Dorsolateral prefrontal cortex stimulation modulates electrocortical measures of visual attention: evidence from direct bilateral epidural cortical stimulation in treatment-resistant mood disorder.

Electrocortical activity is increasingly being used to study emotion regulation and the impact of cognitive control on neural response to visual stimuli. In the current study, we used direct epidural cortical stimulation (EpCS) to examine regional specificity of PFC stimulation on the parietally-maximal late positive potential (LPP), an event-related potential (ERP) biomarker of visual attention to salient stimuli. Five patients with treatment-resistant mood disorders were stereotactically implanted with stimulating paddles over frontopolar (FP) and dorsolateral (DL) prefrontal cortex bilaterally. On their first day of activation, patients underwent sham-controlled EpCS coupled with 64-channel electroencephalograph (EEG) recordings and passive viewing of aversive and neutral images. In addition to sham, patients had either FP or DL prefrontal cortex stimulated at 2 or 4 V while they viewed neutral and aversive pictures. As expected during the sham condition, LPP was larger for aversive compared to neutral stimuli (F(1,4)=232.07, P<.001). Stimulation of DL compared to FP prefrontal cortex resulted in a reduction of the LPP (F(1,4)=8.15, P=.048). These data provide additional and unique support to the role of the DL prefrontal cortex in regulating measures of neural activity that have been linked to emotional arousal and attention. Future studies with EpCS can help directly map out various prefrontal functions in treatment-resistant mood disorder.

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.

Vagus nerve stimulation therapy: a research update.

Over the past 5 years, and especially within the last year, there has been a rapid expansion of vagus nerve stimulation (VNS)-related preclinical research, as well as clinical studies in indications other than epilepsy. The research advances in understanding VNS are occurring in the midst of a blossoming of other forms of therapeutic brain stimulation, such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and deep brain stimulation (DBS). In general, improved understanding of the neurobiological effects of VNS therapy as a function of the different use parameters (frequency, intensity, pulse width, duration, dose) is beginning to guide clinical use and help determine which diseases, in addition to epilepsy, VNS might treat.

Brain effects of TMS delivered over prefrontal cortex in depressed adults: role of stimulation frequency and coil-cortex distance.

Relative regional brain blood flow was measured in 23 clinically depressed adults by using ECD SPECT at baseline and again during actual prefrontal transcranial magnetic stimulation (TMS) following 5 daily sessions of TMS. TMS over prefrontal cortex caused increased activity in cortex directly under the stimulation (inversely correlated with distance from scalp to cortex) and decreased activity in remote regions (anterior cingulate and anterior temporal poles). High-frequency rTMS (20 Hz) caused more relative flow immediately below the TMS coil than did low-frequency rTMS (5 Hz). Confirming the hypotheses tested, repeated daily TMS over the prefrontal cortex in medication-free depressed adults appears to change both local and remote blood flow in a manner that may also depend on the frequency of stimulation and coil to outer cortex distance.

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.

Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome.

This open pilot study of vagus nerve stimulation (VNS) in 60 patients with treatment-resistant major depressive episodes (MDEs) aimed to: 1) define the response rate; 2) determine the profile of side effects; and, most importantly; 3) establish predictors of clinical outcome. Participants were outpatients with nonatypical, nonpsychotic, major depressive or bipolar disorder who had not responded to at least two medication trials from different antidepressant classes in the current MDE. While on stable medication regimens, the patients completed a baseline period followed by device implantation. A 2-week, single blind, recovery period (no stimulation) was followed by 10 weeks of VNS. Of 59 completers (one patient improved during the recovery period), the response rate was 30.5% for the primary HRSD(28) measure, 34.0% for the Montgomery-Asberg Depression Rating Scale (MADRAS), and 37.3% for the Clinical Global Impression-Improvement Score (CGI-I of 1 or 2). The most common side effect was voice alteration or hoarseness, 55.0% (33/60), which was generally mild and related to output current intensity. History of treatment resistance was predictive of VNS outcome. Patients who had never received ECT (lifetime) were 3.9 times more likely to respond. Of the 13 patients who had not responded to more than seven adequate antidepressant trials in the current MDE, none responded, compared to 39.1% of the remaining 46 patients (p =.0057). Thus, VNS appears to be most effective in patients with low to moderate, but not extreme, antidepressant resistance. Evidence concerning VNS' long-term therapeutic benefits and tolerability will be critical in determining its role in treatment-resistant depression.

