Multimodal imaging measures in the prediction of clinical response to deep brain stimulation for refractory depression: A machine learning approach.

OBJECTIVES: This study compared machine learning models using unimodal imaging measures and combined multi-modal imaging measures for deep brain stimulation (DBS) outcome prediction in treatment resistant depression (TRD). METHODS: Regional brain glucose metabolism (CMRGlu), cerebral blood flow (CBF), and grey matter volume (GMV) were measured at baseline using 18F-fluorodeoxy glucose (18F-FDG) positron emission tomography (PET), arterial spin labelling (ASL) magnetic resonance imaging (MRI), and T1-weighted MRI, respectively, in 19 patients with TRD receiving subcallosal cingulate (SCC)-DBS. Responders (n = 9) were defined by a 50% reduction in HAMD-17 at 6 months from the baseline. Using an atlas-based approach, values of each measure were determined for pre-selected brain regions. OneR feature selection algorithm and the naïve Bayes model was used for classification. Leave-out-one cross validation was used for classifier evaluation. RESULTS: The performance accuracy of the CMRGlu classification model (84%) was greater than CBF (74%) or GMV (74%) models. The classification model using the three image modalities together led to a similar accuracy (84%0 compared to the CMRGlu classification model. CONCLUSIONS: CMRGlu imaging measures may be useful for the development of multivariate prediction models for SCC-DBS studies for TRD. The future of multivariate methods for multimodal imaging may rest on the selection of complementing features and the developing better models.Clinical Trial Registration: ClinicalTrials.gov (#NCT01983904).

Aperiodic subthalamic activity predicts motor severity and stimulation response in Parkinson disease.

INTRODUCTION: Rhythmic beta activity in the subthalamic nucleus (STN) local field potential (LFP) is associated with Parkinson disease (PD) severity, though not all studies have found this relationship. We investigated whether aperiodic 'noise' elements of LFP, specifically slope of the 1/f broadband, predict PD motor symptoms and outcomes of STN-DBS. METHODS: We studied micro-LFP from 19 PD patients undergoing STN-DBS, relating the aperiodic 1/f slope and the periodic beta oscillation components to motor severity using the UPDRS-III and improvement with DBS at 1 year. RESULTS: Beta power, not 1/f slope, independently predicted baseline UPDRS-III (r = 0.425, p = 0.020; r = -0.434, p = 0.032, respectively), but multiple regression using both predicted better (F (2, 16) = 6.621, p = 0.008, R2 = 0.453). Only multiple regression using both slope and beta power predicted improvement in UPDRS-III at 1 year post-operatively (F (2, 15) = 6.049, R2 = 0.446, p = 0.012). CONCLUSIONS: Both beta synchronization and slope of the 1/f broadband are informative of motor symptoms in PD and predict response to STN-DBS.

Personality changes with subcallosal cingulate deep brain stimulation in patients with treatment-resistant depression.

BACKGROUND: Deep brain stimulation (DBS) is a promising investigational approach for treatment-resistant depression. However, reports suggesting changes in personality with DBS for movement disorders have raised clinical and ethical concerns. We prospectively examined changes in personality dimensions and antidepressant response to subcallosal cingulate (SCC)-DBS for treatment-resistant depression. METHODS: Twenty-two patients with treatment-resistant depression underwent SCC-DBS. We used the NEO Five-Factor Inventory for personality assessment at baseline and every 3 months until 15 months post-DBS. We assessed depression severity monthly using the Hamilton Depression Rating Scale. RESULTS: We found a significant decrease in neuroticism (p = 0.002) and an increase in extraversion (p = 0.001) over time, showing a change toward normative data. Improvement on the Hamilton Depression Rating Scale was correlated with decreases in neuroticism at 6 months (p = 0.001) and 12 months (p < 0.001), and with an increase in extraversion at 12 months (p = 0.01). Changes on the Hamilton Depression Rating Scale over time had a significant covariate effect on neuroticism (p < 0.001) and extraversion (p = 0.001). Baseline openness and agreeableness predicted response to DBS at 6 (p = 0.006) and 12 months (p = 0.004), respectively. LIMITATIONS: Limitations included a small sample size, a lack of sham control and the use of subjective personality evaluation. CONCLUSION: We observed positive personality changes following SCC-DBS, with reduced neuroticism and increased extraversion related to clinical improvement in depression, suggesting a state effect. As well, pretreatment levels of openness and agreeableness may have predicted subsequent response to DBS. The NEO Five-Factor Inventory assessment may have a role in clinical decision-making and prognostic evaluation in patients with treatment-resistant depression who undergo SCC-DBS.

