animal data suggest that the cingulate may play an important function in mammalian parenting behavior. For example, in rodents cingulate lesions impair maternal behavior. Here, in an attempt to understand the brain basis of human maternal behavior, we had mothers listen to recorded infant cries and white noise control sounds while they underwent functional MRI (fMRI) of the brain. We hypothesized that mothers would show significantly greater cingulate activity during the cries compared to the control sounds. Of 7 subjects scanned, 4 had fMRI data suitable for analysis. When fMRI data were averaged for these 4 subjects, the anterior cingulate and right medial prefrontal cortex were the only brain regions showing statistically increased activity with the cries compared to white noise control sounds (cluster analysis with one-tailed z-map threshold of P < 0.001 and spatial extent threshold of P < 0.05). These results demonstrate the feasibility of using fMRI to study brain activity in mothers listening to infant cries and that the anterior cingulate may be involved in mothers listening to crying babies. We are currently replicating this study in a larger group of mothers. Future work in this area may help (1) unravel the functional neuroanatomy of the parent-infant bond and (2) examine whether markers of this bond, such as maternal brain response to infant crying, can predict maternal style (i.e., child neglect), offspring temperament, or offspring depression or anxiety.

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.

Potential role of the anterior cingulate cortex in PTSD: review and hypothesis.

Many symptoms of PTSD represent conditioned responses to stimuli associated with a traumatic experiences. In this review, we propose that the anterior cingulate--a brain region that appears to be involved in fear-conditioning--is dysfunctional in PTSD, thus facilitating exaggerated emotional and behavioral responses (hyperarousal) to conditioned stimuli. Preclinical studies suggest that the anterior cingulate may serve a critical gating function in modulating conditioned fear responses. As such, this region would be a key component of a neural circuit involved in the pathophysiology of PTSD. An amygdala-locus coeruleus-anterior cingulate circuit may be consistent with evidence for chronic noradrenergic activation documented in PTSD patients. According to this model, efferent noradrenergic projections from the locus coeruleus may dampen anterior cingulate function. This in turn would allow myriad external or internally driven stimuli to produce the exaggerated emotional and behavioral responses characteristic of PTSD. If confirmed in future research, cingulate dysfunction would have important theoretical and treatment implications.

Echoplanar BOLD fMRI of brain activation induced by concurrent transcranial magnetic stimulation.

RATIONALE AND OBJECTIVES: The authors demonstrate the feasibility of combining transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) inside an MR scanner to noninvasively stimulate and image regional brain activity. METHODS: Echoplanar blood oxygen level dependent (BOLD)-based fMRI studies of TMS response were performed on three human volunteers inside a standard 1.5 T MR scanner using independent computer control to interleave echoplanar image acquisition and stimulation of right thumb primary motor cortex with a nonferromagnetic TMS coil. RESULTS: Significant (P< 0.001) response was observed in motor cortex under the TMS coil during stimulation compared to rest, as well in auditory cortex, the latter presumably due to the loud "snap" when the coil was pulsed. CONCLUSIONS: Concurrent TMS stimulation and echoplanar BOLD fMRI imaging is possible. This method has potential for tracing neural circuits with brain imaging, as well as investigating the effects of TMS.