Transcranial magnetic stimulation (TMS) as a research tool in Tourette syndrome and related disorders.

TMS is a technology with much promise for understanding brain function in health and disease. This chapter has reviewed the physics and safety of this new tool. Much basic work remains to be done in order to understand exactly how TMS affects neurons, and the roles that intensity, frequency, and location have on brain activity. Recent work combining TMS with imaging is showing the method for future advances. In the area of TS, TMS has already had a significant impact; 3 studies have hinted that TS patients have a deficient inhibitory system. Other investigators are exploring whether TMS might be used in a therapeutic manner to alter the behavior of dysfunctional circuits. These areas of applying TMS to understanding and perhaps treating TS show much promise. Nonetheless, a great deal of basic work is likely needed before TMS can be fully used as a research tool or treatment modality for TS.

Feasibility of vagus nerve stimulation-synchronized blood oxygenation level-dependent functional MRI.

RATIONALE AND OBJECTIVES: Left cervical vagus nerve stimulation (VNS) by use of an implanted neurocybernetic prosthesis (NCP) system is effective in treating epilepsy, with open data suggesting effectiveness in depression, yet the mechanisms of action are unknown. Our objective was to develop a methodology for performing VNS-synchronized functional magnetic resonance imaging (VNS-fMRI) and then to demonstrate its feasibility for studying VNS effects. METHODS: In nine patients implanted for treatment of intractable depression, a Macintosh computer was used to detect the signal from the implanted VNS stimulator and then to synchronize fMRI image acquisition with its regular firing. RESULTS: With our VNS-fMRI methodology, the blood oxygenation level-dependent response to VNS was shown in brain regions regulated by the vagus nerve: orbitofrontal and parieto-occipital cortex bilaterally, left temporal cortex, the hypothalamus, and the left amygdala. CONCLUSIONS: Vagus nerve stimulation pulses from an NCP system can be detected externally to determine its firing pattern, thus allowing VNS-fMRI studies of VNS-induced brain activity.

A double-blind placebo-controlled case study of the use of donepezil to improve cognition in a schizoaffective disorder patient: functional MRI correlates.

Cognitive impairment in multiple domains is common in patients with schizophrenia and may be a powerful determinant of poor functional ability and quality of life. We report a double-blind, placebo-controlled, cross-over study of donepezil augmentation in a schizoaffective disorder patient stabilized on olanzapine pharmacotherapy. The patient showed significant improvements in several cognitive measures and increased activation of prefrontal cortex and basal ganglia on functional MRI during the donepezil augmentation. In addition, the donepezil augmentation resulted in a reduction of depressive symptoms and in significant improvements in functional abilities and quality of life. Further studies of donepezil augmentation of neuroleptics in schizophrenia are warranted.

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.

Functional impairment in COPD patients: the impact of anxiety and depression.

The authors examined the relationship between functional status and comorbid anxiety and depression and the relationship between utilization of health care resources and psychopathology in elderly patients with chronic obstructive pulmonary disease (COPD). Elderly male veterans (N = 43) with COPD completed anxiety, depression, and functional status measures. The authors constructed regression models to explore the contribution of COPD severity, medical burden, depression, and anxiety to the dependent variables of functional impairment and health care utilization. Anxiety and depression contributed significantly to the overall variance in functional status of COPD patients, over and above medical burden and COPD severity, as measured by the 8 scales of the Medical Outcomes Study (MOS) 36-item Short Form Health Survey. Surprisingly, medical burden and COPD severity did not contribute significantly to overall variance in functional status. Few patients were receiving any treatment for anxiety or depression.

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.