Early post-treatment blood oxygenation level-dependent responses to emotion processing associated with clinical response to pharmacological treatment in major depressive disorder.

INTRODUCTION: Pre-treatment blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has been used for the early identification of patients with major depressive disorder (MDD) who later respond or fail to respond to medication. However, BOLD responses early after treatment initiation may offer insight into early neural changes associated with later clinical response. The present study evaluated both pre-treatment and early post-treatment fMRI responses to an emotion processing task, to further our understanding of neural changes associated with a successful response to pharmacological intervention. METHODS: MDD patients who responded (n = 22) and failed to respond (n = 12) after 8 weeks of treatment with either citalopram or quetiapine extended release, and healthy controls (n = 18) underwent two fMRI scans, baseline (pre-treatment), and early post-treatment (one week after treatment commencement). Participants completed an emotional face matching task at both scans. RESULTS: Using threshold-free cluster enhancement (TFCE) and non-parametric permutation testing, fMRI activation maps showed that after one week of treatment, responders demonstrated increased activation in the left parietal lobule, precentral gyrus, and bilateral insula (all P < 0.05 threshold-free cluster enhancement (TFCE) family-wise error-corrected) to negative facial expressions. Non-responders showed some small increases in the precentral gyrus, while controls showed no differences between scans. Compared to non-responders, responders showed some increased activation in the superior parietal lobule and middle temporal gyrus at the post-treatment scan. There were no group differences between responders, non-responders, and controls at baseline. CONCLUSIONS: One week after treatment commencement, BOLD signal changes in the parietal lobules, insula, and middle temporal gyrus were related to clinical response to pharmacological treatment.

Metabolic activity in subcallosal cingulate predicts response to deep brain stimulation for depression.

Subcallosal cingulate (SCC) deep brain stimulation (DBS) is a promising therapy for treatment-resistant depression (TRD), but response rates in open-label studies were not replicated in a large multicenter trial. Identifying biomarkers of response could improve patient selection and outcomes. We examined SCC metabolic activity as both a predictor and marker of SCC DBS treatment response. Brain glucose metabolism (CMRGlu) was measured with [18F] FDG-PET at baseline and 6 months post DBS in 20 TRD patients in a double-blind randomized controlled trial where two stimulation types (long pulse width (LPW) n = 9 and short pulse width (SPW) n = 11) were used. Responders (n = 10) were defined by a ≥48% reduction in Hamilton Depression Rating Scale scores after 6 months. The response rates were similar with five responders in each stimulation group: LPW (55.6%) and SPW (44.5%). First, differences in SCC CMRGlu in responders and non-responders were compared at baseline. Then machine learning analysis was performed with a leave-one-out cross-validation using a Gaussian naive Bayes classifier to test whether baseline CMRGlu in SCC could categorize responders. Finally, we compared 6-month change in metabolic activity with change in depression severity. All analyses were controlled for age. Baseline SCC CMRGlu was significantly higher in responders than non-responders. The machine learning analysis predicted response with 80% accuracy. Furthermore, reduction in SCC CMRGlu 6 months post DBS correlated with symptom improvement (r(17) = 0.509; p = 0.031). This is the first evidence of an image-based treatment selection biomarker that predicts SCC DBS response. Future studies could utilize SCC metabolic activity for prospective patient selection.

Tract-based analysis of target engagement by subcallosal cingulate deep brain stimulation for treatment resistant depression.

BACKGROUND: Deep brain stimulation (DBS) of subcallosal cingulate cortex (SCC) is a promising investigational therapy for treatment-resistant depression (TRD). However, outcomes vary, likely due to suboptimal DBS placement. Ideal placement is proposed to stimulate 4 SCC white matter bundles; however, no quantitative data have linked activation of these target tracts to response. OBJECTIVE: Here we used the volume of tissue activated (VTA) and probabilistic diffusion tensor imaging (DTI) to quantify tract activation relating to response. METHODS: DTI was performed in 19 TRD patients who received SCC-DBS. We defined clinical response as >48% reduction from baseline in the Hamilton Depression Rating Scale. Bilateral VTAs were generated based on subject-specific stimulation parameters. Patient-specific tract maps emanating from the VTAs were calculated using whole-brain probabilistic DTI. The four target tracts were isolated using tract-specific quantification and examined for overlap with DBS activated tissue. RESULTS: Medial frontal and temporal projections were stimulated in all responders at 6 and 12 months. Individual tract-based generalized linear mixed model analysis revealed a significant tract-by-response interaction at both 6 (F(1,135) = 3.828, p = 0.001) and 12 (F(1,135) = 5.688, p < 0.001) months, with post hoc tests revealing a response-related increase in cingulum activation at 6 months (t(135) = 2.418, p = 0.017) and decrease in forceps minor activation at 12 months (t(135) = -2.802, p = 0.006). CONCLUSIONS: A wider profile of white matter tracts, particularly to the medial frontal, was associated with DBS response. Cingulum bundle stimulation may promote early response and excess stimulation of the forceps minor might be detrimental. Our work supports prospective patient-specific targeting to inform personalized DBS.

Rostral anterior cingulate glutamate predicts response to subcallosal deep brain stimulation for resistant depression.

BACKGROUND: Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) provided benefit for treatment-resistant depression (TRD) in open-label studies but failed in a recent randomized sham-controlled trial. Informed patient selection, based on reliable biomarkers, is needed to optimize outcome. We investigated if rostral anterior cingulate (rACC) glutamate/glutamine concentration could serve as a potential biomarker of response. METHODS: Sixteen adults with TRD (Major Depression; MDD = 14; Bipolar Depression; BD =2) underwent proton magnetic resonance spectroscopy using a short-echo proton spectroscopy with a voxel placed in the rACC, prior to DBS. Improvement in depression was assessed using the 17-item Hamilton Rating Scale for Depression (HDRS). Glutamate and glutamine concentrations at baseline in the rACC were examined in relation to clinical outcomes at six months. RESULTS: Lower baseline glutamate predicted significant reduction in HDRS scores in all TRD patients (p = 0.018), and predicted both HDRS reduction (p = 0.002) and 6-month response outcome in MDD-TRD patients (p = 0.013). Neither baseline glutamine nor glutamine/glutamate ratio significantly related to outcome or symptom improvement. LIMITATIONS: Our study was limited by sample size, though it is large for a DBS study. We measured from a single voxel in the brain, so we cannot be certain our findings are specific to the rACC. CONCLUSIONS: These preliminary results suggest that baseline rACC-glutamate concentration could serve as a response-predictive biomarker for SCC-DBS, particularly in patients with resistant major depression. If our findings are replicated and validated, rACC-glutamate may provide a basis to prospectively select TRD patients to improve likelihood of response to SCC-DBS.

Long versus short pulse width subcallosal cingulate stimulation for treatment-resistant depression: a randomised, double-blind, crossover trial.