Structural and functional neuroimaging of electroconvulsive therapy and transcranial magnetic stimulation.

Neuroimaging has long been utilized to provide a measure of the effects of electroconvulsive therapy (ECT) on brain structure and function as well as to better understand its mechanisms of action. In a similar fashion, functional neuroimaging may provide the means to elucidate both the underlying neurobiological effects and therapeutic potential of transcranial magnetic stimulation (TMS). This article will review findings of neuroimaging studies of both TMS and ECT, concentrating on how such studies may help guide treatment.

A controlled trial of daily left prefrontal cortex TMS for treating depression.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a new technology for noninvasively stimulating the brain. Several studies have suggested that daily stimulation of the left prefrontal cortex with TMS for 2 weeks has probable antidepressant effects. We conducted a parallel-design, double-masked, sham-controlled study to address whether 2 weeks of daily TMS over the left prefrontal cortex has antidepressant activity greater than sham. METHODS: Thirty medication-free adult outpatients with nonpsychotic, major depressive (n = 21) or bipolar (n = 9) (depressed phase) disorder who were in a current major depression (Hamilton Rating Scale for Depression [HRSD] 21-item score of >18) were treated each weekday for 2 weeks. Subjects were randomly assigned to receive either daily active (20 subjects) or sham (10 subjects) stimulation. Additionally, the 20 active subjects were equally divided between slower (5 Hz) and faster (20 Hz) frequency treatment. Antidepressant response was defined as greater than a 50% improvement in the baseline HRSD. RESULTS: Active TMS resulted in significantly more responders (9/20) than did sham (0/10) (chi(2) = 6.42, p <.01). The number of responders did not differ significantly between the two active cells (3/10 faster and 6/10 slower). Expressed as a percent change from baseline, active TMS subjects had significantly greater improvement on the Beck Depression Inventory as well as the Hamilton Anxiety Rating Scale than did those who received sham. CONCLUSIONS: Daily left prefrontal TMS for 2 weeks significantly reduced depression symptoms greater than did sham. The two forms of active TMS treatment did not differ significantly.

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).

Single-dose pharmacokinetics of methylphenidate in CYP2D6 extensive and poor metabolizers.

Six adults phenotyped as either extensive (N = 4) or poor (N = 2) metabolizers for cytochrome P450 (CYP) 2D6 were given a 10-mg oral dose of methylphenidate (MPH) on two separate occasions with and without quinidine, a potent CYP2D6 inhibitor. Quinidine had no significant effect on the pharmacokinetics of either MPH or ritalinic acid, its major metabolite, in either group of CYP2D6 metabolizers. These data suggest a lack of involvement of CYP2D6 in the metabolism of MPH. Drugs that are inhibitors of CYP2D6 when taken concurrently with MPH should not affect its plasma concentration.

Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol.

Ethylphenidate was recently reported as a novel drug metabolite in two overdose fatalities where there was evidence of methylphenidate and ethanol coingestion. This study explores the pharmacokinetics of ethylphenidate relative to methylphenidate and the major metabolite ritalinic acid, in six healthy subjects who received methylphenidate and ethanol under controlled conditions. Subjects (three males, three females) received a single oral dose of methylphenidate (20 mg; two 10-mg tablets) followed by consumption of ethanol (0.6 g/kg) 30 min later. Methylphenidate, ritalinic acid, and ethylphenidate were quantified using liquid chromatography-tandem mass spectrometry. Ethylphenidate was detectable in the plasma and urine of all subjects after ethanol ingestion. The mean (+/-S.D.) area under the concentration versus time curve for ethylphenidate was 1.2 +/- 0.7 ng/ml/h, representing 2.3 +/- 1.3% that of methylphenidate (48 +/- 12 ng/ml/h). A significant correlation was observed between the area under the concentration versus time curve of methylphenidate and that of ethylphenidate. In view of the known dopaminergic activity of racemic ethylphenidate, it remains possible that under certain circumstances of higher level dosing, e.g., in the abuse of methylphenidate and ethanol, the metabolite ethylphenidate may contribute to drug effects.