BACKGROUND: Stimulation adjustment is required to optimise outcomes of deep brain stimulation (DBS) for treatment-resistant depression, but controlled data for ideal stimulation parameters are poor or insufficient. We aimed to establish the efficacy and safety of short pulse width (SPW) and long pulse width (LPW) subcallosal cingulate DBS in depression. METHODS: We did a double-blind, randomised, crossover trial in an academic hospital in Calgary, AB, Canada. Patients had DSM IV-defined major depressive disorder and bipolar depression (20-70 years old, both sexes) and did not respond to treatment for more than 1 year, with a score of 20 or more on the 17-item Hamilton Depression Rating Scale (HDRS) at recruitment. Patients underwent bilateral DBS implantation into the subcallosal cingulate white matter using diffusion tensor imaging tractography. Patients were randomly assigned 1:1 without stratification using a computerised list generator to receive either SPW (90 µs) or LPW (210-450 µs) stimulation for 6 months. Patients and the clinician assessing outcomes were masked to the stimulation group. Keeping frequency constant (130 Hz), either pulse width or voltage was increased monthly, based on response using the HDRS. Patients who did not respond to treatment (<50% reduction in HDRS from baseline) at 6 months crossed over to the opposite stimulation for another 6 months. All patients received individualised cognitive behavioural therapy (CBT) for 12 weeks. The primary outcome was change in HDRS at 6 months and 12 months using intention-to-treat analysis. This study is registered with ClinicalTrials.gov, NCT01983904. FINDINGS: Between Dec 5, 2013, and Sept 30, 2016, of 225 patients screened for eligibility, 23 patients were selected for DBS surgery. After one patient withdrew, 22 (mean age 46·4 years, SEM 3·1; 10 [45%] female, 12 [55%] male) were randomly assigned, ten (45%) to LPW stimulation and 12 (55%) to SPW stimulation. Patients were followed up at 6 months and 12 months. There was a significant reduction in HDRS scores (p<0·0001) with no difference between SPW and LPW groups (p=0·54) in the randomisation phase at 6 months. Crossover groups did not show a significant decrease in HDRS within groups (p=0·15) and between groups (p=0·21) from 6-12 months. Adverse events were equal between groups. Worsening anxiety and depression were the most common psychological adverse events. One patient in the SPW group died by suicide. INTERPRETATION: Both LPW and SPW stimulation of subcallosal cingulate white matter tracts carried similar risks and were equally effective in reducing depressive symptoms, suggesting a role for both pulse width and amplitude titration in optimising clinical outcomes in patients with treatment-resistant depression. FUNDING: Alberta Innovates Health Solutions.

Intrinsic thalamocortical connectivity varies in the age of onset subtypes in major depressive disorder.

BACKGROUND: Differences in the thalamocortical system have been shown in patients with major depressive disorder (MDD). Given prior evidence of phenotypic heterogeneity by the age of onset in MDD, we examined whether differences in thalamocortical connectivity could identify biological subtypes of MDD defined by the age of illness onset. METHODS: A total of 94 subjects including 20 early-onset (EO) MDD (onset, 18 years), 34 adult-onset (AO) MDD, and 40 healthy controls (HCs) underwent resting-state functional MRI. Blood-oxygen-level-dependent time courses were extracted from six cortical regions of interest (ROIs) consisting of frontal, temporal, parietal, and occipital lobes and precentral and postcentral gyri. Each ROI's time course was then correlated with each voxel in thalamus, while covarying out signal from every other ROI. RESULTS: The analysis of variance results showed significant main effects of group in frontal and temporal connectivity with thalamus. Group contrasts showed a right fronto-thalamic hypo-connectivity only in AO-MDD, but not in EO-MDD, when compared to HCs. However, direct comparison between EO-MDD and AO-MDD showed no differences. Furthermore, there was a right temporal-thalamic hyperconnectivity in both EO-MDD and AO-MDD patients relative to HCs. These results were not accounted for by sex, age, or illness burden. CONCLUSION: The age of illness onset may be a source of heterogeneity in fronto-thalamic intrinsic connectivity in MDD.

The impact of age of onset on amygdala intrinsic connectivity in major depression.

BACKGROUND: Early-onset major depressive disorder (EO-MDD), beginning during childhood and adolescence, is associated with more illness burden and a worse prognosis than adult-onset MDD (AO-MDD), but little is known about the neural features distinguishing these subgroup phenotypes. Functional abnormalities of the amygdala are central to major depressive disorder (MDD) neurobiology; therefore, we examined whether amygdala intrinsic connectivity (IC) can differentiate EO-MDD from AO-MDD in a cohort of adult MDD patients. SUBJECTS AND METHODS: Twenty-one EO-MDD (age of onset ≤18 years), 31 AO-MDD patients (age of onset ≥19 years), and 19 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (7 minutes). Amygdala seed-based resting-state functional connectivity was compared between groups. RESULTS: AO-MDD patients showed loss of inverse left amygdala-left dorsolateral prefrontal cortex IC and increased inverse left amygdala-left inferior parietal IC, compared to both HCs and EO-MDD. EO-MDD showed a switch from inverse to positive IC with right dorsomedial prefrontal cortex, compared to HCs and AO-MDD. This effect was removed when we controlled for illness burden. CONCLUSION: Alterations in amygdala IC with the default-mode network were specifically related to EO-MDD, whereas amygdala IC with executive cognitive control regions was preferentially disrupted in AO-MDD. Increased illness burden, an important clinical marker of EO-MDD, accounted for its specific effects on amygdala IC. Brain imaging has the potential for validation of clinical subtypes and can provide markers of prognostic value in MDD patients.

Thalamocortical connectivity in major depressive disorder.

BACKGROUND: Major Depressive Disorder (MDD) is highly prevalent and potentially devastating, with widespread aberrations in brain activity. Thalamocortical networks are a potential candidate marker for psychopathology in MDD, but have not yet been thoroughly investigated. Here we examined functional connectivity between major cortical areas and thalamus. METHOD: Resting-state fMRI from 54 MDD patients and 40 healthy controls were collected. The cortex was segmented into six regions of interest (ROIs) consisting of frontal, temporal, parietal, and occipital lobes and pre-central and post-central gyri. BOLD signal time courses were extracted from each ROI and correlated with voxels in thalamus, while removing signals from every other ROI. RESULTS: Our main findings showed that MDD patients had predominantly increased connectivity between medial thalamus and temporal areas, and between medial thalamus and somatosensory areas. Furthermore, a positive correlation was found between thalamo-temporal connectivity and severity of symptoms. LIMITATIONS: Most of the patients in this study were not medication naïve and therefore we cannot rule out possible long-term effects of antidepressant use on the findings. CONCLUSION: The abnormal connectivity between thalamus and temporal, and thalamus and somatosensory regions may represent impaired cortico-thalamo-cortical modulation underlying emotional, and sensory disturbances in MDD. In the context of similar abnormalities in thalamocortical systems across major psychiatric disorders, thalamocortical dysconnectivity could be a reliable transdiagnostic marker.

Prolonged hypothermia in rat: a safety study using brain-selective and systemic treatments.

Hypothermia is an effective neuroprotectant for cardiac arrest and perinatal ischemic injury. Hypothermia also improves outcome after traumatic brain injury and stroke. Although the ideal treatment parameters (duration, delay, and depth) are not fully delineated, prolonged cooling is usually more effective than shorter periods. There is the concern that extended cooling may be hazardous to brain plasticity and cause damage. In order to evaluate this possibility, we assessed the effects of 3 days of systemic hypothermia (32°C) in rats subjected to a sham stroke surgery. There were no detrimental behavioral effects or signs of brain damage. As even longer cooling may be needed in some patients, we cooled (∼32°C) the right hemisphere of rats for 3 or 21 days. Physiological variables, functional outcome, and measures of cell injury were examined. Focal brain cooling for 21 days modestly decreased heart rate, blood pressure, and core temperature. However, focal hypothermia did not affect subsequent behavior (e.g., spontaneous limb usage), cell morphology (e.g., dendritic arborization, ultrastructure), or cause cell death. In conclusion, prolonged mild hypothermia did not harm the brain of normal animals. Further research is now needed to evaluate whether such treatments affect plasticity after brain injury.

Treatments (12 and 48 h) with systemic and brain-selective hypothermia techniques after permanent focal cerebral ischemia in rat.

Mild hypothermia lessens brain injury when initiated after the onset of global or focal ischemia. The present study sought to determine whether cooling to approximately 33 degrees C provides enduring benefit when initiated 1 h after permanent middle cerebral artery occlusion (pMCAO, via electrocautery) in adult rats and whether protection depends upon treatment duration and cooling technique. In the first experiment, systemic cooling was induced in non-anesthetized rats through a whole-body exposure technique that used fans and water mist. In comparison to normothermic controls, 12- and 48-h bouts of hypothermia significantly lessened functional impairment, such as skilled reaching ability, and lesion volume out to a 1-month survival. In the second experiment, brain-selective cooling was induced in awake rats via a water-cooled metal strip implanted underneath the temporalis muscle overlying the ischemic territory. Use of a 48-h cooling treatment significantly mitigated injury and behavioral impairment whereas a 12-h treatment did not. These findings show that while systemic and focal techniques are effective when initiated after the onset of pMCAO, they differ in efficacy depending upon the treatment duration. A direct and uncomplicated comparison between methods is problematic, however, due to unknown gradients in brain temperature and the use of two separate experiments. In summary, prolonged cooling, even when delayed after onset of pMCAO, provides enduring behavioral and histological protection sufficient to suggest that it will be clinically effective. Nonetheless, further pre-clinical work is needed to improve treatment protocols, such as identifying the optimal depth of cooling, and how these factors interact with cooling method.

Use of prolonged hypothermia to treat ischemic and hemorrhagic stroke.

Therapeutic (induced) hypothermia (TH) has been extensively studied as a means to reduce brain injury following global and focal cerebral ischemia, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). Here, we briefly review the clinical and experimental evidence supporting the use of TH in each condition. We emphasize the importance of systematically evaluating treatment parameters, especially the duration of cooling, in each condition. We contend that TH provides considerable protection after global and focal cerebral ischemia, especially when cooling is prolonged (e.g., >24 h). However, there is presently insufficient evidence to support the clinical use of TH for ICH and SAH. In any case, further animal work is needed to develop optimized protocols for treating cardiac arrest (global ischemia), and to maximize the likelihood of successful clinical translation in focal cerebral ischemia.

Comparison of 12, 24 and 48 h of systemic hypothermia on outcome after permanent focal ischemia in rat.

Mild hypothermia reduces injury in models of global and focal cerebral ischemia even when initiated after the insult. Neuroprotection depends critically upon the duration of hypothermia with longer treatments often being more efficacious. However, the ideal treatment duration is not known for most insults and this knowledge would facilitate clinical studies. Thus, we compared 12, 24 and 48 h of systemic hypothermia (33 degrees C vs. normothermia) initiated 1 h after permanent middle cerebral artery occlusion (pMCAO), which was produced by permanent occlusion of the carotid arteries and cauterization of the distal MCA in rat. Behavioral recovery and lesion volume were determined 7 days after pMCAO. All three treatments significantly and equally attenuated neurological deficits (e.g., forelimb placing response). Conversely, stepping error rate in the horizontal ladder test was significantly reduced only by the 24-h (18.7%) and 48-h treatments (11.7%) compared to normothermic rats (34.4%), and the 48-h treatment was significantly better than the 12-h treatment (28.8%). Similarly, brain injury was significantly reduced by 24-h (78.8 mm(3) lesion volume) and 48-h (66.8 mm(3)) treatments compared to normothermia (142.6 mm(3)), and the 48-h treatment was significantly better than the 12-h duration (114.6 mm(3)). In separate experiments cerebral edema was measured via wet-dry weight measurements and significantly reduced by hypothermia (e.g., from 83.7% water in the injured cortex of normothermic rats to 81.4% in rats cooled for one day), but for this there were no significant duration effects. In summary, prolonged hypothermia treatment provides superior protection overall, but this is not explained by reductions in edema.

Spontaneous temperature changes in the 2-vessel occlusion model of cerebral ischemia in rats.

Transient global ischemia (ISC) in rats and humans causes selective and delayed neuronal death in the hippocampal CA1 sector. It is clear from rodent studies that hyperthermia aggravates, whereas hypothermia lessens, this injury. In this study we sought to relate core (Tc) and brain (Tb) temperature, measured via telemetry probes, after ISC produced in rats by bilateral common carotid artery occlusion combined with systemic hypotension (2-VO model). We also tested whether spontaneous postischemic temperature fluctuations occurred and whether they were related to cell death as previous studies indicate. We report that Tc and Tb readings are similar and are highly correlated before and after 10 min of 2-VO ISC. In the second experiment, rats were subjected to 8, 9, or 10 min of 2-VO ISC. Despite a range in CA1 injury among these animals, there was no evidence of post-ISC hyperthermia, contrary to earlier work, and neither temperature nor the physiological variables measured during ISC (e.g., glucose) predicted injury. Our findings suggest that, under the present conditions, 2-VO rats do not experience postoperative hyperthermia, which can be adequately measured with Tc telemetry probes.

The effects of selective brain hypothermia on intracerebral hemorrhage in rats.

Prolonged hypothermia effectively treats global cerebral ischemic injury in animal models as well as in cardiac arrest victims. Furthermore, clinical trials, based upon encouraging animal findings, are underway to assess efficacy in ischemic stroke. Intracerebral hemorrhage (ICH) is a more devastating stroke, but one that shares mechanisms of injury with ischemia. Accordingly, ICH may be amenable to hypothermia treatment. In this study we tested whether selective brain hypothermia improves outcome after an ICH in rats created by infusing 100 microL of autologous whole blood into the striatum. Striatal hypothermia ( approximately 32 degrees C) was induced with a novel method (implanted cooling coil) that does not cause systemic cooling, thereby providing a safer and potentially more effective treatment for stroke than systemic hypothermia. Edema occurred for 4 days after ICH, but it peaked at 3 days ( approximately 5%). At this time it was significantly reduced (to approximately 2%) by cooling starting 1 h after ICH (3 day duration). Next, we determined whether 1 and 12 h delayed cooling treatments (4 day duration) would lessen functional impairment and lesion size. Untreated (normothermic) ICH resulted in significant forelimb use asymmetry, as well as deficits in walking and skilled reaching. These deficits were unaffected by hypothermia, as was the volume of tissue lost ( approximately 20 mm(3)) at 1 month. Thus, attenuated edema did not result in behavioral or histological benefit. In conclusion, while additional research with alternative cooling protocols and ICH models are required, these findings suggest that while hypothermia lessens edema, it will not be directly neuroprotective after ICH.

A simple method to induce focal brain hypothermia in rats.

Hypothermia reduces cell death and promotes recovery in models of cerebral ischemia, intracerebral hemorrhage and trauma. Clinical studies report significant benefit for treating cardiac arrest and studies are investigating hypothermia for stroke and related conditions. Both local (head) and generalized hypothermia have been used. However, selective brain cooling has fewer side effects than systemic cooling. In this study, we developed a method to induce local (hemispheric) brain hypothermia in rats. The method involves using a small metal coil implanted between the Temporalis muscle and adjacent skull. This coil is then cooled by flushing it with cold water. In our first experiment, we tested whether this method induces focal brain hypothermia in anesthetized rats. Brain temperature was assessed in the ipsilateral cortex and striatum, and contralateral striatum, while body temperature was kept normothermic. Focal, ipsilateral cooling was successfully produced, while the other locations remained normothermic. In the second experiment, we implanted the coil, and brain and body temperature telemetry probes. The coil was connected via overhead swivel to a cold-water source. Brain hypothermia was produced for 24 h, while body temperature remained normothermic. A third experiment measured brain and body temperature along with heart rate and blood pressure. Brain cooling was produced for 24 h without significant alterations in pressure, heart rate or body temperature. In summary, our simple method allows for focal brain hypothermia to be safely induced in anesthetized or conscious rats, and is, therefore, ideally suited to stroke and trauma studies.

Incomplete assessment of experimental cytoprotectants in rodent ischemia studies.

BACKGROUND: Inadequate preclinical testing (e.g., rodent studies) has been partly blamed for the failure of many cytoprotectants to effectively treat stroke in humans. For example, some drugs went to clinical trial without rigorous functional and histological assessment over long survival times. In this study, we characterized recent experimental practices in rodent cytoprotection experiments to determine whether the limitations of early studies have been rectified. METHODS: We identified 138 rodent cytoprotection studies published in several leading journals (Journal of Neuroscience, Stroke, Journal of Cerebral Blood Flow and Metabolism and Experimental Neurology) for 2000-2002 and compared these to those published in 1990. From each study we determined the ischemia model, age and sex of the animal, the histological and functional endpoints used, and the methodology used to assess intra- and postischemic temperature. RESULTS: Ninety-eight percent of recent studies used young adult rodents and most used males. Most studies (60%) did not assess functional outcome and survival times were often < or = 48 hr (66%) for focal ischemia and < or = 7 days (80%) for global ischemia. Over 60% of the experiments relied solely upon rectal temperature during ischemia and only 32.6% of ischemia studies measured temperature after surgery. The 1990 data were similar. CONCLUSIONS: Many investigators ignore the need to assess long-term functional and histological outcome and do not accurately represent clinical conditions of ischemia (e.g., use of aged animals). In addition, intra- and postischemic temperature measurement and control is frequently neglected or inadequately performed. Further clinical failures are likely.